EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: The purposes of this study were to determine the incidence of acute pancreatitis after living donor hepatectomy and to investigate potential risk factors and outcomes.

Materials and Methods: Clinical data of all donors who underwent donor hepatectomy between January 2015 and December 2016 in our liver transplant institute were reviewed. Donor data were obtained from a prospectively maintained database. The donors were divided into 2 groups according to whether they developed postoperative pancreatitis. The following data were compared between the 2 groups: demo-graphic information (age, sex), body mass index, type of hepatectomy (right, left, or left lateral), intraoperative cholangiographic findings, operative time, blood loss, graft data (graft weight, remnant liver ratio), duration of postoperative hospital stay, and postoperative morbidity and mortality (if any). Pancreatitis severity and treatment outcomes were also examined in patients with postoperative pancreatitis.

Results: Our study included 348 donors who underwent donor hepatectomy for living-donor liver transplant. Postoperative pancreatitis developed in 6 donors (1.7%). We found no statistical differences between patients with and without postoperative pancreatitis in terms of demographic and intra-operative findings. Neither loco-regional nor systemic complications of pancreatitis developed in any of the patients. Therefore, all were classified as having mild pancreatitis according to revised Atlanta classification. The mean APACHE II score was 5.2 ± 1.2 points (range, 4-7 points). All patients with postoperative pancreatitis received conservative-supportive treatment.

Conclusions: Although postoperative pancreatitis is a rarely reported complication in living liver donors, it should always be considered, especially in patients who unpredictably deteriorate in the postoperative period. Proper recognition and timely treatment can help avoid serious consequences.

Key words : Hepatectomy, Liver transplantation, Postoperative complications

The number of liver transplants has gradually increased, while the shortage of deceased donor organs continues to be a worldwide problem. In the United States, more than 16 000 patients are currently on wait lists for livers according to the Organ Procurement and Transplantation Network. More than 2000 candidates from this list die every year, although over 7000 liver transplants are performed annually in the United States.¹ Living-donor liver transplant (LDLT) is the main alternative solution to reduce the shortage of organs.

The first LDLT was performed in Brazil in 1988, and the first successful case was reported in Australia.^2,3 The first adult-to-adult living donor liver transplant (A2ALL) was performed in Hong Kong in 1993.4 Today, LDLT accounts for approximately 5% of liver transplants performed in the United States.1 In some countries, like ours, this rate reaches over 80%.

Beyond reducing the number of patients on wait lists, LDLT has some potential advantages, including detailed donor screening, optimal timing for transplant, and minimal cold ischemia time.⁵ Despite all of these advantages, LDLT has been controversial since its beginning. Ethical concerns regarding LDLT are associated with potential morbidity and mortality for donors. Today, the risk of various complications for donors is over 20%, and a second operation is rarely needed. The most common complications for donors are infections, biliary leakage, and gastric stasis. Mortality after LDLT has been reported at 0% (Japan), 0.3% (United States), and < 1% (Europe), with risks likely to decrease further as surgeons gain more experience with this procedure.⁶

Acute pancreatitis may develop in the post-operative period of various surgical procedures. Diagnosis of postoperative acute pancreatitis (PAP) is often difficult, and it has a higher complication risk than those associated with other causes. The mechanism of PAP is usually not revealed but is mostly attributed to transient intraoperative hypotension and pancreatic trauma caused by intraoperative manipulations. In addition, some intraoperative or postoperative medications and interventions (such cholangiography) may increase the risk of PAP.

he purposes of this study were to determine the incidence of PAP after living-donor hepatectomy and to investigate its potential risk factors and the outcomes of patients with PAP.

Materials and Methods

Patients
Clinical data of all donors who underwent donor hepatectomy in our liver transplant institute between January 2015 and December 2016 were reviewed. Donor data were obtained from a prospectively maintained database. The study protocol was approved by the Institute Ethics Committee.

The donors were divided into 2 groups according to whether they developed PAP. The following data were compared between the 2 groups: demographic information (age, sex), body mass index (BMI), type of hepatectomy (right, left, or left lateral), intraoperative cholangiographic findings, operative time, blood loss, graft data (graft weight, remnant liver ratio), duration of postoperative hospital stay, and postoperative morbidity and mortality (if any). Pancreatitis severity and treatment outcomes were also examined in the PAP group.

Diagnosis of acute pancreatitis
In our study, patients with 2 of the following 3 criteria were considered as having acute pancreatitis: (1) acute onset of a persistent, severe, epigastric pain often radiating to the back; (2) serum lipase or amylase levels at least 3 times greater than the upper limit of normal; and (3) typical findings of acute pancreatitis on computed tomography. The severity of pancreatitis was determined by the revised Atlanta classification.7 We preferred the APACHE II scale as the prognostic scoring system to avoid miscal-culation due to liver enzymes, which are criteria of the Ranson and Imrie systems.

Donor selection in our institute
Donor candidates should be between 18 and 60 years of age and in excellent physical condition. They must have a relationship with the recipient within the third degree of consanguinity. In addition, willingness to be a donor candidate must be entirely voluntary. After they undergo a full psychiatric evaluation, donor candidates must pass a 3-step elimination system defined by Trotter, which is used in many transplant centers.⁸ In the first step, candidates undergo blood group determinations, complete blood counts, biochemical laboratory tests, viral profiles, and urine cultures. In the second step, eligible candidates are examined by abdominal Doppler ultrasonography and contrast-enhanced multislice computed tomography to determine hepatosteatosis and vascular variations. Finally, volumetric measurements are performed utilizing contrast-enhanced multislice computed tomography. A liver biopsy is performed on candidates with a BMI greater than 30 kg/m² or hepatosteatosis greater than 20%. Candidates are not accepted as donors if they have a mismatched blood group, a positive viral serology, an estimated remnant volume lower than 26%, or a hepatosteatosis rate exceeding 20%.

Surgical technique of donor hepatectomy in our institute
A reverse L incision is preferred for donor hepatectomies in our institute. First, a meticulous cholecystectomy is done. Next, a cholangiography is routinely performed through the cystic duct to assess the biliary anatomy. The right lobe of the liver is mobilized by dividing the right coronary and triangular ligaments with ligation of the tiny hepatic veins draining the caudate lobe. If there is an inferior hepatic vein larger than 5 mm, it is preserved for anastomosis. Afterward, the right hepatic artery and right portal vein are freed by hilar dissection. The demarcation line is determined by temporary clamping of the right portal vein and right hepatic artery. Parenchymal transection is achieved with the use of a Cavitron ultrasonographic aspirator (Valleylab, Boulder, CO, USA), if necessary, with the Pringle maneuver. Hemostasis for vessels smaller than 3 mm is performed using bipolar coagulation or hemoclips. Larger vessels or biliary components are ligated with sutures or clips. Transection of the bile duct is always initiated after parenchymal transection is entirely completed. Transection is performed at least 2 mm away from the remnant bile duct in a single action to avoid damaging the remnant bile duct. The remnant bile duct is then closed horizontally with 6-0 monofilament nonabsorbable sutures. The retrieval procedure is finished by clamping and dividing the right hepatic artery, right portal vein, and right hepatic vein. The right portal vein and hepatic vein stump are closed. Biliary leakage from the closed stump or from the transected area is checked twice by saline and methylene blue injection into a cystic duct catheter immediately after stump closure. The falciform ligament is sutured to the anterior abdominal wall to fix the remnant left lobe. One drain is placed into the hemi-hepatectomy cavity. To remove the left lateral segment (segments 2 and 3; left liver hepatectomy) or the left liver (segments 2, 3, and 4), we free this part of the liver from the connective tissues. Parenchymal transection is performed as described above. The artery, hepatic vein, portal vein, and biliary duct branches are isolated and cut.

Postoperative care in our institute
All patients are followed in the intensive care unit at least overnight for monitoring. Prophylactic antibiotics are usually discontinued within 24 hours after surgery. Low-molecular-weight heparins are not routinely used. The urinary catheter and nasogastric tube are removed on day 1. The abdominal drain is removed if there are no abnormal drainage fluids and if the amount of drainage is less than 50 mL/day. In the first week, when remnant liver regeneration is the fastest, liver function tests (alanine transaminase, aspartate transaminase, alkaline phosphatase, gamma glutamyltransferase, total and direct bilirubin, prothrombin time), renal function tests (urea, creatinine), blood electrolytes (sodium, chloride, potassium, calcium), and complete blood count parameters are checked daily.

After discharge, donors are evaluated at follow-up visits on the 1st, 3rd, 6th, and 12th months after surgery. These routine visits are often discontinued after the first year. Donors are instructed to return if they had any complaints or abnormalities at any point during follow-up. All postoperative com-plications are assessed according to the Clavien classification system (Table 1)⁹ and are recorded to a prospectively maintained database.

Statistical analyses
All data management and statistical analyses were performed using SPSS software (SPSS: An IBM Company, version 20, IBM Corporation, Armonk, NY, USA). Categorical variables were compared using the Pearson chi-square or Fisher exact test where appropriate. Continuous variables were compared using the 2-tailed t test or the Wilcoxon signed rank test where appropriate.

During the study period, 348 donors underwent donor hepatectomy for LDLT. Of these donors, 211 (60.6%) were male and 137 (39.4%) were female. The mean (SD) age was 28.8 (7.9) years (range, 18-56 y). Postoperative pancreatitis developed in 6 donors (1.7%) during our study period (PAP group).

Demographic variables
In patients who developed PAP, the mean (SD) age was 25.6 (10.2) years (range, 19-45 y). Four of these patients (66.7%) were male. The mean (SD) BMI was 22.4 (3.4) kg/m2 (range, 19.2-29.3 kg/m2) in the PAP group. There were no statistical differences between the PAP and non-PAP groups in terms of demographic findings (Table 2).

Intraoperative variables
During the study period, right hepatectomy was performed in 303 donors (87.1%), left in 15 donors (4.3%), and left lateral in 30 donors (8.6%). The mean (SD) graft weight was 653 (192) g (range, 180-1125 g), and the mean (SD) estimated ratio of the remnant liver volume was 35.2% (6.2%) (range, 27%-86%). The Pringle maneuver was needed in 33 donors (9.5%). The mean (SD) intraoperative blood loss was 320 (110) mL (range, 100-800 mL), and the mean (SD) operative time was 280 (63) minutes. During intraoperative cholangiography, Wirsung duct was visualized in 43 donors (12.4%).

All patients in the PAP group underwent right hepatectomy. In the PAP group, the mean (SD) graft weight was 685 (85) g (range, 570-830 g), and the mean (SD) estimated ratio of the remnant liver volume was 33.2% (3.2%) (range, 30%-36 %). The mean (SD) intraoperative blood loss was 280 (90) mL (range, 200-350 mL), and the mean (SD) operative time was 292 (43) minutes. During intraoperative cholangiography, Wirsung duct was not visualized in any of the PAP group donors. Also, the Pringle maneuver was not performed in any PAP group donor. There were no statistical differences between the PAP and non-PAP group patients in terms of intraoperative findings (Table 3).

Postoperative variables
During the study period, the mean (SD) duration of postoperative hospitalization was 7.5 (3.2) days. Various postoperative complications, including PAP, were encountered in 68 donors (19.5%). Radiologic intervention (Clavien grade 3a) or reoperation (Clavien grade 3b) was required in 25 donors (7.2%) and 12 donors (3.4%), respectively. No mortality occurred during the study period.

The mean (SD) duration of postoperative hospitalization was 20.3 (4.9) days in the PAP group, which was statistically longer than in the non-PAP group (7.3 [2.6] days). Although acute pancreatitis was diagnosed before discharge in 3 patients, 3 patients were readmitted with acute pancreatitis symptoms within 2 or 3 days after discharge.

Outcomes
Neither loco-regional nor systemic complications of pancreatitis developed in any of the patients. Therefore, all patients were classified as having mild pancreatitis according to the revised Atlanta classification. The mean (SD) APACHE II score was 5.2 (1.2) points (range, 4-7 points). All patients with PAP received conservative-supportive treatment. The patients received no food or water by mouth while intravenous fluid hydration was provided with monitoring of hemodynamic and input and output parameters. Analgesics were administered for pain relief. All patients underwent multislice computed tomography with a triphasic protocol for differential diagnoses (Figure 1). Demographic and clinical characteristics of donors in the PAP group are summarized in Table 4.

Since the Hippocratic Corpus, “primum non nocere (first, do no harm)” has been the most fundamental principle of medical practice. Donor safety is the most essential issue in donor hepatectomies in which a healthy individual undergoes surgery. However, it is also an undeniable fact that hepatectomies are complex and risky operations. A thorough understanding of the risks and benefits of the donor and recipient is needed to properly weigh the ethical issues. Although the first successful LDLT was conducted in 1989, this method was not widespread in Europe and the United States due to concerns about donor safety until about the 2000s.

In the literature, postoperative complication rates in living liver donors have been quite variable, ranging from 0% to 67%. This wide variety in complication rates is mostly due to different definitions and the lack of a standardized classification system, which is further confounded by a bias against reporting complications. In addition, the low complication rates of Far East centers can be attributed to a number of demographic features such as nonobese and small-size donors and better compatibility in a more homogeneous population. Another explanation may be the experience levels of surgeons with living donor hepatectomy.^10,11 The A2ALL consortium was founded under the sponsorship of the National Institutes of Health with the contribution of 10 liver transplant centers in the United States. They collect data on patients assessed at these centers for living liver donation. The consortium reported an overall complication rate of 39% among 740 living liver donors (707 right lobes). They also confirmed that increasing center experience was not associated with a reduction in complication rates.12 In our study, the overall postoperative complication rate was 19.5%. Our overall complication rate seems in the median of those reported from the United States and Far East countries.

At least 19 donor deaths due to postoperative complications have been reported worldwide until 2006, which implies a mortality rate of 0.2% to 0.5%. In addition, 3 donors had to undergo liver transplant procedures themselves.^13-17 The mortality rate for living liver donors is at least 5-fold greater than for living kidney donors (0.03%).¹⁸

Postoperative acute pancreatitis arises in 1% to 3% of patients who have undergone major upper abdominal surgery; furthermore, it was reported after cardiac, renal, and parathyroid surgery.¹⁹ Postoperative acute pancreatitis is a relatively frequent complication after open biliary tract surgery. The incidence of PAP is 4% to 10% depending on the procedure performed and the definition of pancreatitis after open biliary tract surgery. The most risky operations for PAP are common bile duct explorations and transduodenal sphincterotomies or sphincteroplasties. Postoperative acute pancreatitis has a higher complication rate than pancreatitis associated with other causes.^20-24

Hyperamylasemia is frequently encountered in patients undergoing hepatic resection.^24,25 Although pancreatitis after major hepatectomy is mainly subclinical, it can contribute to distant organ failure.²⁶ The pathophysiology of pancreatic dysfunction after hepatic resection has not been elucidated. The main risk factors suggested to explain the hyper-amylasemia after hepatectomies are the presence of chronic liver disease, the extent of hepatectomy, and portal congestion caused by vascular control of the liver during these surgical procedures.²⁷Miyagawa and associates reported that use of the Pringle maneuver increased the incidence of postoperative hyperamylasemia and that the level of hyper-amylasemia was increased by portal congestion with longer vascular occlusion time.²⁸ Hashimoto and associates reported similar results after trying various types of hepatic vascular control in humans. They reported a lower incidence of hyperamylasemia in patients who have undergone hemihepatic vascular occlusion.²⁹

In contrast, Kubota and associates performed a series of hepatectomies in which they also occluded the superior mesenteric artery during hepatic vascular control to prevent increased portal pressure by eliminating the arterial ﬂow to organs that drain into the portal circulation. There was no signiﬁcant difference in postoperative hyperamylasemia compared with conventional hepatectomy. They concluded that portal congestion was not the only reason for postoperative hyperamylasemia and that other factors, such as extent of the resection, may play a more important role.³⁰

There was some evidence about oxidative damage to the pancreas after hepatic ischemia-reperfusion injury.³¹ Varsos and associates inves-tigated the mechanisms of pancreatic injury after major hepatectomy in a porcine model. Their findings suggested that reactive oxygen species produced during vascular control may contribute to portal congestion in the development of pancreatitis after major hepatectomy. Their results support that pancreatitis after major hepatectomy is probably multifactorial.³²

Postoperative acute pancreatitis has been reported in 1.5% to 8% of recipients after liver transplant. Postoperative acute pancreatitis has an aggressive course in these patients, with high mortality ranging from 37.5% to 63%.³³ However, PAP is a rare complication in living liver donors. To our knowledge, the reported rate of 1.7% in this study is the highest PAP rate in living liver donors reported to date.

In a study by the Japanese Liver Transplantation Society, in which 1853 living liver donors were analyzed for postoperative complications, PAP was reported in only 2 patients (0.1%). In that comprehensive study, alopecia was reported in 8 patients (0.4%, 4 times of PAP).¹⁰ Similarly, no PAP cases were reported in the A2ALL consortium study, which included 707 living liver donors from the United States.¹²Also, we have not reported any PAP cases in our previous study, which included 500 consecutive donors between 2007 and 2011.³⁴ To our knowledge, until now, the highest rate of PAP in living liver donors was reported by Morioka and associates.³⁵ They reported 3 PAP cases (0.9%) in 335 living liver donors. It is obvious that these rates are quite below the expected rates. The probable cause for this is the difficulty with its diagnosis. Early signs and symptoms of PAP (including one or more of the following: abdominal pain, fever, nausea, vomiting, and decreased bowel sounds) are not specific and may be easily explained by other reasons. In addition, the severity of symptoms can be inconsistent. Therefore, it is probable that PAP has been missed in many living liver donors. However, it should always be considered, especially in patients who unpredictably deteriorate in the postoperative period.

If not considered, PAP can lead to worrisome results. Recently, Reddy and associates³⁶ from India reported a postoperative death of 29-year-old woman donor due to possible severe PAP. In that case, acute pancreatitis had not been considered among the differential diagnoses, and the patient, who had continued deterioration, had undergone relaparotomy with differential diagnosis of bowel perforation or ischemia. After the patient’s death, PAP was diagnosed retrospectively. Visualization of Wirsung duct during intraoperative cholangiography had been considered as the primary cause of acute pancreatitis.

This unfortunate case has prompted our consideration of PAP more often in living liver donors, leading us to quickly perform the necessary examinations for PAP and record the data. We believe that this is the reason for the difference between our above-mentioned previous study34 and this study.

In our study, all of the patients had mild pancreatitis with mean 5.2 ± 1.2 APACHE II score. Neither loco-regional nor systemic complications of pancreatitis developed in any of the patients. All patients with PAP could be treated with conservative-supportive methods. One of the aims of this study was to examine possible factors that predict PAP development. However, we could not identify any predictive factors, including cholangiographic visu-alization of Wirsung duct, the Pringle maneuver, operative time, blood loss, and BMI.

The most important limitation of our study was that the number of patients in the PAP group was too small to obtain appropriate statistical data. Therefore, there is a need for multicentric prospective studies involving a greater number of patients to confirm our results.

Although PAP is a rarely reported complication in living liver donors, it should always be considered, especially in patients who unpredictably deteriorate in the postoperative period. With proper recognition and timely treatment, serious consequences can be avoided.

Volume: 20 Issue: 4 April 2022

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