Auxiliary heterotopic partial liver transplantation in pigs with acute liver failure

Fulminant hepatic failure is usually fatal without liver transplantation; however, orthotopic liver transplantation is often difficult to perform due to the high risk of coagulopathy and the development of multiple organ failure. Auxiliary heterotopic partial liver transplantation (APLT), however, has the potential to provide an effective hepatic support system considering that the host liver is left in situ and the surgical procedure is less invasive. In this report, we describe the beneficial effects of performing 60% APLT on the hepatic function and survival of pigs with acute hepatic failure induced by hepatic artery ligation. The pigs were divided into a control group of nine animals (group 1) that had portal vein and hepatic artery ligation with a side-to-side portacaval shunt, and an APLT group of seven animals (group 2) that had portal vein and hepatic artery ligation with APLT. The two left lateral lobes of the donor liver were resected, reducing the liver weight to about 60%, and the graft was placed in the right subhepatic space. No deaths occurred intraoperatively. In group 1, eight pigs died of massive liver necrosis within 48 h and one died between 48 and 72 h (median surivival 23 h). In group 2, two pigs died within 72 h due to preservation or anesthetic problems, but five survived for more than 3 days (median survival 13.4 days), with a significant difference between the two groups (P<0.05). One animal was killed 30 days after APLT and excellent graft function was demonstrated by the synthesis of clotting factors, ammonia detoxification, and glucohomeostasis. Moreover, evidence of hepatic regeneration was found in the transplanted livers. These results indicate that APLT provides metabolic support and improves survival in animals with induced acute liver failure.     

Combined Liver–Kidney Transplantation for Primary Hyperoxaluria Type 2: A Case Report

Combined liver/kidney transplant is the preferred transplant option for most patients with primary hyperoxaluria type 1 (PH1) since orthotopic liver transplantation replaces the deficient liver‐specific AGT enzyme, thus restoring normal metabolic oxalate production. However, primary hyperoxaluria type 2 (PH2) is caused by deficient glyoxylate reductase/hydroxypyruvate reductase (GRHPR), and this enzyme is widely distributed throughout the body. Though the relative abundance and activity of GRHPR in various tissues is not clear, some evidence suggests that the majority of enzyme activity may indeed reside within the liver. Thus the effectiveness of liver transplantation in correcting this metabolic disorder has not been demonstrated. Here we report a case of 44‐year‐old man with PH2, frequent stone events, and end‐stage renal disease; he received a combined liver/kidney transplant. Although requiring confirmation in additional cases, the normalization of plasma oxalate, urine oxalate, and urine glycerate levels observed in this patient within a month of the transplant that remain reduced at the most recent follow‐up at 13 months suggests that correction of the GRHPR deficiency in PH2 can be achieved by liver transplantation.     

Intraoperative hemodynamics in liver transplantation comparing orthotopic with heterotopic transplantation in the pig

The intraoperative hemodynamic changes and several graft function parameters were studied comparing orthotopic liver transplantation with auxiliary partial liver transplantation (APLT) in the pig. Thirty-one Yorkshire pigs (ca. 25 kg b.w.) were randomly allocated to OLT (n = 16) or APLT (n = 15). During the construction of portal anastomosis the median cardiac output dropped to 67% of the initial value in OLT and to 49% in APLT (P less than 0.02). Median duration of the portal flow interruption was shorter in APLT: 15 min versus 48 min in OLT (P less than 0.002). After unclamping of the aorta, the median systolic blood pressure dropped to 75 mmHg in OLT and to 90 mmHg in APLT (P less than 0.02). APLT is less time-consuming: median duration of transplantation was 128 min versus 165 min in OLT (P less than 0.002). SGOT levels were lower in APLT than in OLT (median SGOT on the first postoperative day 67 was IU/L versus 177 IU/L, P less than 0.002). It is concluded that APLT is a shorter procedure than OLT with a shorter portal flow interruption, being less offensive to the recipient.     

可量化的受体门静脉干预调节猪辅助性部分肝移植两肝门静脉血流竞争

目的 观察不同程度的受体肝门静脉缩窄对猪辅助性部分肝移植(APLT)受体肝和移植肝门静脉血流竞争的防治作用,探讨一种可量化的受体肝门静脉干预标准.方法 32头健康幼猪按体重相近原则配对,取右半肝作为供肝,切除受体肝左叶,共行16次APLT.根据移植后受体门静脉缩窄程度,将其分为4组:对照组(n=5,门静脉未行处理),缩窄1/4组(n=4,受体门静脉宽度缩窄1/4),缩窄1/3组(n=4,缩窄1/3)和结扎组(n=3,门静脉结扎).定期观察各组受体肝和移植肝的体积大小、血流状况及组织结构的变化.结果 术中电解质变化各组基本相似,血流动力学变化以对照组和缩窄1/4组较为平稳;各组存活率和最长存活时间均以缩窄1/4组最优;门静脉造影示缩窄1/4组两肝之门静脉均得到较好显影,未见明显造影剂淤积和血管扩张;多普勒超声示各组移植肝门静脉依次增宽,流速分别为0.220、0.293、0.336和0.400 m/s,受体门静脉流速分别为0.275、0.294、0.328和0 m/s;两肝体积、充盈度和包膜紧张度以缩窄1/4组最为适中,坏死程度亦以缩窄1/4组最轻.结论 在供受体体重相近且无明显肝硬化时,为防治APLT门静脉血流竞争,以受体门静脉宽度缩窄1/4较为适宜.     

异位辅助性分肝移植供肝切取与植入体会

目的　为临床辅助性肝移植的开展,探索供肝切取及植入方法。　方法　猪异位辅助性部分肝移植13例,供肝切取按预分离方法分为A、B两组,A组标准法5例,B组快速灌注法8例。　结果　A组供肝质量优良为100%,B组供肝质量优良占88%。辅肝移植手术时间为122±28min,腔静脉和门静脉吻合时间为40±12min。　结论　如条件允许应首选标准法预分离,血流动力学不稳定时,可行快速灌注法预分离。     

Deceleration of Regenerative Response Improves the Outcome of Rat with Massive Hepatectomy

Small residual liver volume after massive hepatectomy or partial liver transplantation is a major cause of subsequent liver dysfunction. We hypothesize that the abrupt regenerative response of small remnant liver is responsible for subsequent deleterious outcome. To slow down the regenerative speed, NS‐398 (ERK1/2 inhibitor) or PD98059 (selective MEK inhibitor) was administered after 70% or 90% partial hepatectomy (PH). The effects of regenerative speed on liver morphology, portal pressure and survival were assessed. In the 70% PH model, NS‐398 treatment suppressed the abrupt replicative response of hepatocytes during the early phase of regeneration, although liver volume on day 7 was not significantly different from that of the control group. Immunohistochemical analysis for CD31 (for sinusoids) and AGp110 (for bile canaliculi) revealed that lobular architectural disturbance was alleviated by NS‐398 treatment. In the 90% PH model, administration of NS‐398 or PD98059, but not hepatocyte growth factor, significantly enhanced survival. The abrupt regenerative response of small remnant liver is suggested to be responsible for intensive lobular derangement and subsequent liver dysfunction. The suppression of MEK/ERK signaling pathway during the early phase after hepatectomy makes the regenerative response linear, and improves the prognosis for animals bearing a small remnant liver.     

Efficacy of preoperative portal vein embolization prior to major hepatectomy for patients with impaired liver function: A retrospective study

Hepatocellular carcinoma (HCC) is often associated with chronic liver disease, such as hepatitis or cirrhosis, and this association may limit the use of surgery as a therapy, and if surgery is pursued, may give rise to postoperative hepatic failure. We evaluated the outcome in patients with HCC given preoperative portal vein embolization (PVE) before they underwent major hepatectomy. After PVE, portal pressure increased significantly. Two weeks after PVE, both the volume of the non-embolized lobe and the 15-min indocyamine green retention rate (ICG R15) were significantly increased. The prognostic score, calculated on the basis of age, ICG R15, and the resection rate, was significantly decreased. The operative mortality rate was significantly lower in patients who underwent PVE before surgery than in patients who did not receive PVE. The cumulative survival rate of the PVE patients, even those with cirrhosis of the liver, was significantly higher. Prior PVE appears to allow more extensive major hepatectomy and to lessen the risk of this invasive surgery. However, patients in whom the portal pressure immediately after PVE was more than 30cm H₂O and/or whose prognostic score exceeded 50 points developed postoperative hepatic failure. These features should be kept in mind when it is decided whether surgery is indicated. Nevertheless, preoperative PVE appears to be a beneficial procedure for patients undergoing major hepatectomy, particularly those with chronic liver disease.     

A comparative study on changes in hemostasis in orthotopic and auxiliary liver transplantation in pigs

We compared blood loss and hemostasis in pigs which had undergone either orthotopic liver transplantation (OLT) (group A, n=12) or auxiliary heterotopic partial liver transplantation (APLT) (group B, n=11). Blood samples were taken at regular intervals during and after the operations. In both groups, nine animals survived longer than 24 h and data from these animals were used for analysis. Median (range) intraoperative blood loss was 825 ml (250–1500 ml) in OLT and 425 ml (300–750) in APLT (P<0.01). Routine clotting times, as the activated partial thromboplastin time, prothrombin time and thrombin time, showed no major intraoperative changes in either group. Fibrinogen levels decreased in both groups, but no significant difference was found between the two groups. The only significant difference between group A and B was a more sustained increase in fibrinolytic activity after graft recirculation in group A. Post-operatively, restoration of fibrinogen, antithrombin-III and ₂-antiplasmin levels was slightly faster in group B, resulting in significantly higher levels during the first day. We conclude that, in this animal model, APLT is associated with significantly lower blood loss and less severe fibrinolytic activity, than OLT. This difference might result from the lack of an anhepatic period and the reduced surgical trauma in auxiliary heterotopic liver transplantation.     

Sequential combined liver-kidney transplantation for a one-year-old boy with infantile primary hyperoxaluria type 1

We present the case of a one-year-old male patient with infantile primary hyperoxaluria type 1 (PH1). The patient visited hospital because of growth delay and poor feeding when he was six months old, and was diagnosed as PH1 with chronic renal failure. He underwent peritoneal dialysis until receiving a living-related liver transplantation when he was seventeen months old, and after the operation, underwent hemodialysis or hemodiafiltration four times per week. Six months after the liver transplantation, his serum oxalate level decreased to around 20 micromol/l and a living-related kidney transplantation was successfully performed. Nine months have passed since the kidney transplantation, and the patient's liver and kidney functions have been good and his growth and development much better than before the sequential liver and kidney transplantation. However, his serum and urine oxalate levels remained high and he has required high dose hydration to prevent deposition of calcium oxalate crystals in his grafted kidney. The key-points for treating infantile PHI patients are summarized as follows; 1) make a precise diagnosis as soon as possible, 2) perform a combined liver-kidney transplantation successfully, 3) conduct careful monitoring of the serum and urine oxalate levels and continue adequate hydration after kidney transplantation until the serum and urine oxalate levels normalize. Furthermore, cooperation between the medical staff and the patient's family seems to be essential.     

Functional portal flow competition after auxiliary partial orthotopic living donor liver transplantation in noncirrhotic metabolic liver disease

Auxilliary partial orthotopic liver transplantation (APOLT) was introduced initially as a tentative or permanent support for patients with potentially reversible fulminant hepatic failure and has extended its indication to congenital metabolic disorder of the liver that has otherwise normal functional integrity. Postoperative management of APOLT is complicated because of functional portal flow competition between the native and graft liver. The native portal vein diversion to the graft is sometimes indicated to prevent functional competition; however, it is still an open question whether this technique can be theoretically indicated for APOLT patients. The authors report a on patient with ornithine transcarbamylase deficiency who received APOLT from a living donor without native portal vein diversion. Because of functional portal vein competition between the native and graft liver, the patient had to have portal vein diversion, portal vein embolization, and finally native hepatectomy to induce the graft regeneration after APOLT. After the experience of the current case, primary portal vein diversion for APOLT with noncirrhotic metabolic liver disease patients to prevent functional portal flow competition is recommended.     

Inhibition of Matrix Metalloproteinase‐9 Attenuates Acute Small‐for‐Size Liver Graft Injury in Rats

Ischemia/reperfusion (I/R) and portal hypertension have been implicated in small‐for‐size liver graft dysfunction. Matrix metalloproteinases‐2 and ‐9 (MMP‐2/9) are critically proposed to involve in hepatic I/R injury and activated by hemodynamic force. We hypothesized that MMP‐2/9 overexpression played a crucial role in acute graft injury following small‐for‐size liver transplantation (LT). Rats were randomly assigned into four groups: 75% partial hepatectomy (PH); 100% LT; 25% LT and 25% LT treated with CTT peptide (MMP‐2/9 inhibitor). ELISA, real‐time PCR, gelatin zymography and immunohistochemistry were used to determine the expression pattern of MMP‐2/9 in liver tissue. MMP‐9 expression was significantly increased 6 h after reperfusion and reached a peak 12 h in the 25% LT group, whereas MMP‐2 was expressed in all groups invariably. Compared with the 25% LT group, rats from CTT‐treated group exhibited markedly decreased alanine aminotransferase and total bilirubin values, downregulated proinflammatory cytokines, attenuated malondialdehyde (MDA) and myeloperoxidase (MPO) activities, and improved liver histology. Likewise, MMP‐9 inhibition significantly reduced number of TUNEL‐positive cells and caspase‐3 activity, along with decreased protein levels of Fas and Fas‐L. Specifically, rat survival was also improved in the CTT‐treated group. These results support critical function of MMP‐9 involved in acute small‐for‐size livergraft injury.     

Oxalate retinopathy is irreversible despite early combined liver‐kidney transplantation in primary hyperoxaluria type 1

In primary hyperoxaluria type 1 (PH1), systemic oxalate deposition (oxalosis) in end‐stage renal disease (ESRD) is associated with high morbidity and mortality, particularly in children with infantile oxalosis (IO). Combined liver and kidney transplantation (CLKT) is the only curative treatment option in these patients. After CLKT, systemic oxalosis decreases continuously, although only insufficient data are available regarding oxalate retinopathy (ROx), leading to severe visual impairment. We analyzed long‐term follow‐up data of ROx in 13 patients undergoing CLKT for PH1 at our center between 1998 and 2018. Age at transplantation was 1.3‐14.2 years, including nine patients with IO. We performed visual acuity testing, slit lamp investigation, funduscopy, fundus photography, and spectral‐domain optical coherence tomography (SD‐OCT) imaging. Severe (grade 2‐4) ROx was present in all nine children with IO but not in the four patients developing ESRD in adolescence. A significant negative correlation was found between age at onset of ESRD and grade of ROx (r = ?0.66; P < .001). Notably, follow‐up assessment after CLKT demonstrated no regression of ROx after a median of 5.3 years (range 0.6‐14). The data show that despite early CLKT in IO, ROx is irreversible and the concomitant visual deterioration occurs prior to transplantation.     

Protective effects of simultaneous splenectomy on small‐for‐size liver graft injury in rat liver transplantation

Splenectomy is an effective technique in living donor liver transplantation (LDLT) with small‐for‐size (SFS) liver grafts for overcoming SFS liver graft injury. However, the protective mechanism of splenectomy is still unclear. The aim of this study was to investigate how splenectomy could attenuate SFS graft injury through the measurement of biochemical factors, particularly the expression of endothelin (ET)‐1, which is a key molecule of microcirculatory disorders by mediating sinusoidal vasoconstriction. We performed rat orthotopic liver transplantation using SFS liver grafts with or without splenectomy. We investigated intragraft expression of ET‐1 mRNA and hepatic protein levels of ET‐1. In addition, portal pressure, hepatic injury and morphological changes, and survival rate were evaluated. In result, intragraft ET‐1 mRNA expression after SFS liver transplantation was significantly downregulated by splenectomy, and hepatic expression of ET‐1 in SFS grafts was rarely observed. Splenectomy inhibited the increase in portal pressure, ameliorated SFS liver graft injury and improved the graft survival rate after SFS liver transplantation. In conclusion, splenectomy improved the SFS liver injury and decreased the expression of ET‐1 by attenuating portal hypertension on SFS liver transplantation. Downregulation of intragraft ET‐1 expression plays important roles in the protective mechanism of splenectomy in SFS liver transplantation.     

A Novel Technique for Auxiliary Partial Liver Transplantation With Reno-Portal Anastomosis and Avoidance of the Hepatoduodenal Ligament

Auxiliary liver transplantation (ALT) is a treatment for acute liver failure when regeneration of the native liver is possible or for metabolic disorders. In selected cases ALT and orthotopic liver transplantation (OLT) have similar survival when ALT is performed in the orthotopic position (auxiliary partial orthotopic liver transplantation, APOLT). Drawback of ALT with portal vein to portal vein anastomosis is the frequent occurrence of thrombosis, compromising both graft and native liver, and the necessity of a significant resection. To avoid division of portal flow we performed ALT with an end-to-end anastomosis between the graft portal vein and the left renal vein of the recipient (reno-portal ALT, REPALT). The hepatic artery was anastomosed to the aorta using an iliac arterial graft conduit. The bile duct was anastomosed to the stomach. In the two cases presented here excellent immediate graft function occurred with rapid regeneration of the graft and without early vascular complications.     

Portal vein embolization vs. portal vein ligation for induction of hypertrophy of the future liver remnant

The objective of this study was to assess the efficacy of right portal vein embolization (PVE) vs. right portal vein ligation (PVL) for induction of hypertrophy of the left lateral liver lobe before extended right hepatectomy. Thirty-four patients with primary or secondary liver tumors and estimated remnant functional liver parenchyma of less than 0.5% of body weight underwent either right PVE (transcutaneous, n= 10; transileocolic, n =7) or right PVL (n=17). Liver volume was assessed by CT scan before occlusion of the right portal vein and prior to resection. There were no deaths. The morbidity rate in each group was 5.8% (PVE, 1 abscess; PVL, 1 bile leak). The increase in liver volume was significantly higher after PVE compared with PVL (188±81 ml vs. 123±58 ml) (P= 0.012). Postoperative hospital stay was significantly shorter after PVE in comparison to PVL (4±2.9 days vs. 8.1±5.1 days;P<0.01). Curative liver resection was performed in 10 of 17 patients after PVE and 11 of 17 patients after PVL. PVE and PVL were found to be feasible and safe methods of increasing the remnant functional liver volume and achieving resectability for extended liver tumors. PVE results in a significantly more efficient increase in liver volume and a shorter hospital stay. Presented at the Forty-Third Annual Meeting of The Society for Surgery of the Alimentary Tract, San Francisco, California, May 19–22, 2002 (oral presentation).     

Auxiliary partial liver grafting in rats: effect of host hepatectomy on graft regeneration,and review of literature on surgical technique

Auxiliary partial liver transplantation (APLT) is beneficial for fulminant liver failure when there is potential for recovery of the diseased liver. However, the impact of host hepatectomy on regeneration of the grafted liver is unclear. In this study, we modified a previous rat model of auxiliary whole liver transplantation without portal vein reconstruction, and studied the effect of host hepatectomy on regeneration of the cut liver graft. Thirty percent of the liver was heterotopically transplanted, to connect the recipient's left renal artery and vein with the graft's aortic cuff of the hepatic artery and inferior vena cava, respectively, using a cuff technique; 30% of the recipient liver then was cut. The control group was left intact. The liver grafts were weighed preoperatively and 2 weeks postoperatively. This procedure prevented congestion of the graft liver and achieved a high success rate, even when performed by a surgeon who was relatively inexperienced with the technique. The weight of the grafted liver in the host hepatectomized group significantly increased (P < 0.05) compared with that of the control group. We developed an experimental model of APLT and reviewed the literature on rat heterotopic liver transplantation, and compared the surgical techniques.     

Cadaveric orthotopic auxiliary split liver transplantation and kidney transplantation: an alternative for type 1 primary hyperoxaluria

Liver transplantation (LTX) corrects the enzymatic defect responsible for type 1 primary hyperoxaluria (PH1). It has been advocated in combination with kidney transplantation (KTX) in patients with renal failure from PH1 because KTX alone can result in early graft loss. A 58-year-old male patient with PH1 on hemodialysis underwent resection of the left lateral segment of the liver followed by orthotopic auxiliary left lateral segment liver transplantation and kidney transplantation from a deceased donor. The serum oxalate dropped from 34.8 micromol/L before transplant to 3.6-8.3 in the first months posttransplant to <1 micromol/L (normal range 0.4-3.0). One year after posttransplant, the patient has an iothalamate glomerular filtration rate of 58 ml/min. Orthotopic auxiliary LTX is an alternative to whole LTX in PH1. By using a split deceased donor liver, it does not deprive the donor pool and protects the recipient from liver failure in case of graft loss.     

Plasma calcium oxalate supersaturation in children with primary hyperoxaluria and end-stage renal failure.

BACKGROUND: Children with primary hyperoxaluria type 1 (PH 1) are at great risk to develop systemic oxalosis in end-stage renal disease (ESRD), as endogenous oxalate production exceeds oxalate removal by dialytic therapy. As oxalate accumulates, calcium oxalate (CaOx) tissue deposition occurs. Children with other causes of ESRD, however, are not prone to CaOx deposition despite elevated plasma oxalate (POx) levels. METHODS: Our study objective was to examine the potential mechanisms for these observations. We measured POx, sulfate, citrate, and calculated CaOx saturation (betaCaOx) in 7 children with ESRD caused by PH 1 and in 33 children with non-PH-related ESRD. Maintenance hemodialysis (HD) was performed in 6 PH 1 and 22 non-PH patients: Pre- and post-HD levels were analyzed at this point and were repeated twice within 12 months in 5 PH 1 and 14 non-PH patients. Samples were obtained only once in 12 patients (one PH 1) on peritoneal dialysis (PD). After liver-kidney or kidney transplantation, plasma levels were measured repetitively. RESULTS: The mean POx was higher in PH 1 (125.7 +/- 17.9 micromol/liter) than in non-PH patients (44.2 +/- 3.3 micromol/liter, P < 10(-4)). All other determined anions did not differ between the two groups. betaCaOx was higher in PH 1 (4.71 +/- 0.69 relative units) compared with non-PH children (1.56 +/- 0.12 units, P < 10(-4)). POx and betaCaOx were correlated in both the PH 1 (r = 0.98, P < 2 x 10(-4)) and the non-PH group (r = 0.98, P < 10(-4)). POx and betaCaOx remained stable over time in the non-PH children, whereas an insignificant decline was observed in PH 1 patients after six months of more aggressive dialysis. betaCaOx was supersaturated (more than 1) in all PH 1 and in 25 out of 33 non-PH patients. Post-HD betaCaOx remained more than 1 in all PH 1, but in only 2 out of 22 non-PH patients. In non-PH children, POx and betaCaOx decreased to normal within three weeks after successful kidney transplantation, whereas the levels still remained elevated seven months after combined liver-kidney transplantation in two PH 1 patients. CONCLUSION: Systemic oxalosis in PH 1 children with ESRD is due to higher POx and betaCaOx levels. As betaCaOx remained supersaturated in PH 1 even after aggressive HD, oxalate accumulation increases, and CaOx tissue deposition occurs. Therefore, sufficient reduction of POx and betaCaOx is crucial in PH 1 and might only be achieved by early, preemptive, combined liver-kidney transplantation or liver transplantation alone.     

Portal blood flow and liver regeneration in auxiliary partial orthotopic liver transplantation in a canine model

Functional competition has been shown to lead to a detrimental outcome in auxiliary liver transplantation. We evaluated the interaction in auxiliary partial orthotopic liver transplantation between the native liver and the graft in terms of portal flow and regeneration. The need for diversion of the portal flow to the graft was also assessed. Reduced-size liver grafts were transplanted orthotopically after partial hepatectomy in beagles. There were two groups: the preserved group, where portal inflow to the native liver was preserved, and the ligated group, where it was interrupted. Portal flow was measured serially and liver regeneration was evaluated on postoperative day 5. Functional competition was not observed in the preserved group. On the other hand, ligation of the native liver portal vein had no obviously detrimental effects on the remnant native liver. This leads to the conclusion that the portal vein to the native liver can be safely ligated to prevent functional competition.