Most patients with cirrhosis have a combination of hypersplenism, which is manifested by splenomegaly and a decrease in one or more blood cells (mainly platelets and white blood cells). Traditional treatment measures have major limitations and/or complications. The authors have pioneered a new minimally invasive measure of splenic radiofrequency ablation for the treatment of hypersplenism internationally. This article summarizes the authors’ nearly 10 years of experimental and clinical practice experience from multiple perspectives, including the working principle, treatment access, safety, clinical efficacy, and a combined combined multi-modality treatment model of splenic radiofrequency ablation to improve safety and efficacy. This paper can provide valuable reference for other units to carry out this new technology.
Hypersplenism (hypersplenism) is one of the common clinical syndromes in patients with cirrhosis, manifested by splenomegaly and reduction of one or several blood cells (mainly platelets and white blood cells), with an incidence of 50-64% [1]. The development of cirrhotic hypersplenism is the result of multiple factors [2]: (i) hepatocellular insufficiency, which is currently considered to be the source of thrombocytopenia; (ii) excessive retention and accelerated destruction of blood cells (platelet-based) by the enlarged spleen; (iii) production of platelet antibodies in the body; and (iv) inhibition of bone marrow hematopoiesis by hepatitis B virus (HBV) or hepatitis C virus (HCV).
When patients with severe hypersplenism (leukocytes <2.0×109/L and/or platelets <30-50×109/L) have coexisting hepatocellular carcinoma or gastrointestinal bleeding, it will greatly interfere with clinicians' rational choice of therapeutic measures such as tumor resection surgery or radiotherapy/chemotherapy, endoscopic treatment, or even HBV/HCV antiviral therapy, thus causing delay in the disease; in addition, unreasonable treatment choices will increase patients' complications, mortality and social medical burden. Therefore, it is necessary to explore multi-strategy hypersplenism treatment approaches that meet the needs of different conditions. The following is a description of the current treatment options for hypersplenism [2,3], especially our experience with radiofrequency ablation for hypersplenism in the past 10 years.
1. Traditional hypersplenism treatment methods
1.1 Internal treatment
Internal treatment is mainly for severe hypersplenism with infection and bleeding tendency or preoperative preparation. Granulocyte (macrophage) colony-stimulating factor (GM-CSF/G-CSF) can stimulate granulocyte production and effectively raise peripheral blood leukocyte levels for the purpose of correcting leukopenia. Platelet transfusion is the most effective treatment for thrombocytopenia; recent molecular drugs (e.g., recombinant human IL-11, recombinant human TPO) that stimulate megakaryocyte development and platelet production are effective in raising peripheral blood platelet levels; TPO (thrombopoietin) is the main factor that regulates platelet production and is almost always synthesized by the liver, therefore Liver insufficiency and thrombocytopenia are closely related. However, the efficacy of medical treatment for hypersplenism is not durable [2,3].
1.2 Splenectomy
The spleen is the largest peripheral lymphoid organ in the body and plays a key role in immune response and immunomodulation, and it is an important immune barrier for the prevention of intestinal-derived infections associated with cirrhosis. In addition, the spleen is also a blood filter; blood storage in the enlarged spleen serves as an “autologous blood bank” for the body’s regulation during gastrointestinal hemorrhage, gaining time for resuscitation and slowing down ischemia-reperfusion damage to vital organs. “OPSI is more common in children <6 years of age, with a mortality rate of 35-60%.
Splenectomy can improve hypersplenism to a great extent. However, splenectomy is highly invasive, with complication rates of 15-61% and operative mortality rates that can be as high as 5-13% [2-5]. Complications of splenectomy include abdominal bleeding, pancreatic tail injury and pancreatic leak, peritoneal effusion, pleural effusion, pulmonary atelectasis, and liver failure. In particular, the elevated platelets and hypercoagulable state of the body that occurs after splenectomy predispose to secondary portal vein thrombosis (PVT) and deep vein thrombosis. The incidence of symptomatic PVT after splenectomy is 2-8% [5,6], and the mortality rate of acute PVT is 40-50% [3,5,6], and portal vein occlusion or vessel wall mechanization after PVT can make future liver transplantation more difficult or unsuccessful. Although laparoscopic splenectomy has the advantage of being minimally invasive, factors such as intraoperative CO2 pneumoperitoneum and slow visceral blood flow can significantly increase the incidence of postoperative PVT by up to 55% [6]. Therefore, the latest treatment paradigm for cirrhosis recommends avoiding splenectomy as much as possible [2,3].
1.3 Partial splenic embolization
Total splenic artery embolization was first performed by Madison in 1973, but all postoperative procedures resulted in splenic abscesses and a very high mortality rate [2]. PSE has been used to treat hypersplenism successfully until 1979, when Spigos et al. applied partial splenic embolization (PSE), which reduces the retention and destruction of blood cells in the spleen by infarcting most of the splenic parenchyma; the splenic venous blood flow decreases sharply after PSE, correspondingly reducing portal vein pressure and the risk of variceal rupture and bleeding [2,7]; liver function and TPO synthesis capacity are improved after PSE [7]. The embolization of 60-70% of the spleen volume is usually required to relieve hypersplenism, and the effect is not obvious when it is <50%; however, if the volume of one embolization is too large, the infarcted spleen parenchyma will liquefy and infect easily secondary to splenic abscess due to untimely absorption, and increase the incidence of liver failure; therefore, in recent years, it has been advocated that embolization of giant spleen should be performed in stages, and the volume of a single embolization should not exceed 50% [7,8,10].
Overall, the complications of PSE remain high, with common complications including fever, abdominal pain, and vomiting; serious complications include pleural effusion, ascites, liver failure, splenic abscess, and PVT; the incidence of PVT is 15-50% [10]; and the overall mortality rate of PSE can be as high as 5.9-7.7% [7-10]. et al [9] reported complications of PSE as abdominal pain (82.4%, 14/17), pleural effusion (17.6%), ascites combined with abdominal infection (11.8%), and splenic abscess (5.9%). Contraindications to PSE include: (i) liver failure; (ii) severe jaundice; (iii) intractable ascites with infection; and (iv) advanced hepatocellular carcinoma in combination.
1.4 Effect of shunt surgery or liver transplantation on hypersplenism
In Western countries, the surgical options for patients with esophagogastric variceal bleeding in cirrhosis with good liver function are mostly distal splenorenal shunt or transjugular intrahepatic portosystemic shunt, while liver transplantation is performed for patients with poor liver function at the end stage. The shunt reduces portal vein pressure and prevents re-rupture of variceal bleeding, but the improvement of hypersplenism is relatively minor [2,3].
Successful liver transplantation completely corrects the hematologic abnormalities of cirrhotic hypersplenism, but the enlarged spleen does not return to normal size 2-4 years after transplantation. This further confirms that the root cause of hypersplenism is cirrhosis.TPO serum levels increase immediately after liver transplantation, peaking at 5-6 d postoperatively. The platelet count starts to rise around 6 d after liver transplantation and peaks at 14 d. TPO levels correlate with pre-liver transplantation platelet counts, and only thrombocytopenic patients show elevated TPO levels after transplantation. Therefore, whether the platelet count is elevated after liver transplantation may also reflect graft function [11].
2. radiofrequency ablation of the spleen
Radiofrequency ablation (RFA) is the use of radiofrequency current (450-500 KHz) to cause ion oscillation around the electrode and frictional heat generation (>50-110°C) to cause local tissue coagulation necrosis to destroy the lesion.RFA is mainly used to treat solid tumors such as liver cancer. We were the first to carry out experimental and clinical studies on RFA for hypersplenism in 2002 internationally, and proved that RFA is relatively safe and effective in treating cirrhotic hypersplenism, significantly relieving hypersplenism, improving liver function, promoting liver regeneration and delaying the process of cirrhosis, and also reducing the risk of esophagogastric variceal bleeding, with better near- and mid-term efficacy [12-16]; meanwhile, because part of the splenic parenchyma is preserved, the immune function associated with the spleen is not affected.
2.1 Rationale of radiofrequency ablation for hypersplenism The effect of radiofrequency thermal energy on the vascular-rich spleen consists of three cascading zones (Figure 1) [12,13]: 1) the central coagulative necrotic zone (different from the “wet necrosis” after PSE, which is not absorbed in time and prone to abscess); 2) the central coagulative necrotic zone (different from the “wet necrosis” after PSE, which is not absorbed in time and prone to abscess); and 3) the central coagulative zone. (ii) a larger surrounding area of thrombotic infarction; and (iii) extensive thermal damage to the splenic sinus and diffuse microthrombosis due to thermal deposition, which can involve the entire remnant spleen and is only seen as a microscopic histological change, with the remnant spleen appearing “normal” on CT and other imaging studies (Figure 2). After resorption of the thrombotic infarct area, only fibrous coagulation necrosis remains; the “normal” remnant spleen tissue undergoes “oligovascular” remodeling: normal splenic sinuses and microvascular structures are occluded, resorbed, and disappear due to thermal injury, and the remnant spleen parenchyma is extensively fibrotic, with a small number of new capillaries. The parenchyma of the residual spleen is extensively fibrotic, with a small number of new capillaries and a significant reduction in size (solid change of the residual spleen) (Figure 3). The extent of splenic parenchymal destruction by RFA is determined by the amount of heat deposited in the spleen. Unlike liver RF ablation, because the splenic parenchyma is rich in blood, it is easy to expand the ablation volume by heat transfer, i.e., the maximum diameter of splenic destruction by single ablation with a 5 cm diameter multi-electrode RF needle can be more than 10 cm, which far exceeds the diameter of liver RFA of about 5 cm. However, because of the rich blood supply and rapid blood flow in the splenic parenchyma, heat may be carried away by the rapid blood flow (heat-sinking effect), which may weaken the effect of splenic ablation. Therefore, from the perspective of clinical operation, it is necessary to control the splenic blood flow, which can expand the ablation range and improve the efficacy, as well as increase the safety of the operation and reduce the risk of bleeding. In addition, from the treatment principle and clinical efficacy, it can be found that splenic RFA is safer and more effective than PSE in reducing the size of the spleen [12-16].
2.2 RF ablation of the spleen with access to hypersplenism by RFA should choose a RF ablation device with higher power and larger ablation radius. Currently, we routinely use the RITA 1500X RF generator of AngioDynamics, USA, with an output power of 250 W and a multi-electrode RF ablation needle (StarBurstTM XL) with a maximum deployment diameter of 5-7 cm.
Access to the spleen for RFA can be chosen from open subabdominal, ultrasound or CT-guided percutaneous splenic puncture, and laparoscopic approaches. The advantages of laparoscopic operation are that it allows immediate intraoperative observation of active bleeding in the operating needle tract after ablation, and appropriate isolation of the peritoneal organs around the spleen and even cold water irrigation can be done to avoid operation and heat conduction related In addition, laparoscopic operations can be combined with liver biopsy, cholecystectomy, radiofrequency ablation of liver cancer, and other operations. In a few cases, we also choose ultrasound-guided percutaneous splenic puncture ablation, mainly for some patients with a history of abdominal surgery or giant spleen.
For our splenic RFA, we routinely choose to operate under general anesthesia, mainly considering the patient’s tolerability. In China, Wu Yuxuan et al [17] also tried CT-guided operation under local anesthesia, and the scope of ablation was limited due to consideration of patient tolerance and operation time.
2.3 Safety of RFA for hypersplenism The spleen is rich in blood sinusoids, and invasive operations targeting the spleen have a high risk of bleeding complications. Patients with hypersplenism in cirrhosis have some degree of coagulation abnormalities, and uncontrollable bleeding leading to death after splenic RF ablation has been reported [18]. From our experience in clinical practice the risk of bleeding can be avoided with reasonable case selection and correct operation. In our initial 40 RF ablation cases, there were no serious complications such as bleeding, hyperthermia, pancreatitis, splenic abscess, liver failure or mortality after RFA [16], and minor complications were fever (<38.5°C, 15%), tolerable pain in the splenic region (25%) and hematuria (5%), and left pleural effusion (28%) was self-absorbing within a short time and rarely required puncture drainage. To avoid causing pleural effusion, the puncture site can be chosen from the middle and lower pole of the spleen. The puncture site avoids the splenic hilum area, which can avoid bleeding from the postoperative needle tract [14-16].
2.4 Clinical efficacy of RFA for hypersplenism The efficacy of RFA of the spleen for hypersplenism is closely related to the ablation of spleen volume, and patients who ablate >40% of the spleen volume can obtain lasting hematocrit improvement after surgery.CT volumetric measurements show that the ablation extent of RFA accounts for (42±12)% of the spleen volume; the average reduction of the spleen volume to about 50% of the original volume 1 year after surgery. During the 2-year follow-up after RFA, liver function parameters (ALT, AST, PT, and albumin) and red blood cells continued to be normal, and platelet and white blood cell counts began to fall back at 6 months postoperatively, but remained significantly higher than preoperatively at 2 years (P<0.001), and liver function Child-Pugh scores improved significantly.Doppler hemodynamic examination revealed that splenic RFA after splenic Venous and portal venous blood flow was significantly reduced after RFA in the spleen, while hepatic arterial blood flow was significantly increased and was 2.1 times the preoperative value at 5 d postoperatively. Liver hyperplasia and volume were significantly increased after RFA compared with preoperative values (P=0.031), and liver hyperplasia and increased hepatic artery blood flow were closely correlated (r=0.76, P<0.001). Studies suggest that increased hepatic artery blood flow and effective oxygen supply to the liver after RFA induces regeneration of the sclerotic liver, thus improving liver function and hypersplenism [14-16].
Because of the reduction in portal blood flow and pressure after splenic RF ablation, splenic RF ablation delays or prevents the risk of GI bleeding in patients with portal hypertension, especially in patients with combined splenic artery blockade. Our 2-year follow-up of patients with previous GI bleeding found no recurrence of GI bleeding.
2.5 Splenic artery trunk block technique and splenic artery steal syndrome Clinicians are aware of splenic artery steal syndrome (SASS) after liver transplantation [19-21], but little attention has been paid to SASS in combination with cirrhotic patients.SASS refers to the presence of splenomegaly, splenic artery thickening tortuosity, accelerated blood flow, hepatic artery slenderness, and reduced arterial blood flow are pathophysiological changes in patients with cirrhosis (Figure 4). The predominance of the splenic artery competes with and “steals” most of the blood flow from the abdominal trunk, which inevitably leads to a decrease in hepatic artery flow, resulting in inadequate arterial perfusion of the liver and persistent hepatocellular damage. after effective control of HBV virus but continued progression of cirrhosis.
In patients with hypersplenism undergoing radiofrequency ablation of the spleen, we routinely perform 3D reconstruction of the hepatic artery and portal vein to clarify the presence of SASS and thus decide whether to perform a combination of treatments for SASS: splenic artery ligation or splenic artery embolization. Splenic artery occlusion followed by splenic RFA has obvious clinical efficacy: splenic RFA is safer to operate, ablates a larger volume of spleen in the same time, and significantly improves the efficacy of splenic RF ablation.
3. Other hypersplenism treatment methods
Clinically, chemical and physical measures such as anhydrous alcohol injection, splenic radiotherapy, microwave ablation and high-intensity focused ultrasound have also been tried to treat hypersplenism, expecting to achieve the effect of treating hypersplenism by destroying part of the spleen parenchyma. However, from the clinical results, all of the above methods have shortcomings such as safety or poor efficacy, and cannot be carried out routinely in clinical practice.
4.Summary
Although there are many treatment options for hypersplenism in cirrhosis, except for liver transplantation, which is a radical treatment for the primary disease, all of them are palliative treatments with unsatisfactory medium- and long-term effects. Among the palliative treatments, PSE and splenectomy are still more frequently used, but both have corresponding indications and complications. rFA for hypersplenism has shown great promise, and several units at home and abroad have started related studies, and its safety has been greatly improved as we have improved the corresponding adjuvant operations [12-16]. In addition to the studies already conducted on the simultaneous combined treatment of hypersplenism and hepatocellular carcinoma with RFA [16], we are also conducting a clinical study of RFA for hypersplenism combined with endoscopic treatment of gastroesophageal varices to provide a new minimally invasive treatment option for patients with cirrhotic hypersplenism combined with HCC and esophageal static gastric varices.