Authors: Huang Mengxiu, Wang Jing, Lv Shaocheng, Jiang Tao, Pan Fei, He Qiang, Lang Ren
Source: Chinese Journal of Hepatobiliary Surgery, 2021, 27(12)
summary
Hypersplenism (hypersplenism) is a common spleen disorder that usually refers to a clinical syndrome of increased spleen volume and/or cytopenia of various causes. Hypersplenism is most commonly secondary to cirrhosis portal hypertension. Liver transplantation can effectively relieve hypersplenism in patients with cirrhosis, but some patients have persistent or recurrent hypersplenism after liver transplantation. Other treatment modalities for postoperative refractory hypersplenism include splenectomy, partial splenic artery embolization, etc. This article reviews the research progress of hypersplenism after liver transplantation with liver cirrhosis and hypersplenism.
Hypersplenism (hypersplenism) is the most common spleen disease, usually refers to the clinical syndrome of increased spleen volume and cytopenia caused by various reasons, and its diagnosis is determined based on: (1) when blood cells are reduced, the corresponding precursor cells are active or normal in bone marrow proliferation; (2) Symptoms of cytopenia after splenectomy are relieved or return to normal[1]. Hypersplenism can be divided into primary hypersplenism, secondary hypersplenism and occult hypersplenism according to the etiology, of which hypersplenism caused by portal hypertension in cirrhosis is the most common secondary hypersplenism. Cirrhosis, portal hypertension is a major driver of hypersplenism, in which blood flow is obstructed, the spleen is passively engorged and enlarged, and blood cells trapped in the spleen are engulfed by active macrophages, resulting in peripheral cytopenia [2]. Cytopenias, especially thrombocytopenia, due to hypersplenism, affect perioperative management to varying degrees, and invasive testing or treatment of patients with severe thrombocytopenia (platelet count < 50,000/mm3) significantly increases bleeding risk [3]. Intractable hypersplenism after liver transplantation may cause thrombocytopenia, refractory ascites, and gastrointestinal bleeding, so preoperative management of hypersplenism should be important [4]. Liver transplantation is the most ideal means for the treatment of hypersplenism secondary to portal hypertension in cirrhosis, most patients can get significant relief of hypersplenism, but some patients will have refractory hypersplenism or hypersplenism recurrence after surgery, the pathogenesis of the latter two is not fully understood, liver transplantation or postoperative splenectomy, partial splenic artery embolization and other treatments are also controversial. This article reviews the research progress of hypersplenism after liver transplantation with cirrhosis.
First, the current situation of hypersplenism
Cirrhosis is liver damage caused by one or more factors or primary diseases, and the most common cause in mainland China is viral hepatitis, especially viral hepatitis B (hepatitis B). Patients with end-stage cirrhosis usually have secondary hypersplenism due to portal hypertension, and the incidence is 15%~70% [5]. Spleen-derived immune cells and cytokines enter the liver through the portal vein bloodstream, causing liver damage, liver fibrosis and inhibition of liver regeneration, and the cirrhosis of the liver enters the systemic circulation by releasing chemokines and other pathways, causing the activation and migration of splenocytes, further aggravating the damage of the liver. The hepato-splenic axis may be an important target for future nonsurgical treatment of cirrhosis and hypersplenism [6].
The pathogenesis of splenomegaly has been studied in more detail, and obstruction of portal blood flow leads to passive congestion of the spleen, showing congestive enlargement, but long-term congestion will further proliferate the spleen [7]. The mechanism of cytopenia is widely discussed, but in general, it mainly includes the following three.
(1) Spleen obstruction study abroad said: after the formation of portal hypertension, spleen congestion hematoma enlarged, the volume can be increased by 8~10 times [8], the number of blood cells in the spleen blood circulation is significantly increased, can be increased to the normal range of 5.5~20.0 times [9], so more blood cells are blocked in the spleen, glucose in the spleen is overconsumed, pH value is reduced, resulting in blood cells are more likely to be destroyed by macrophages. Other studies have shown that in macrophages of patients with hypersplenism, lipopolysaccharide-toll-like receptor-nuclear factor κB pathway is regulated, microRNA615-3P expression is increased, macrophage activation is stimulated, and blood cells are phagocytosed and destroyed also increase [10].
(2) Humoral inhibition: It is reported that there are at least 30 humoral factors associated with cytopenia in patients with hypersplenism, on the one hand, reducing the production of blood cells, such as erythropoietin, thrombopoietin and other synthetic reductions, causing cytopenia [11]; On the other hand, cytokines such as macrophage colony-stimulating factor, transforming growth factor-β, interferon-γ, and interleukin-10 accelerate cytokines by promoting the transformation of monocytes into macrophages [12].
(3) Autoimmune theory: The spleen is the largest immune organ in the human body, and anti-blood cell antibodies may be increased when the splenomegaly occurs. Platelet-associated immunoglobulins (PAIgs) mediate the destruction of platelets by macrophage phagocytosis by binding to platelet glycoproteins. Aref et al. [13] found that the spleen is the main site of PAIgs production, and there is a significant negative correlation between platelet count and PAIgs in patients with hepatitis C cirrhosis, and PAIgs decreased significantly after splenectomy, and platelet count recovered.
Immune system disorders in patients with cirrhosis can also lead to loss of autoantigen tolerance or platelet antigenicity, with antiplatelet glycoprotein IIb/IIIa antibodies reported in approximately 20 percent of patients and antiplatelet glycoprotein Ia/IIa antibodies in approximately 13 percent of patients [14]. In addition to this, antithrombopoietin receptor antibodies may reduce platelet production by reducing thrombopoietin activity [15].
In conclusion, portal hypertension caused by cirrhosis is the most important pathogenesis of hypersplenism, but different types of primary diseases may lead to different degrees of cytopenia, and may also affect the outcome of hypersplenism after liver transplantation, which needs to be further studied.
Second, the outcome of hypersplenism after liver transplantation
1. Hypersplenism relief:
Liver transplantation can fundamentally improve liver function in patients and is the most ideal treatment for secondary hypersplenism, and liver transplantation can effectively alleviate secondary hypersplenism in most patients with cirrhosis [16]. Studies have found that patients with a significant increase in platelet count and spleen volume after liver transplantation have been found to be directly related to platelet recovery [17]. Egami et al. [18] followed up 55 children with broodstock liver transplantation and found that within 2 years after liver transplantation, the spleen volume continued to decrease and the platelet count increased.
Some scholars measured the volume of the spleen before and after liver transplantation and the platelets at the corresponding time points by post-imaging technology, and concluded that the recovery rate of hypersplenism within 10 months after liver transplantation was (78.79±2.29%), and the platelet count of postoperative patients increased significantly compared with preoperative, peaked 2 weeks after surgery, then began to decline and stabilized after 2 months, and the spleen volume decreased significantly within 1 month and tended to be stable [19]. This is roughly the same as the trend of platelet and spleen volume studies obtained by other scholars. More studies at home and abroad have shown that liver transplantation can indeed alleviate secondary hypersplenism in patients with cirrhosis, but clinically, the mechanism of refractory hypersplenism and recurrence of hypersplenism in a small number of patients after surgery is not clear.
2. Recalcitrant hypersplenism and recurrence of hypersplenism:
Although liver transplantation can significantly improve preoperative hypersplenism, some patients still develop refractory hypersplenism or recurrence of hypersplenism after surgery. Scholars observed 100 liver transplant patients and found that 57 of them had persistent thrombocytopenia after surgery [20]. Coelho et al. [21] found that 1 year after liver transplantation, about 16.9% of patients still had hypersplenism, and 4.2% of patients experienced thrombocytopenia recurrence within 1 year. In studies, approximately (17.5±2.31) percent of patients experienced recurrence of hypersplenism [19].
Some scholars believe that during liver transplantation, the continuous activation and consumption of peripheral platelets and the reduction of thrombopoietin synthesis after transplantation will lead to a sharp decrease in platelets after surgery, and platelet levels cannot return to normal levels over time [20]. It is worth noting that the choice of immunosuppressants after liver transplantation also affects the recovery of platelets, for example, mycophenolate mofetils have a certain myelosuppressive effect, resulting in a decrease in platelet count, which may cover up the recovery of hypersplenism, platelets continue to not rise after stopping the drug, only then consider refractory hypersplenism.
In addition, the outcome of postoperative hypersplenism is related to whether the transplanted liver function is good. In a study, 48 children who underwent liver transplantation were divided into functional and non-functional liver transplants, and hypersplenism remained in the non-functional group [21]. Spleen size shrinks shortly after liver transplantation, but splenomegaly due to tissue hyperplasia is often irreversible, and the magnitude of postoperative spleen size change depends on the proportion of tissue hyperplasia to splenomegaly [22]. Therefore, it is also possible that the volume of the spleen after liver transplantation first decreases and then rises. Assessing the severity and prognosis of hypersplenism requires consideration of a variety of factors and reasonable quantitative indicators.
3. Treatment of hypersplenism after liver transplantation
1. Splenectomy:
Splenectomy can correct refractory hypersplenism after transplantation and gradually normalize blood cell counts [23]. Some patients have been shown to have unresolved hypersplenism after transplantation and a series of symptoms of hypersplenism, including thrombocytopenia, abdominal bleeding, and refractory peritoneal effusion, which can be effectively relieved after splenectomy [24]. Splenectomy not only reduces portal pressure and relieves hypersplenism, but also improves liver function [25], which may be associated with the disruption of the hepato-spleen axis and the reduction of spleen-derived cytokines [26].
Some scholars believe that refractory hypersplenism after liver transplantation will not only lead to a large amount of arterial blood into the spleen, increase portal vein pressure, small liver syndrome, but also may occur splenic artery stealage syndrome, reducing liver perfusion [25]. In a study of 113 liver transplant patients, the absence of splenectomy was an independent risk factor for the development of small liver syndrome after liver transplantation [27]. In another retrospective analysis of 84 patients who underwent liver transplantation with advanced cirrhosis and hypersplenomegaly, 41 of whom underwent partial splenectomy at the same time had significantly lower postoperative hypersplenism than those who received liver transplantation alone, but with a relative increase in operative time and intraoperative bleeding [28].
Although some scholars believe that splenectomy should be performed when persistent thrombocytopenia occurs after liver transplantation, the spleen, as the largest immune organ in the human body, will inevitably affect the body's immune function after resection, increase the incidence and mortality rate of perioperative complications, and may also occur postsplenectomy dangerous infections (OPSIs) [29]. The incidence of OPSIs is approximately 4 percent and the case fatality rate is reported to be 2 percent, primarily due to capsular bacteria (eg, pneumococcus) [30,31]. Therefore, it is important to strictly grasp the indications for incision of the spleen after liver transplantation.
2. Splenic artery ligation and partial splenic artery embolism:
Splenic artery ligation can increase blood counts in the short term, but it is not effective in the long term because the collateral circulation of the splenic will gradually establish and open up to increase blood flow to the spleen for a short period of time after splenic artery ligation [32]. Splenic artery ligation has not been shown to promote platelet level recovery after liver transplantation [33]. Thus, splenic artery ligation is not commonly used and is rarely reported for the treatment of refractory hypersplenism after liver transplantation, but if weak pulsations are found after hepatic artery anastomosis during liver transplantation, splenic artery ligation may be considered to prevent postoperative splenic artery stealing syndrome [34].
Partial splenectomy is also known as "functional splenectomy" because it can reduce the trauma of the patient while preserving part of the spleen, which can protect the patient's immune function [35,36]. Partial splenic artery embolization is less invasive than splenectomy, but the efficacy is not so certain, and its effect on improving hypersplenism is related to the area of embolization of the spleen, so patients with splenomegaly and hypersplenism may face multiple and repeated interventional embolization treatment, increasing the risk of postoperative complications. The most common adverse reaction of some splenic artery ligation is post-embolic syndrome, which usually includes abdominal pain, fever, gastrointestinal symptoms, etc., and it has been reported in the literature that 55%~100% of patients will have post-embolic syndrome [37].
3. Drug treatment:
For hypersplenism, recombinant human granulocyte colony-stimulating factor, a polypeptide chain of cell growth factor, is commonly used to specifically regulate the proliferation and differentiation of granular progenitor cells and enhance the function of mature neutrophils. Studies have found that recombinant human granulocyte colony-stimulating factor helps to increase the level of leukocytes after transplantation, especially to promote the recovery of neutrophils, reduce the risk of postoperative infection, and enhance the function of neutrophil phagocytosis and bactericidal, thereby reducing the risk of postoperative infection [38]. Other drugs (eg, ricordrine, recombinant human thrombopoietin) are also used clinically, but they cannot reverse hypersplenism.
IV. Summary
Hypersplenism is a common complication of portal hypertension in cirrhosis, and liver transplantation can relieve hypersplenism in most patients, and a small number of patients will have refractory hypersplenism or recurrence of hypersplenism. Usually when studying the recovery of hypersplenism, scholars generally select hematological indicators (white blood cells, platelets) and spleen-related indicators (spleen thickness, spleen volume, etc.) as tools to measure the degree of hypersplenism, but each indicator cannot fully represent the severity of hypersplenism. Splenic volume is not always positively correlated with the degree of hypersplenism, and cytopenias may also be present in patients with normal spleen volume [39].
At present, there is no common grading standard for hypersplenism at home and abroad, nor a mathematical model for predicting the outcome of hypersplenism after liver transplantation. There is an urgent need for a reasonable and strict spleen function grading standard and a multicenter, large-sample mathematical model, which can assess the severity and prognosis of hypersplenism on the one hand, and give preventive treatment in advance for patients who may have refractory hypersplenism after liver transplantation. Whether further treatment for refractory hypersplenism after liver transplantation requires not only an assessment of the degree of hypersplenism, but also a balance between benefits and harms. These need to be studied further.
bibliography
[1]
JIANG An,LI Zongfang. Common causes and treatment strategies of hypersplenism[J]. Chinese Journal of Liver Surgery, 2018, 7(2):97-99. DOI: 10.3877/cma.j.issn.2095-3232.2018.02.003.
[2]
LiL, DuanM, ChenW, et al. The spleen in liver cirrhosis: revisiting an old enemy with novel targets[J]. J Transl Med, 2017, 15(1)：111. DOI: 10.1186/s12967-017-1214-8.
[3]
AfdhalN, McHutchisonJ, BrownR, et al. Thrombocytopenia associated with chronic liver disease[J]. J Hepatol, 2008, 48(6)：1000-1007. DOI: 10.1016/j.jhep.2008.03.009.
[4]
ElfekiMA, Paz-FumagalliR, TiemeierAM, et al. Choice of partial splenic embolization technique in liver transplant recipients correlates with risk of infectious complications[J]. Transplant Proc, 2015, 47(10)：2932-2938. DOI: 10.1016/j.transproceed.2015.10.026.
[5]
IshigamiM, IshizuY, OnishiY, et al. Long-term dynamics of hematological data and spleen volume in cirrhotic patients after liver transplantation-various dynamics depending on etiology[J]. Springerplus, 2013, 2：374. DOI: 10.1186/2193-1801-2-374.
[6]
LIANG Qingshan, XIE Jiangang, YIN Jikai, et al. Research progress on the effect of hypersplenism on liver fibrosis[J]. Armed Police Medicine, 2020, 31(12):1073-1076. DOI: 10.3969/j.issn.1004-3594.2020.12.017.
[7]
McKenzieCV, ColonneCK, YeoJH, et al. Splenomegaly: pathophysiological bases and therapeutic options[J]. Int J Biochem Cell Biol, 2018, 94：40-43. DOI: 10.1016/j.biocel.2017.11.011.
[8]
ShahSH, HayesPC, AllanPL, et al. Measurement of spleen size and its relation to hypersplenism and portal hemodynamics in portal hypertension due to hepatic cirrhosis[J]. Am J Gastroenterol, 1996, 91(12)：2580-2583.
[9]
LvY, LauWY, LiY, et al. Hypersplenism: history and current status[J]. Exp Ther Med, 2016, 12(4)：2377-2382. DOI: 10.3892/etm.2016.3683.
[10]
RenS, ZhangS, LiM, et al. NF-κB p65 and c-Rel subunits promote phagocytosis and cytokine secretion by splenic macrophages in cirrhotic patients with hypersplenism[J]. Int J Biochem Cell Biol, 2013, 45(2)：335-343. DOI: 10.1016/j.biocel.2012.11.012.
[11]
Peck-RadosavljevicM. Thrombocytopenia in chronic liver disease[J]. Liver Int, 2017, 37(6)：778-793. DOI: 10.1111/liv.13317.
[12]
PanasiukA, ProkopowiczD, ZakJ, et al. Reticulated platelets as a marker of megakaryopoiesis in liver cirrhosis; relation to thrombopoietin and hepatocyte growth factor serum concentration[J]. Hepatogastroenterology, 2004, 51(58)：1124-1128.
[13]
ArefS, IbrahemL, El MenshawyN, et al. Effect of splenectomy on platelets associated antibodies in hepatitis C patients with thrombocytopenia[J]. Hematology, 2012, 17(2)：118-121. DOI: 10.1179/102453312X13221316477705.
[14]
PanasiukA, ProkopowiczD. Platelet autoantibodies in liver cirrhosis and thrombocytopenia[J]. Rocz Akad Med Bialymst, 2000, 45：54-62.
[15]
IchimataS, KobayashiM, HondaK, et al. Acquired amegakaryocytic thrombocytopenia previously diagnosed as idiopathic thrombocytopenic purpura in a patient with hepatitis C virus infection[J]. World J Gastroenterol, 2017, 23(35)：6540-6545. DOI: 10.3748/wjg.v23.i35.6540.
[16]
CoelhoJC, BalbinotP, NitscheR, et al. Change in platelet count in patients with hypersplenism subjected to liver transplantation[J]. Arq Gastroenterol, 2011, 48(3)：175-178. DOI: 10.1590/s0004-28032011000300004.
[17]
ChikamoriF, NishidaS, SelvaggiG, et al. Effect of liver transplantation on spleen size, collateral veins, and platelet counts[J]. World J Surg, 2010, 34(2)：320-326. DOI: 10.1007/s00268-009-0314-x.
[18]
EgamiS, SugawaraY, MizutaK, et al. Effect of pediatric living-donor liver transplantation on splenomegaly[J]. Transplantation, 2002, 74(11)：1639-1642. DOI: 10.1097/00007890-200212150-00026.
[19]
HE Jian, GUO Qingjun, XIE Yan, et al. Spleen volume measurement by imaging post-processing technology to evaluate the effect of orthotopic liver transplantation in alleviating hypersplenism[J]. Chinese Journal of Organ Transplantation, 2019, 40(2):107-110. DOI: 10.3760/cma.j.issn.0254-1785.2019.02.010.
[20]
StancaCM, FielMI, AledortL, et al. Factors associated with persistent thrombocytopenia after liver transplantation[J]. Transplant Proc, 2010, 42(5)：1769-1773. DOI: 10.1016/j.transproceed.2010.02.075.
[21]
CoelhoJC, BalbinotP, NitscheR, et al. Change in platelet count in patients with hypersplenism subjected to liver transplantation[J]. Arq Gastroenterol, 2011, 48(3)：175-178. DOI: 10.1590/s0004-28032011000300004.
[22]
NascimbeneA, IannaconeM, BrandoB, et al. Acute thrombocytopenia after liver transplant: role of platelet activation, thrombopoietin deficiency and response to high dose intravenous IgG treatment[J]. J Hepatol, 2007, 47(5)：651-657. DOI: 10.1016/j.jhep.2007.06.012.
[23]
TutarNU, IsiklarI, UluEM, et al. Spleen size changes in pediatric liver transplant recipients with functioning grafts[J]. Transplant Proc, 2007, 39(10)：3199-3201. DOI: 10.1016/j.transproceed.2007.08.105.
[24]
JIANG Bin, SONG Shibing, XIU Dianrong, et al. Recovery of hypersplenism after orthotopic liver transplantation[J]. Chinese Journal of General Surgery, 2005, 14(2):122-124. DOI: 10.3969/j.issn.1005-6947.2005.02.012.
[25]
ShimadaM, IjichiH, YonemuraY, et al. The impact of splenectomy or splenic artery ligation on the outcome of a living donor adult liver transplantation using a left lobe graft[J]. Hepatogastroenterology, 2004, 51(57)：625-629.
[26]
KimH, SuhKS, JeonYM, et al. Partial splenic artery embolization for thrombocytopenia and uncontrolled massive ascites after liver transplantation[J]. Transplant Proc, 2012, 44(3)：755-756. DOI: 10.1016/j.transproceed.2012.01.066.
[27]
IkegamiT, ShimadaM, ImuraS. Recent role of splenectomy in chronic hepatic disorders[J]. Hepatol Res, 2008, 38(12)：1159-1171. DOI: 10.1111/j.1872-034X.2008.00384.x.
[28]
AkahoshiT, HashizumeM, TanoueK, et al. Role of the spleen in liver fibrosis in rats may be mediated by transforming growth factor beta-1[J]. J Gastroenterol Hepatol, 2002, 17(1)：59-65. DOI: 10.1046/j.1440-1746.2002.02667.x.
[29]
IkegamiT, ShimadaM, ImuraS. Recent role of splenectomy in chronic hepatic disorders[J]. Hepatol Res, 2008, 38(12)：1159-1171. DOI: 10.1111/j.1872-034X.2008.00384.x.
[30]
YoshizumiT, TaketomiA, SoejimaY, et al. The beneficial role of simultaneous splenectomy in living donor liver transplantation in patients with small-for-size graft[J]. Transpl Int, 2008, 21(9)：833-842. DOI: 10.1111/j.1432-2277.2008.00678.x.
[31]
JiangWT, YangJ, XieY, et al. Simultaneous partial splenectomy during liver transplantation for advanced cirrhosis patients combined with severe splenomegaly and hypersplenism[J]. World J Gastroenterol, 2021, 27(7)：654-665. DOI: 10.3748/wjg.v27.i7.654.
[32]
AltacaG, SciglianoE, GuySR, et al. Persistent hypersplenism early after liver transplant: the role of splenectomy[J]. Transplantation, 1997, 64(10)：1481-1483. DOI: 10.1097/00007890-199711270-00020.
[33]
ZHOU Guangpeng,ZHU Zhijun,WEI Lin. Research progress in the treatment of secondary hypersplenism in patients with portal hypertension in liver cirrhosis[J]. Chinese Journal of Hepatobiliary Surgery, 2019, 25(12):952-956. DOI: 10.3760/cma.j.issn.1007-8118.2019.12.018.
[34]
XuZJ, ZhengLQ, PanXN. Partial embolization as re-treatment of hypersplenism after unsuccessful splenic artery ligation[J]. World J Gastroenterol, 2015, 21(4)：1365-1370. DOI: 10.3748/wjg.v21.i4.1365.
[35]
TroisiR, CammuG, MiliternoG, et al. Modulation of portal graft inflow: a necessity in adult living-donor liver transplantation？[J]. Ann Surg, 2003, 237(3)：429-436. DOI: 10.1097/01.SLA.0000055277.78876.B7.
[36]
XIONG Chaojie, YU Zhewei, HU Yangke, et al. Effects of splenic artery ligation on liver function recovery and hypersplenism during liver transplantation[J]. Chinese Journal of General Surgery, 2020, 35(7):516-520. DOI: 10.3760/cma.j.cn113855-20190808-00457.
[37]
JinGY, LvCZ, TangD, et al. Effect of partial splenic embolization on the immune function of cirrhosis patients with hypersplenism[J]. Asian Pac J Trop Med, 2016, 9(7)：702-706. DOI: 10.1016/j.apjtm.2016.05.005.
[38]
LiLY, ChenHZ, BaoYC, et al. Successful treatment of hypersplenism in Wilson's disease by partial splenic embolization[J]. J Invest Surg, 2018, 31(2)：75-81. DOI: 10.1080/08941939.2016.1278058.
[39]
AticiAE, BostanciEB, OzerI, et al. Use of granulocyte colony-stimulating factor for neutropenia after orthotopic liver transplantation: report of two cases[J]. Transplant Proc, 2011, 43(3)：909-911. DOI: 10.1016/j.transproceed.2010.11.019.
[40]
BoyerTD, HabibS. Big spleens and hypersplenism: fix it or forget it？[J]. Liver Int, 2015, 35(5)：1492-1498. DOI: 10.1111/liv.12702.
Contact information for platform cooperation
Tel: 010-51322382
Email: [email protected]
Welcome to pay attention to the WeChat matrix of general space
General space subscription account
General Space CLUB service number
General space video number
General space assistant