SEARCH

SEARCH BY CITATION

Keywords:

  • hepatectomy;
  • microsurgery;
  • rat;
  • segmentectomy;
  • technique

Abstract

  1. Top of page
  2. Abstract
  3. Rat and mouse liver anatomy
  4. Models of liver resection
  5. Liver regeneration model
  6. Models for assessment of hepatic metastasis
  7. Models of acute liver failure
  8. Techniques of liver resection
  9. Liver resections using microsurgical techniques
  10. Non-conventional anatomical resections
  11. Limitations of rodent models of hepatic resections
  12. Conclusions
  13. Acknowledgements
  14. References

Small rodents are the most used experimental models in liver surgical research. Hepatic resections in rodents are commonly performed to study liver regeneration, acute liver failure, hepatic metastasis, hepatic function, ‘small-for-size’ transplantation and metabolic response to injury. Most resections require only basic skills, are fast, reliable and highly reproducible. The partial hepatectomy technique in rodents can be improved by microsurgical techniques, which permit individualized dissection and ligature of the vascular and biliary branches with minimal operative morbidity and mortality. This is particularly relevant for murine models of liver resection. However, it requires advanced microsurgical skills. Here, we review the models, surgical techniques, results and limitations of partial liver resections in rodent models. We also reported for the first time segmentectomies of the median lobe in rodent models.

Rats and mice are the most commonly used experimental models in liver surgical research. Hepatic resections in rodents are performed to study liver regeneration, acute liver failure, tumour dormancy of hepatic metastasis, hepatic function and response to stress and trauma (1–12). Because each lobe has its own pedicle containing a portal triad, hepatic resections of various extents in rodents are simple and highly reproducible. Hepatectomies in both the rat and mouse require basic surgical skills and have been performed with high success rates (1, 2, 11, 13–17). In this review, we outline various models, different techniques and limitations of hepatic resections.

Rat and mouse liver anatomy

  1. Top of page
  2. Abstract
  3. Rat and mouse liver anatomy
  4. Models of liver resection
  5. Liver regeneration model
  6. Models for assessment of hepatic metastasis
  7. Models of acute liver failure
  8. Techniques of liver resection
  9. Liver resections using microsurgical techniques
  10. Non-conventional anatomical resections
  11. Limitations of rodent models of hepatic resections
  12. Conclusions
  13. Acknowledgements
  14. References

The rat liver is divided into four main lobes: caudate lobe (CL), right liver lobe (RLL), median lobe (ML) and the left lateral lobe (LLL).

The CL is divided into three parts: caudate process, anterior (AC) and posterior caudate lobes (PC). The RLL is divided in superior right lobe (SRL) and inferior right lobe (IRL) (15–17) (see Fig. 1). The ML is divided into two parts: the right median lobe (RML) and the left median lobe (LML). This study from Kongure and colleagues utilized liver corrosion casts to characterize rat liver lobes and compared them with the human liver segmentation defined by Couinaud. According to their study, the rat CL, LLL, LML, RML, IRL and SRL represent in humans segments: (I and IX); II; (III and IV); (V and VIII); VI; and VII respectively (18). Although the anatomy of the mouse liver has not been described in as much detail as the rat liver, its lobular anatomy is very similar to the rat liver (19, 20). One particularity of the mouse liver is that it has a gall bladder, while in the rat it is absent. In both species the inferior vena cava is intrahepatic.

image

Figure 1.  A–D. Most common surgical anatomy of the rat liver with main vascular and biliary elements (visceral view of the liver). (A) Approximate percentages of total liver weight for each lobe. (B) Hepatic veins distribution. (C) Portal vein ramification. The hepatic artery branches follow in close proximity the portal vein branches. (D) Biliary system. CP, caudate process; AC, anterior caudate lobe; PC, posterior caudate lobe; SRL, superior right lateral lobe; IRL, inferior right lateral lobe; ML, median lobe; RML, right portion of the medial lobe; LML, left portion of the medial lobe; LLL, left lateral lobe; MF, main or median fissure (umbilical fissure); LF, left fissure; RF, right fissure; FL, falciform ligament. The liver anatomy of the mouse is similar to the rat; however, the gall bladder is absent.

Download figure to PowerPoint

Models of liver resection

  1. Top of page
  2. Abstract
  3. Rat and mouse liver anatomy
  4. Models of liver resection
  5. Liver regeneration model
  6. Models for assessment of hepatic metastasis
  7. Models of acute liver failure
  8. Techniques of liver resection
  9. Liver resections using microsurgical techniques
  10. Non-conventional anatomical resections
  11. Limitations of rodent models of hepatic resections
  12. Conclusions
  13. Acknowledgements
  14. References

The classic rat model of partial hepatectomy in rats is based on the seminal experiments by Higgins and Anderson (1) from 1931. These investigations demonstrated that resection of the two anterior lobes (ML and LLL) is easy to perform and creates a highly standardized liver reduction of approximately 70%. The classical 70% hepatectomy model in rats is the most popular because it has been extensively studied and can be accomplished in an expedited fashion with a single ligature of the common pedicle (1, 13). It is also commonly used in auxiliary liver transplantation models (21).

In other models, 90, 95 and 97% liver tissue resections are used to study liver regeneration and acute liver failure (15, 22, 23). In the 90% hepatectomy the right lobes, ML and the LLL are resected. In the 95% hepatectomy model, the AC is also removed, while in the 97% hepatectomy the AC and PC are removed, and only the paracaval portion remains. Other extents of resection can also be performed, but with more technical difficulty and higher complication rates (Fig. 2).

image

Figure 2.  Schematic description of partial hepatectomies in the rat (anterior view of the liver) and approximate parenchymal volumes. These values slightly change in the mouse (refer to the text). Hepatectomies ranging from 5 to 95% of total liver weight can be easily performed with high reproducibility using microsurgical techniques because the parenchymal mass of which lobe is relatively constant. Approximately, the percentages of liver weight per lobe are SRL 12%, IRL 10%, ML 38% (RML 25% and LML 13%), LLL 30%, AC 4%, PC 4%, CP 2–3%. In the classic 70% hepatectomy, the left lateral (LL) and the medial (ML) lobes are removed. Isolated resections of the MLL or LLL should preferentially not be performed because cholestatic and vascular complications are more common. SRL, superior right lobe; IRL, inferior right lobe; ML, median lobe; RML, right median lobe; LML, left median lobe; LLL, left lateral lobe; AC, anterior caudate lobe; PC, posterior caudate lobe; CP, caudate process.

Download figure to PowerPoint

In the mouse the relative volume of the lobes slightly differs from the rat. The right superior lobe represents 16.6±1.4%, the right inferior 14.7±1.4%, the ML 26.2±1.9% and the LLL represents 34.4±1.9% (24), while in the rat it represents approximately 22, 10, 38 and 30% respectively (15–17). On the other hand, in humans, the average volume ratios of the left lateral segments (II and III), left medial segment (IV), CL (I and IX), right anterior segments (V and VIII) and right posterior segments (VI and VII) are 17, 14, 2, 37 and 30% respectively (25).

Commonly performed partial hepatectomies in mice remove 60% (ML+LL), 75% (ML+LL+IRL) and 83% (ML+LL+IRL+CL) (24, 26) of the liver parenchyma. Twenty-one days after resection of the ML and LL in the mouse, the remaining lobes IRL, SRL, AC and PC represent 55, 26, 9 and 10% respectively (27).

Liver regeneration model

  1. Top of page
  2. Abstract
  3. Rat and mouse liver anatomy
  4. Models of liver resection
  5. Liver regeneration model
  6. Models for assessment of hepatic metastasis
  7. Models of acute liver failure
  8. Techniques of liver resection
  9. Liver resections using microsurgical techniques
  10. Non-conventional anatomical resections
  11. Limitations of rodent models of hepatic resections
  12. Conclusions
  13. Acknowledgements
  14. References

The process of hepatic regeneration in rodents and humans is similar, and the results obtained from rodents are applicable to the human liver (28). The rat 70% hepatectomy is the most valuable and most extensively studied animal model for liver regeneration (1, 2,13).

The hepatic regeneration process is triggered promptly after injury, and in the rat, the DNA replication begins as early as 16 h after resection. After a 70% hepatectomy in the rat, the weight of the liver remnant at 24 and 72 h is 45 and 70% of the original liver weight respectively. Between 7 and 14 days, the liver volume is 93%, and by day 20 it completely recovers its original volume by hyperplasia of the remaining lobes (1). Also in humans, the regeneration process occurs quickly. The liver mass doubled at 7 days in the donor liver and 14 days in the recipient after right-lobe transplantation. Donor and recipient livers reached their original weight by 60 days after surgery (29). However, despite recovery of parenchymal weight the regeneration and remodelling processes continue.

The speed of liver regeneration is proportional to the amount of hepatic tissue resected. Interestingly, it has also been shown that the regenerative capacity of individual remnant lobes is significantly different (26). In addition, too large (>85%) or too small (<30%) resections may result in slow cell proliferation (28).

Models for assessment of hepatic metastasis

  1. Top of page
  2. Abstract
  3. Rat and mouse liver anatomy
  4. Models of liver resection
  5. Liver regeneration model
  6. Models for assessment of hepatic metastasis
  7. Models of acute liver failure
  8. Techniques of liver resection
  9. Liver resections using microsurgical techniques
  10. Non-conventional anatomical resections
  11. Limitations of rodent models of hepatic resections
  12. Conclusions
  13. Acknowledgements
  14. References

Models of hepatectomy have been used in studies of liver metastasis after direct hepatic inoculation, or after intraportal or intrasplenic injection of tumour cells. The induction of tumour by carcinogens in the rat with spontaneous liver metastases closely mimics the natural history of colon cancer. However, only a low yield of primary cancer, e.g. colonic cancer (in<50% of cases) and liver metastases (approximately 25%), is obtained after 6 months of latency. Direct intraportal injection of colon carcinoma cells is the most-used model. Although it bypasses the natural evolution of colon cancer, this simple model produces liver metastases 6 weeks after injection of tumour cells in up to 100% of cases. This model has been used to study tumour biology, tumour-induced angiogenesis, surgical and adjuvant therapy for liver metastasis, as well as the influence of hepatic regeneration on the reactivation of dormant metastases and tumour growth (30).

In this model, 8 weeks after injection of colon carcinoma cells (DHD K12 cells) into the portal vein of BD IX rats, 60% of animals did not show apparent liver metastases. However, after a 70% hepatectomy, 12 weeks after the injection of colon carcinoma cells, 62% of these animals developed macroscopic metastases compared with 20% in sham-operated controls. This means that liver micrometastases may have been present at 8 weeks and had not developed until stimulation by liver regeneration after hepatectomy (30, 31).

In cases of random spread of hepatic metastases, tumourectomy alone, non-anatomical resections (wedge resection) and segmentectomies may be used.

Models of acute liver failure

  1. Top of page
  2. Abstract
  3. Rat and mouse liver anatomy
  4. Models of liver resection
  5. Liver regeneration model
  6. Models for assessment of hepatic metastasis
  7. Models of acute liver failure
  8. Techniques of liver resection
  9. Liver resections using microsurgical techniques
  10. Non-conventional anatomical resections
  11. Limitations of rodent models of hepatic resections
  12. Conclusions
  13. Acknowledgements
  14. References

Models of acute liver failure are important to investigate the underlying molecular mechanisms and to test liver-support strategies. These models are divided into toxic-induced, surgically induced (partial hepatectomy, clamping) or mixed. Toxic injury can be induced by: paracetamol, carbon tetrachloride, LPs, thioacetamide, concanavilin A, D-galactosamine. Surgical models of acute liver failure are divided into total hepatectomy, partial hepatectomies, and partial or total liver devascularization (32).

Small-for-size syndrome

Models of hepatic resection and partial liver transplantation have also been used to study small-for-size syndrome. One study showed that immediately after classical 70% hepatectomy the hepatic arterial blood flow decreased (from 0.4±0.12 to 0.33±0.03 ml/min/g liver), the portal venous inflow increased (from 0.90±0.30 to 2.20±0.26 ml/min/g liver), the total hepatic blood flow increased (from 1.30±0.39 to 2.53±0.26 ml/min/g liver) and the portal pressure elevated (from 8.80±0.7 to 11.9±1.7 cm H2O) (4).

Portal hyperperfusion in small-for-size livers, in case of major hepatic resections or transplantation, might seriously impair post-operative liver regeneration. The altered physiological state results in increased portal blood flow, which induces shear stress and damage to sinusoidal endothelial cells and Kupfer cell activation, which contributes to acute liver failure (33). In these models, a major hepatic resection (e.g. 90%) or a total hepatectomy followed by small-for-size graft (25–30% of original volume) liver transplantation are performed (33–36). When transplantation is used as a model, a classical 70% hepatectomy is performed in the donor animal before harvesting the organ.

Following a 70% resection, nearly 100% of rats survive (23). Larger resections result in hyperperfusion of the remnant liver and ischaemia/reperfusion injury (small-for-size syndrome) with consequent massive fatty change, congestion and centrilobular necrosis (35). Panis et al. (35) showed increased necrosis following progressive increase in the hepatectomy extent. Following a 75, >85 and >90% hepatectomy, survival rates were 100, 18 and 0% respectively. The increased mortality associated with large resections can be reduced by administration of glucose solution (22, 37). The survival rate of 90% hepatectomy could be increased from 5 to 60% by addition of glucose 20% in drinking water (22, 23). Roger et al. (37) introduced the 95% hepatectomy with a survival rate of only 20%, even with the addition of glucose. Madrahinov reported a 1-week survival rate of 100 and 66% following a 90 and 95% respectively. However, in this study, all animals died of liver failure within 4 days after a 97% hepatectomy (15).

Eguchi et al. (38) described a model of resection–ligation. In this model, the LLLs and MLs (68%) were resected, and the ligated RLLs (24%) were left in place, while the caudal lobes (8%) were left intact. They reported a 90% mortality rate at 48 h after surgery, proceeded by grade III encephalopathy beginning at 22–24 h, and associated with deterioration of liver function tests, and increased ammonia and lactate levels.

In the mouse, Inderbitzin and colleagues showed that liver regeneration was excellent up to 75% partial hepatectomy. On the other hand, 83% resection resulted in animal death after 2–4 days (26). However, in this experiment only one subcutaneous dose (1 ml) of glucose 1% was given post-operatively. Another study showed that all of the 70% hepatectomized mice were alive at 1 week, but the 90% hepatectomized mice all died within 24 h after hepatectomy despite free access to glucose 10% (39).

Techniques of liver resection

  1. Top of page
  2. Abstract
  3. Rat and mouse liver anatomy
  4. Models of liver resection
  5. Liver regeneration model
  6. Models for assessment of hepatic metastasis
  7. Models of acute liver failure
  8. Techniques of liver resection
  9. Liver resections using microsurgical techniques
  10. Non-conventional anatomical resections
  11. Limitations of rodent models of hepatic resections
  12. Conclusions
  13. Acknowledgements
  14. References

Liver resections in rodents are very well tolerated with minimal operative mortality. So far, four techniques for hepatic resection in rodents have been described:

1. The classical technique (Ligature en-bloc at the base of the lobe). Although this is the most commonly used technique, it carries the highest risk for injuries because the mass ligature may compromise elements of other pedicles. The risk of vena cava stenosis and liver congestion is particularly high when only one ligature for both the median and LLLs' pedicles is performed, owing to compression of the vein after mass ligation. This procedure can be performed through conventional (open) (1, 40), or the laparoscopic technique (41). However, the laparoscopic approach does not seem to provide any advantage over other techniques. It is time-consuming and requires specialized and costly equipment.

2. The haemostatic clip technique. This is a slight modification of the classical technique, where titanium clips are applied to the pedicle instead of using sutures. This procedure is fast, but is associated with similar complications of the mass ligature technique. In addition, concerns with interference on the regeneration process have been raised, although this has not been confirmed in subsequent investigations (42, 27).

3. The vessel-oriented parenchyma-preserving technique. This technique reported by Madrahimov requires no prior ligation at the liver hilum (15). Sequential piercing sutures, proximal to the clamp, are positioned according to topographical vascular anatomy. Although this technique is faster than the microsurgical technique, described below, it may cause injury of other vascular branches because vessels are not individually visualized. Hence, it is not recommended for resection of the right or left segments of the ML.

4. The vessel-oriented microsurgical technique. This technique, first reported by Kubota et al. (43), is similar to the technique for clinical hepatectomies. The portal vein and hepatic artery branches are ligated before the resection of the lobe, and the hepatic veins are ligated within the lobe during parenchyma resection (in a similar fashion of the parenchyma-preserving technique). The advantages of this technique are reduced risk of bleeding from the stump and reduced risk of vena cava constriction. It is also more appropriate for segmental hepatectomies, e.g. resection of the right or left portion of the ML, after delineation of the ischaemic line following the ligature. The disadvantages are requirement of microsurgical skills and equipment, risk of portal vein injury during dissection and its more time-consuming nature (43).

Liver resections using microsurgical techniques

  1. Top of page
  2. Abstract
  3. Rat and mouse liver anatomy
  4. Models of liver resection
  5. Liver regeneration model
  6. Models for assessment of hepatic metastasis
  7. Models of acute liver failure
  8. Techniques of liver resection
  9. Liver resections using microsurgical techniques
  10. Non-conventional anatomical resections
  11. Limitations of rodent models of hepatic resections
  12. Conclusions
  13. Acknowledgements
  14. References

Hepatic resection may be improved by microsurgical techniques because they permit individualized dissection and ligature of small vascular and biliary branches of the middle and left lateral liver lobes, while avoiding damage to the remaining lobes and other complications (tear of extrahepatic biliary tree and biliary fistula, vena cava stenosis). This contributes to reducing complications and make results more homogenous.

To our knowledge, the first description of the use of microsurgery to perform hepatectomy in rodents was from Holmin in 1982. However, he used a microscope (10 × magnification) not to perform the parenchymal dissection and resection but to perform a portocaval shunt before a total hepatectomy in a rat model of acute liver failure (44). In fact, Kubota in 1997 and Rodriguez in 1999 were the first to report the use of a microscope to perform vascular isolation of individual pedicles for partial hepatectomies in the rat (13, 43). While in a study from Higgins, utilizing the classical technique without optical magnification, the postoperative mortality rate following a 70% hepatectomy was 25% (n=220), Rodriguez reported no morbidity and 0% mortality (n=20) utilizing the microscopic approach (1, 13). Another study published by Greene and Puder (45) obtained 96% survival rate after 70% hepatectomy in the mouse model using magnifying operative loupes.

Non-conventional anatomical resections

  1. Top of page
  2. Abstract
  3. Rat and mouse liver anatomy
  4. Models of liver resection
  5. Liver regeneration model
  6. Models for assessment of hepatic metastasis
  7. Models of acute liver failure
  8. Techniques of liver resection
  9. Liver resections using microsurgical techniques
  10. Non-conventional anatomical resections
  11. Limitations of rodent models of hepatic resections
  12. Conclusions
  13. Acknowledgements
  14. References

Microsurgical techniques permit anatomical segmentectomies. Isolated resection of the LLL or ML as well as segmental resections of the left or right portion of the ML represents a technical challenge. Although the LLL is easily resectable, care should be taken to avoid ligature of the branches to the ML, which will lead to ischaemia of the lateral aspect of this lobe. In addition, some biliary ducts of the LML may drain into branches of the LLL, implying the existence of a biliary functional inter-relationship between the left medial lobe and the LLL. Thus, the isolated resection of either the LLL or ML may sometimes result in cholestasis of the adjacent lobe (17, 46).

Isolated resection of the right or left sectors of the ML and resection of the superior or inferior aspect of the LLL require delicate dissection of the hilar region and intrahepatic ligation of individual vascular and biliary branches. For resection of the right portion of the middle lobe (which represents segments IV, V and VIII in humans according to Kongure) (18), the inferior pedicle of the ML (which is the first portal branch to the ML together with the arterial branch) should be ligated and divided. The superior pedicle of the ML lies close to the superior aspect of the SRL (Fig. 3A, B). For resection of the left portion of the middle lobe, which represents segment III in humans, (18) the second portal branch (superior pedicle) to this lobe should be ligated and divided. It lies in close proximity to the hepatic vein draining the left portion of this lobe and can be easily visualized after removal of the overlying peritoneum (Fig. 3C, D).

image

Figure 3.  (A, B) Ligature of the inferior pedicle of the median lobe of the rat liver. This pedicle (shown here suture ligated) supplies the right portion of the right median lobe (RML). The superior pedicle of the median lobe is depicted here by the asterisk (*). (C and D) Ligation of the superior pedicle of the median lobe [in (C), magnification × 20]. The superior pedicle of the median lobe supplies the left portion (LML) and is shown here suture ligated (arrow). The location of the inferior pedicle of the median lobe is marked here by the asterisk (*). Shortly after these ligations, an ischaemic line (dotted line) on the medial lobe ML (B and D) equivalent to Cantlie's line can be seen on the falciform ligament insertion line, from the suprahepatic vena cava to the main liver fissure (umbilical fissure). The resection of the RML (equivalent in humans to segments IV, V and VIII) and the LML (equivalent to segment III in humans) can only be performed using microsurgical techniques. Dissection and ligation should be very careful to avoid injuries of the vascular and biliary system of the adjacent segment. Scale bar 0.6 cm.

Download figure to PowerPoint

The LLL has also two vascular pedicles (inferior and superior) and two independent venous drainages (15–17), which also permits anatomical segmentectomies in this lobe. The first vascular pedicle, supplying the inferior part of the LLL, lies on the bottom of this lobe, while the second is located superior–posterior and close to the left hepatic vein (Fig. 4). In either one of these segmentectomies (left medial or right medial), after ligating the vascular pedicle, the ischaemic line can be visualized on both visceral and parietal surfaces of the liver. Then, the parenchyma can be resected 2 mm away from the perfused area. These segmentectomies are more difficult to perform in the mouse because the structures are much smaller and more delicate (the mouse is in average 20 times smaller than a rat). Figure 5A–D shows the ligation of the pedicles of the left portion of the medial lobe and LLL in the mouse.

image

Figure 4.  (A–C) Ligature of the inferior vascular pedicle of the left lateral lobe (LLL, arrow 1) of the rat liver demarcates an ischaemic line (dotted line) on the anterior (B) and posterior (C) surface of this lobe. This ischaemic area represents 3/4 of the LLL and either represents an individual segment, equivalent to the human segment III, or is a subsegment of the LLL. (D–F) After ligature of the inferior pedicle (arrow 1), the superior vascular pedicle was ligated (arrow 2) and the whole LLL turned to be ischaemic (area demarcated by the dotted line, E and F). The area supplied by the superior pedicle may be the equivalent of the segment II in humans. Magnification × 2.

Download figure to PowerPoint

image

Figure 5.  (A) Anterior view of the mouse liver showing the location of the gall bladder (GB) and falciform ligament (FL). (B) Visceral view of the mouse liver. (C) Ligature of the portal pedicles of the left medial lobe (LML, *), left hepatic artery (+), and portal pedicle of the left lateral lobe (LLL, #). (D) After ligature of these portal pedicles, the LML and LLL become ischaemic (area delineated by the dotted line lateral to the falciform ligament – left hemihepatectomy). Scale bar 0.25 cm.

Download figure to PowerPoint

The individual isolation of the portal vein branch from the arterial branch and bile duct may be necessary in some experiments that investigate individual effects of arterial or portal isolation. This dissection is difficult to perform, because they are fragile and closely adherent and surrounded by connective tissue. One manoeuvre that helps this dissection is by flushing pressured saline solution with a syringe close to the pedicle elements. The author successfully used this technique to perform vascular dissection in a kidney transplantation model (47). Hydrodissection can display the correct plane of dissection while reducing risks of injuries.

The main advantage of hepatectomies using microsurgical techniques is that it is possible to perform several extents of hepatectomy, including segmental resections, while reducing the risks of vascular and cholestatic complications.

Limitations of rodent models of hepatic resections

  1. Top of page
  2. Abstract
  3. Rat and mouse liver anatomy
  4. Models of liver resection
  5. Liver regeneration model
  6. Models for assessment of hepatic metastasis
  7. Models of acute liver failure
  8. Techniques of liver resection
  9. Liver resections using microsurgical techniques
  10. Non-conventional anatomical resections
  11. Limitations of rodent models of hepatic resections
  12. Conclusions
  13. Acknowledgements
  14. References

The use of rat and mouse models in liver surgery research is limited by their small size and limited knowledge on rodent liver anatomy (16, 17, 46). As in humans, the rat and mouse liver vasculature and biliary system show a great anatomical variability. In addition, the liver anatomy of rodents and its correlation to the human liver is not completely understood.

The best anatomical model proposed so far is from Kongure and colleagues. In this model, the whole LLL corresponds to human segment II and the LML corresponds to segment III. However, his study did not consider that the LLL has two individual vascular supplies and drainages (Figs 1 and 4), which are prerequisites for segmental denomination. Based on topography and proportions, the small superior segment of the LLL could be considered equivalent to human segment II and the larger inferior segment to human segment III. If this is the case, the LML would be equivalent to segment IV, while the RML would be equivalent only to segments V and VIII. The falciform ligament in humans runs from a point to the left of the vena cava to a point to the left of the gall bladder, and the area between the falciform ligament and Cantlie's line (imaginary line from the vena cava to the gall bladder) represents segment IV. Kongure proposed the equivalence of the rat segments assuming that the location of the rat falciform ligament is the same as in humans. If we consider the falciform ligament to define the nomenclature of the rat liver lobes, the LML could be the equivalent to segment III because it lies directly to the left of the falciform ligament. However, in the mouse, which is phylogenetically much closer to the rat, the falciform ligament lies between the vena cava and gall bladder, located in the main liver fissure (Fig. 5). The main fissure marks the division of the medial lobe into left and right portions. Similar to the mouse, the rat falciform ligament runs between the vena cava and the main liver fissure (the rat has no gall bladder) and may have the equivalent position to Cantlie's line in humans. Taking these facts into consideration, the rat LML could be the equivalent to segment IV, and not to segment III.

One pitfall of segmentectomies of the right or left portions of the middle lobe is that they may be associated with liver congestion in the animals in which the vein draining the left portion of the ML joins the left hepatic vein (draining the LLL) to form a common trunk before draining to the vena cava. In addition, some biliary ducts of the LML may drain into branches of the LLL, implying the existence of a biliary functional inter-relationship between the left medial lobe and the LLL. Thus, the isolated resection of either the LLL or the ML may sometimes result in cholestasis of the adjacent lobe (16, 17, 46).

Results obtained in rodent models cannot be fully translated to humans because the kinetics of liver regeneration in different species is not the same. The amount of remnant hepatic tissue compatible with life in rodents seems to be less than in humans. While in humans the maximum amount of liver that can be tolerated is 70–80% of the original volume (25, 48–52), rodents can survive even after a 90–95% hepatectomy (15).

Models of acute liver failure based only on reduction of liver mass (hepatectomy) are in general not reversible and not associated with the same level of tissue damage and necrosis commonly seen in clinical setting (caused by toxic and viral agents). In order to overcome this problem one can subsequently add liver stress after liver resection with tissue ischaemia (vascular clamping) or toxic agents. Another model proposed a combination of major liver resection with hepatocyte transplantation as a possible approach to recover liver function (37).

Surgical models of acute liver failure do not exactly reproduce the clinical picture seen in patients, e.g. neurological complications (encephalopathy, increased intracranial pressure and somnolence). In only few models of subtotal hepatectomy neurological complications can be noted. Another limitation is that, after major resection, liver function tests, hypoglycaemia and injury markers (aspartate aminotransferase, alanine aminotransferase) do not change in a similar fashion as in humans (32).

Conclusions

  1. Top of page
  2. Abstract
  3. Rat and mouse liver anatomy
  4. Models of liver resection
  5. Liver regeneration model
  6. Models for assessment of hepatic metastasis
  7. Models of acute liver failure
  8. Techniques of liver resection
  9. Liver resections using microsurgical techniques
  10. Non-conventional anatomical resections
  11. Limitations of rodent models of hepatic resections
  12. Conclusions
  13. Acknowledgements
  14. References

Despite some limitations, the use of rodent models of partial hepatectomies provides essential tools to study many important phenomena in liver research. To perform lobectomies only basic surgical skills are needed, and they have been performed with high reproducibility and have been very well tolerated with minimal operative mortality. Recently, an increasing number of studies have used the mouse model of partial hepatectomy. Because of the availability of large varieties of genetically modified mice (knockout, transgenic), and monoclonal antibodies, more relevant and more specific questions can be answered using this model. In addition, the mouse model is more cost effective because mice require fewer amounts of expensive reagents and the housing costs are decreased. However, microsurgical skills are necessary for this approach.

Increased knowledge of the rat and mouse liver surgical anatomy and more advanced microsurgical skills permit individualized dissection, and individual ligature of vascular and biliary branches. However, more investigation to determine the correlation between rodent and human liver anatomy is needed.

References

  1. Top of page
  2. Abstract
  3. Rat and mouse liver anatomy
  4. Models of liver resection
  5. Liver regeneration model
  6. Models for assessment of hepatic metastasis
  7. Models of acute liver failure
  8. Techniques of liver resection
  9. Liver resections using microsurgical techniques
  10. Non-conventional anatomical resections
  11. Limitations of rodent models of hepatic resections
  12. Conclusions
  13. Acknowledgements
  14. References
  • 1
    Higgins GM, Anderson RM. Experimental pathology of the liver. I. Restoration of the liver of the white rat following partial surgical removal. Arch Pathol Lab Med 1931; 12: 186202.
  • 2
    Fausto N, Riehe KJ. Mechanisms of liver regeneration and their clinical implications. J Hepatobiliary Pancreat Surg 2005; 12: 1819.
  • 3
    Aleksandrowicz R, Gawlik Z, Wisniewska IE, Tarlowska H. Physiological aspects of the partial hepatectomy in rats. Acta Physiol Pol 1981; 32: 68192.
  • 4
    Lin PW. Hemodynamic changes after hepatectomy in rats studied with radioactive microspheres. J Formos Med Assoc 1990; 89: 17781.
  • 5
    De Jong KP, Brouwers M, Huls GA, et al. Liver cell proliferation after partial hepatectomy in rats with liver metastases. Anal Quant Cytol Histol 1998; 20: 5968.
  • 6
    Panis Y, Nordlinger B, Delelo R, et al. Experimental colorectal liver metastases. Influence of sex, immunological status and liver regeneration. J Hepatol 1990; 11: 537.
  • 7
    De Jong KP, Lont HE, Bijma AM, et al. The effect of partial hepatectomy on tumor growth in rats: in vivo an in vitro studies. Hepatology 1995; 22: 126372.
  • 8
    Lu MD, Chen JW, Xie XY, Liang LJ, Huang JF. Portal vein embolization by fine needle ethanol injection: experimental and clinical studies. World J Gastroenterol 1999; 5: 50610.
  • 9
    Grisham JW. A morphologic study of deoxyribonucleic acid synthesis and cell proliferation in regenerating rat liver; autoradiography with thymidine-H3. Cancer Res 1996; 22: 8429.
  • 10
    Bucher NL, Swaffield MN. The rate of incorporation of labeled thymidine into the deoxyribonucleic acid of regenerating rat liver in relation to the amount of liver excised. Cancer Res 1964; 24: 161125.
  • 11
    Weinbren K, Taghizadeh A. The mitotic response after subtotal hepatectomy in the rat. Br J Exp Pathol 1965; 46: 4139.
  • 12
    Rozga J, Jeppsson B, Bengmark S. Portal branch ligation in the rat. Reevaluation of a model. Am J Pathol 1986; 125: 3006.
  • 13
    Rodriguez G, Lorente L, Duran HJ, Aller MA, Arias J. A 70% hepatectomy in the rat using a microsurgical technique. Int Surg 1999; 84: 1358.
  • 14
    Pinto M, Herzberg H, Barnea A, Shenberg E. Effects of partial hepatectomy on the immune responses in mice. Clin Immunol Immunopathol 1987; 42: 12332.
  • 15
    Madrahimov N, Dirsch O, Broelsch C, Dahmen U. Marginal hepatectomy in the rat: from anatomy to surgery. Ann Surg 2006; 244: 8998.
  • 16
    Martins PN, Neuhaus P. Surgical anatomy of the liver, hepatic vasculature and bile ducts in the rat. Liver Int 2007; 27: 38492.
  • 17
    Lorente L, Aller MA, Rodriguez J, et al. Surgical anatomy of the liver in Wistar rats. Surg Res Comm 1995; 17: 11321.
  • 18
    Kongure K, Ishizaki M, Nemoto M, Kuwano H, Makuuchi M. A comparative study of the anatomy of the rat and human livers. J Hepatobiliary Pancreat Surg 1999; 6: 1715.
  • 19
    Hummel KP, Richardson FL, Fekete E. Anatomy. In: GreenEL, ed. Biology of the Laboratory Mouse. New York: MacGraw-Hill, 1966; 247307.
  • 20
    Cook MJ. The Anatomy of the Laboratory Mouse. London: Academic Press, 1965; 8795.
  • 21
    Wang J, Tahara K, Hakamata Y, et al. Auxiliary partial liver grafting in rats: effect of host hepatectomy on graft regeneration, and review of literature on surgical technique. Microsurgery 2002; 22: 3717.
  • 22
    Gaub J, Iversen J. Rat liver regeneration after 90% partial hepatectomy. Hepatology 1984; 4: 9024.
  • 23
    Emond J, Capron-Laudereau M, Meriggi F, Bernuau J, Reynes M, Houssin D. Extent of hepatectomy in the rat: evaluation of basal conditions and effect of therapy. Eur Surg Res 1989; 21: 2519.
  • 24
    Inderbitzin D, Gass M, Beldi G, et al. Magnetic resonance imaging provides accurate and precise volume determination of the regenerating mouse liver. J Gastrointest Surg 2004; 8: 80611.
  • 25
    Leelaudomlipi S, Sugawara Y, Kaneko J, Matsui Y, Ohkubo T, Makuuchi M. Volumetric analysis of liver segments in 155 living donors. Liver Transplant 2002; 8: 6124.
  • 26
    Inderbitzin D, Studer P, Sidler D, et al. Regenerative capacity of individual liver lobes in the microsurgical mouse model. Microsurgery 2006; 26: 4659.
  • 27
    Nikfarjam M, Malcontenti-Wilson C, Fanartzis M, Daruwalla J, Christophi C. A model of partial hepatectomy in mice. J Invest Surg 2004; 17: 2914.
  • 28
    Fausto N. Liver regeneration: from laboratory to clinic. Liver Transplant 2001; 7: 83544.
  • 29
    Marcos A, Fisher RA, Ham JM, et al. Liver regeneration and function in donor and recipient after right lobe adult to adult living donor liver transplantation. Transplantation 2000; 69: 13759.
  • 30
    Panis Y, Nordlinger B, Delelo R, et al. Experimental colorectal liver metastases. Influence of sex, immunological status and liver regeneration. J Hepatol 1990; 11: 537.
  • 31
    Panis Y, Ribeiro J, Chretien Y, Nordlinger B. Dormant liver metastases: an experimental study. Br J Surg 1992; 79: 2213.
  • 32
    Rahman TM, Hodgson HJ. Animal models of acute hepatic failure. Int J Exp Pathol 2000; 81: 14557.
  • 33
    Glanemann M, Eipel C, Nussler AK, Vollmar B, Neuhaus P. Hyperperfusion syndrome in small-for-size livers. Eur Surg Res 2005; 37: 33541.
  • 34
    Yao A, Li X, Pu L, et al. Impaired hepatic regeneration by ischemic preconditioning in a rat model of small-for-size liver transplantation. Transpl Immunol 2007; 18: 3743.
  • 35
    Panis Y, McMullan DM, Emond JC. Progressive necrosis after hepatectomy and the pathophysiology of liver failure after massive resection. Surgery 1997; 121: 1429.
  • 36
    Zhong Z, Theruvath TP, Currin RT, Waldmeier PC, Lemasters JJ. NIM811, a mitochondrial permeability transition inhibitor, prevents mitochondrial depolarization in small-for-size rat liver grafts. Am J Transplant 2007; 7: 110311.
  • 37
    Roger V, Balladur P, Honiger J, et al. A good model of acute hepatic failure: 95% hepatectomy. Treatment by transplantation of hepatocytes. Chirurgie 1996; 121: 4703.
  • 38
    Eguchi S, Lilja H, Hewitt WR, Middleton Y, Demetriou AA, Rozga J. Loss and recovery of liver regeneration in rats with fulminant hepatic failure. J Surg Res 1997; 72: 11222.
  • 39
    Makino H, Togo S, Kubota T, et al. A good model of hepatic failure after excessive hepatectomy in mice. J Surg Res 2005; 127: 1716.
  • 40
    Ralli EP, Dum ME. Simplified technique of partial hepatectomy in the rat with fat liver. Proc Soc Exp Biol 1951; 77: 18890.
  • 41
    Krahenbuhl L, Feodorovici M, Renzulli P, Schafer M, Abou-Shady M, Baer HU. Laparoscopic partial hepatectomy in the rat: a new resectional technique. Dig Surg 1998; 15: 1404.
  • 42
    Schaeffer DO, Hosgood G, Oakes MG, St Amant LG, Koon CE. An alternative technique for partial hepatectomy in mice. Lab Anim Sci 1994; 44: 18990.
  • 43
    Kubota T, Takabe K, Yang M. Minimum sizes for remnant and transplanted livers in rats. J Hepatobiliary Pancreat Surg 1997; 4: 398403.
  • 44
    Holmin T, Alinder G, Herlin P. A microsurgical method for total hepatectomy in the rat. Eur Surg Res 1982; 14: 4207.
  • 45
    Greene AK, Puder M. Partial hepatectomy in the mouse: technique and perioperative management. J Invest Surg 2003; 16: 99102.
  • 46
    Lorente L, Aller MA, Duran HJ, Cejalvo D, Lloris JM, Arias J. Extrahepatic biliary anatomy in wistar rats. Surg Res Comm 1995; 17: 318.
  • 47
    Martins PN. Kidney transplantation in the rat: a modified technique using hydrodissection. Microsurgery 2006; 26: 5436.
  • 48
    Shirabe K, Shimada M, Gion T, et al. Postoperative liver failure after major hepatic resection for hepatocellular carcinoma in the modern era with special reference to remnant liver volume. J Am Coll Surg 1999; 188: 3049.
  • 49
    Schindl MJ, Redhead DN, Fearon KC, Garden OJ, Wigmore SJ. The value of residual liver volume as a predictor of hepatic dysfunction and infection after major liver resection. Gut 2005; 54: 28996.
  • 50
    Renz JF, Busuttil RW. Adult-to-adult living-donor liver transplantation: a critical analysis. Semin Liver Dis 2000; 20: 41124.
  • 51
    Fan ST, Lo CM, Liu CL, Yong BH, Chan JK, Ng IO. Safety of donors in live donor liver transplantation using right lobe grafts. Arch Surg 2000; 135: 33640.
  • 52
    Zou Y, Brandacher G, Margreiter R, Steurer W. Cervical heterotopic arterialized liver transplantation in the mouse. J Surg Res 2000; 93: 97100.