Author Affiliations: Division of Gastroenterology (Cagin YF, Atayan Y and Erdogan MA); Division of Internal Medicine (Dagtekin F); and Division of Biostatistics and Medical Informatics (Colak C), Medical Faculty, Inonu University, Malatya 44280, Turkey

Corresponding Author: Yasir Furkan Cagin, MD, Division of Gastroenterology, Medical Faculty, Inonu University, Malatya 44280, Turkey (Tel: +90-422-3410660ext4112; Fax: +90-422-3410036; Email: yafur@hotmail.com)

 

© 2016, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(16)60092-9

Published online May 9, 2016.

 

 

Contributors: CYF proposed the study. CYF, AY and EMA performed the research and wrote the first draft. DF collected and analyzed the data. CC performed statistical analysis. All authors contributed to the design and interpretation of the study and to further drafts. CYF is the guarantor.

Funding: None.

Ethical approval: Not needed.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: Portal vein thrombosis (PVT) is due to many risk factors, but its pathogenesis is still not clearly understood. To identify the risk factors for PVT, we analyzed the clinical characteristics and complications associated with PVT in cirrhotic patients.

 

METHODS: We studied patients with liver cirrhosis who were admitted to our unit from April 2009 to December 2014. The patients were divided into the PVT and non-PVT groups, and were compared by variables including gender, age, the etiology of cirrhosis, stage of cirrhosis, complications, imaging, and treatment.

 

RESULTS: PVT was found in 45 (9.8%) of 461 cirrhotic patients admitted to our hospital. Most patients (45.9%) had hepatitis B virus (HBV)-related cirrhosis, with a similar distribution of etiologies between the groups. However, there was no positive relationship between PVT and etiologies of cirrhosis. Most patients (71.5%) were in the stage of hepatic decompensation. No statistically significant differences were found in complications including esophageal varices, ascites, and hepatic encephalopathy between the groups. However, there was a significant positive correlation between hepatocellular carcinoma (HCC) and PVT (P<0.01). In 30 patients with PVT, thrombosis occurred in the portal vein and/or portal branches, 37.8% were diagnosed on ultrasound.

 

CONCLUSIONS: The incidence of PVT was 9.8%, mainly in patients with HBV-related cirrhosis. The development of PVT was associated with the severity of liver disease and HCC.

 

(Hepatobiliary Pancreat Dis Int 2016;15:499-503)

KEY WORDS: portal vein thrombosis; cirrhosis; clinical presentation

 

 

Cirrhosis is the last stage of various types of chronic liver disease (CLD).^[1] Cirrhosis is an increasing cause of morbidity and mortality worldwide.^[2] Significant clinical complications, such as hepatic encephalopathy, ascites, hepatorenal syndrome (HRS), and esophageal variceal hemorrhage, may be due to portal hypertension inherent in cirrhosis.^[3]

 

Portal vein thrombosis (PVT) is considered a rare^[4] but gradually increasing complication that is more likely to occur during late-stage liver cirrhosis.^[5] The incidence of PVT in patients with cirrhosis varies according to the severity of the disease.^[6] The prevalence of PVT in cirrhosis ranges from 0.6% to 26% in different studies.^[7,8] Although several risk factors have been proposed for PVT, it is considered to be a multifactorial process,^[9] and its pathogenesis is still not clearly understood.^[10] Hepatic structural derangement reduces portal flow which may be the main responsible mechanism for thrombosis in cirrhotic patients.^[11] The outcomes of PVT depend on the extension, duration, and site of the thrombus.^[12] PVT may occur acutely or chronically. Although the two types of PVT have similar pathologic causes, the treatments are different.^[13] PVT is considered an acute event when symptoms occur within 60 days, with no evidence of portal hypertension or collateral circulation on clinical, radiological, or endoscopic evaluation.^[14] Doppler ultrasound is usually sufficient for a diagnosis of PVT, whereas computed tomography (CT) and magnetic resonance (MR) angiography are more sensitive in the assessment of the extent of the thrombus within the portal venous system.^[13]

 

The aim of the present study was to determine the clinical characteristics and complications associated with PVT in cirrhotic patients.

 

 

From April 2009 to December 2014, a total of 461 cirrhotic patients (286 males and 175 females) were identified in the computerized hospital administrative registration system. The various parameters, including demographic data, clinical manifestations, complications, and PVT were analyzed. Liver cirrhosis was diagnosed based on clinical findings or morphological features. Decompensation was defined a priori as a composite outcome involving the appearance of one or several of the following features: clinically detectable ascites, hepatic encephalopathy, variceal bleeding, jaundice, and serum bilirubin of >2.5 mg/dL. A total of 45 cirrhotic patients were found to have PVT in this study. All registered PVT diagnoses were based on either Doppler ultrasound, CT angiography, or MR imaging. Each PVT was identified as partial or complete, with the extension of the thrombus definitions. The patients were analyzed according to the location and degree of thrombosis, imaging findings, and treatment.

 

The cirrhotic patients were classified into two groups: PVT group (n=45) and non-PVT group (n=416). We measured the above-mentioned variables and compared the two groups statistically.

 

The data were given as frequencies with percentages and medians (range). The relationships between group variables and other categorical variables were examined with the Chi-square test and Yates’ correction for continuity. The test of normality for continuous variables was performed with the Shapiro-Wilk test. The Mann-Whitney U test was utilized to compare the continuous variables. All 2-tailed P values <0.05 were considered statistically significant. SPSS version 22.0 was used for all analyses.

 

 

PVT was found in 45 patients (26 males and 19 females) with an overall prevalence of 9.8% in cirrhotic patients in the current study. Age and gender were not different between the two groups. The etiology, cirrhotic stages, and incidences of hepatic encephalopathy, ascites, and esophageal varices were not significantly different between the two groups (P>0.05, Table 1). PVT occurred in 16 (35.6%) of the patients with hepatitis B virus (HBV)-related cirrhosis, and in 12 (26.7%), 8 (17.8%), 4 (8.9%), and 2 (4.4%) patients with cryptogenic cirrhosis, hepatitis C virus (HCV)-related cirrhosis, alcoholic hepatitis, and autoimmune hepatitis, respectively. Among the patients with PVT, 10 (22.2%) were in hepatic compensated stage and 35 (77.8%) in hepatic decompensated stage. The incidence of HCC was significantly higher in the PVT group than in the non-PVT group (28.9% vs 13.4%, P=0.009, Table 1). Four PVT patients were diagnosed simultaneously with the diagnosis of HCC.

 

The occurrence of acute PVT in the cirrhotic patients was 5.2%, but in chronic PVT, 4.6%. Complications, including ascites and varices, were observed in >60% of the patients with PVT.

 

Most PVT patients were diagnosed by CT angiography and 80% of the PVT patients received conservative treatment. Esophageal and gastric varices were treated with band ligation prior to initiating anticoagulation therapy. Anticoagulation therapy was given with low molecular weight heparin and then switched to an oral anticoagulant (warfarin) when the patient was stable and with no planned invasive procedures. Hemorrhage occurred in 3 patients (2 chronic PVT and 1 acute PVT) and they were discontinued the anticoagulation therapy.

 

Systemic anticoagulation was initiated in six patients who had no risk of bleeding from varices according to the endoscopic sign. Band ligation was performed in two patients due to the risk of esophageal bleeding. Anticoagulation was also used in patients with chronic mesenteric venous thrombosis. Three patients with complete mesenteric thrombosis were complicated with intestinal necrosis based upon clinical, radiographic, or laboratory parameters. Abdominal exploration was performed and the infarcted small bowel was resected. These patients died after 3, 7 and 10 days, respectively. Liver transplantation as a therapeutic option was performed in 4 patients.

 

Partial PVT was diagnosed in 60% of the patients and complete PVT in 40%. Solely the portal vein or its branches were thrombosed in 30 (66.7%) patients. The thrombosis extended to the splenic vein (SV) in four (8.9%) patients and to the superior mesenteric vein (SMV) in one (2.2%) patient. PVT was detected in the entire porto-spleno-mesenteric venous axis in 6 (13.3%) patients (Table 2).

 

A total of 29 (64.4%) PVT patients had esophageal varices, 26.7% had portal hypertensive gastropathy, 20% had gastric varices, 6.7% had variceal hemorrhage, and 66.7% had ascites. Five out of the 29 patients with esophageal varices also had gastric varices. Esophageal varices and bleeding were more frequent in patients with chronic PVT (Table 3).

 

 

In the present study, PVT was found in 9.8% of cirrhotic patients as reported previously.^{[4, 15]} Some studies^[16-18] reported a higher incidence (10%-25%) of PVT in cirrhotic patients. This large variability may be mostly explained by the diagnostic tool used, operator’s experience, and disease characteristics such as the inclusion or exclusion of patients with HCC.^[7] In addition, PVT may not raise an attention unless the main trunk of the portal vein was blocked. Therefore, the rates seem to be lower than the true prevalence. This situation was confirmed by an autopsy study.^[19] For this reason, it is very important to investigate whether there is PVT in all cirrhotic patients, because it affects the choice of therapy and prognosis of the patients.

 

Etiological factors have also been shown to have an effect on PVT prevalence. Nonami et al^[20] reported that HBV is the most common cause of PVT, and the present study showed a similar result. These results verify that HBV is the major risk factor of PVT. Cryptogenic cirrhosis was detected as the second most frequent cause. Sakugawa et al^[21] found that obesity and type 2 diabetes mellitus were more common in patients with cryptogenic cirrhosis. In addition, liver architectural changes in the development of PVT may also contribute to these etiological factors. These results may indicate that one or more factors contribute to the formation of PVT. However, the impact of causal factors of cirrhosis on the PVT incidence has not yet been comprehensively studied.

 

Theoretically, it is well-known that the development of PVT is more common in advanced liver disease. In particular, it is much higher in transplant candidates.^[12] The results of our study support this because most patients with PVT were in the decompensated stage of cirrhosis. Moreover, each clinical finding that constituted the decompensated stage, including hepatic encephalopathy, ascites, and esophageal variceal bleeding, increased the likelihood of development of PVT. Thus, whenever there is a finding of decompensation, such as ascites, gastrointestinal bleeding, or hepatic encephalopathy, the presence of PVT should always be suspected and investigated. Nevertheless, one conceivable clarification for these results could be that PVT is merely an outcome of more advanced liver disease which leads to more severe occlusion of portal venous inflow. This indicates that PVT is not independently related to the deterioration of liver disease.

 

PVT in patients with cirrhosis may be related to malignancy or other factors, including inflammatory and infectious diseases of the liver, bowel, or pancreas, as well as hypercoagulable states.^[12] PVT occurs frequently as a complication of HCC in cirrhosis, and it may be a sign of advanced tumor stage.^{[14, 22]} PVT is an important prognostic factor that influences survival in patients with HCC.^[23] This factor is also important for treatment, because PVT in a patient with cirrhosis and HCC determines the therapeutic strategy. It can even cause the patient to be ineligible for surgical treatment. We found similar results, with significant differences in HCC rates between the two groups. In addition, PVT should be investigated in patients with HCC because of some PVT patients with HCC were diagnosed at the time of HCC diagnosis.^[24]

 

Acute and chronic PVT are different stages of the condition. In patients with cirrhosis, it may be difficult to define acute or chronic PVT; this is mostly based on the presence of collateral circulation and signs of portal hypertension.^{[7, 25]} The formation of acute or chronic PVT is important in the patient’s clinical presentation and prognosis, as acute PVT can involve more serious signs. In our study, the results confirmed that acute PVT is more common than chronic PVT in cirrhosis, as previously reported.^[26]

 

The most common complications of PVT in this study were esophageal and gastric varices, portal hypertensive gastropathy, varices bleeding, and ascites. The majority of patients with esophageal varices had chronic PVT, which was consistent with previously reported.^[26] Our results confirmed that varices are quite frequent in cirrhotic patients with PVT, as previously reported.^[27] Gastrointestinal bleeding occurred more often in the PVT group than in the other groups.^[28] Thus, all PVT patients should be investigated endoscopically for varices. The complications of cirrhosis are likely to increase the risk of PVT. The reverse is also possible. Our results also confirmed this condition.

 

Whether the PVT is complete or partial is important for the treatment. In particular, it is known that patients with complete PVT are poor candidates for liver transplantation.^[29] However, it is well-known that most patients with PVT have partial thrombosis.^{[29, 30]} Complete and permanent portal venous occlusion was exhibited merely in a few patients with PVT.^[5] A previous study^[31] showed that in 41 (74.5%) of 55 patients, the thrombus was partial, whereas in our study 60% were partial PVT. The complete thrombosis of the superior mesenteric vein was usually symptomatic due to the lack of an proficient collateral circulation in the mesenteric region and presented with intestinal ischemia or infarction.^[4] Our patients with complete mesenteric thrombosis presented intestinal infarction.

 

PVT manifests with different clinical features according to the site and extent of the obstruction in the portal venous system.^[32] The clinical presentation of patients with complete mesenteric thrombosis can be more severe than that of those with thrombosis in other locations. Our patients with complete mesenteric thrombosis also showed intestinal necrosis or died. In addition, thrombus extension is important because of technical difficulties with intra-operative anastomoses. This situation may also adversely affect the consequences of liver transplantation.^{[33, 34]} In a study of 55 patients with PVT and cirrhosis, 45% had thrombosis of only the portal vein or its branches, 3.6% had thrombosis extending to the SV, 23.6% had a thrombosed SMV, and 21.8% had thrombosis of the entire porto-spleno-mesenteric venous axis.^[31] In the current study, the site and extent of the obstruction in the portal venous system were different among the PVT patients.

 

Ultrasound and Doppler ultrasound are almost always highly accurate and sufficient for detecting PVT. However, especially in acute PVT, CT and MR imaging are more sensitive than Doppler for evaluating the extension of a thrombus.^{[35, 36]} A study^[8] reported that 73% of ultrasound examinations failed to detect PVT. In our study, the results from an ultrasound and CT were almost equal and demonstrated that PVT can be diagnosed earlier by Doppler ultrasound.

 

There is no consensus associated with the optimal management of PVT in cirrhotic patients. Although there are a few studies on the factors that affect the extent or the recanalization of thrombosis, the impact of PVT on the course of cirrhosis has not been investigated. The presence of PVT increases the complications that influence the treatment of cirrhosis. Patients with PVT who receive therapy (β-blockers, vitamin K antagonists, low molecular weight heparin) have better recanalization rates than those who do not receive therapy. However, PVT, especially thrombus extension, affects the outcome of liver transplantation.^[37] For this reason, PVT should be treated before liver transplantation. PVT prior to liver transplantation is an independent poor prognostic factor.^{[38, 39]}  One reason for the success of the transplantation also depends on the techniques used in vascular anastomosis.^[40] The majority of our patients were treated conservatively.

 

The limitations of this study are of retrospective nature. We did not know whether the patients who had undergone liver transplantation received treatment for PVT and whether PVT has an effect on the survival of liver transplant patients. Moreover, data collected from a single center are not universally applicable.

 

In conclusion, PVT could take place in 9.8% of the cirrhotic patients, mostly in HBV-related cirrhosis and advanced liver disease. PVT is associated with the complications of cirrhosis. A close relationship exists between HCC and PVT.

 

 

1 Wiegand J, Berg T. The etiology, diagnosis and prevention of liver cirrhosis: part 1 of a series on liver cirrhosis. Dtsch Arztebl Int 2013;110:85-91. PMID: 23451000

2 Blachier M, Leleu H, Peck-Radosavljevic M, Valla DC, Roudot-Thoraval F. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol 2013;58:593-608. PMID: 23419824

3 Rahimi RS, Rockey DC. Complications of cirrhosis. Curr Opin Gastroenterol 2012;28:223-229. PMID: 22343347

4 Amitrano L, Guardascione MA, Brancaccio V, Margaglione M, Manguso F, Iannaccone L, et al. Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis. J Hepatol 2004;40:736-741. PMID: 15094219

5 Nery F, Chevret S, Condat B, de Raucourt E, Boudaoud L, Rautou PE, et al. Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study. Hepatology 2015;61:660-667. PMID: 25284616

6 Raja K, Jacob M, Asthana S. Portal vein thrombosis in cirrhosis. J Clin Exp Hepatol 2014;4:320-331. PMID: 25755579

7 Tsochatzis EA, Senzolo M, Germani G, Gatt A, Burroughs AK. Systematic review: portal vein thrombosis in cirrhosis. Aliment Pharmacol Ther 2010;31:366-374. PMID: 19863496

8 Francoz C, Valla D, Durand F. Portal vein thrombosis, cirrhosis, and liver transplantation. J Hepatol 2012;57:203-212. PMID: 22446690

9 Chen H, Trilok G, Wang F, Qi X, Xiao J, Yang C. A single hospital study on portal vein thrombosis in cirrhotic patients - clinical characteristics & risk factors. Indian J Med Res 2014;139:260-266. PMID: 24718401

10 Ponziani FR, Zocco MA, Garcovich M, D’Aversa F, Roccarina D, Gasbarrini A. What we should know about portal vein thrombosis in cirrhotic patients: a changing perspective. World J Gastroenterol 2012;18:5014-5020. PMID: 23049208

11 Fimognari FL, Violi F. Portal vein thrombosis in liver cirrhosis. Intern Emerg Med 2008;3:213-218. PMID: 18274708

12 Valla DC, Condat B. Portal vein thrombosis in adults: pathophysiology, pathogenesis and management. J Hepatol 2000;32:865-871. PMID: 10845677

13 Kinjo N, Kawanaka H, Akahoshi T, Matsumoto Y, Kamori M, Nagao Y, et al. Portal vein thrombosis in liver cirrhosis. World J Hepatol 2014;6:64-71. PMID: 24575165

14 Parikh S, Shah R, Kapoor P. Portal vein thrombosis. Am J Med 2010;123:111-119. PMID: 20103016

15 Ravaioli M, Zanello M, Grazi GL, Ercolani G, Cescon M, Del Gaudio M, et al. Portal vein thrombosis and liver transplantation: evolution during 10 years of experience at the University of Bologna. Ann Surg 2011;253:378-384. PMID: 21183851

16 Okuda K, Ohnishi K, Kimura K, Matsutani S, Sumida M, Goto N, et al. Incidence of portal vein thrombosis in liver cirrhosis. an angiographic study in 708 patients. Gastroenterology 1985;89:279-286. PMID: 4007419

17 Kumar A, Sharma P, Arora A. Review article: portal vein obstruction--epidemiology, pathogenesis, natural history, prognosis and treatment. Aliment Pharmacol Ther 2015;41:276-292. PMID: 25475582

18 Fimognari FL, De Santis A, Piccheri C, Moscatelli R, Gigliotti F, Vestri A, et al. Evaluation of D-dimer and factor VIII in cirrhotic patients with asymptomatic portal venous thrombosis. J Lab Clin Med 2005;146:238-243. PMID: 16194685

19 Wanless IR, Wong F, Blendis LM, Greig P, Heathcote EJ, Levy G. Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension. Hepatology 1995;21:1238-1247. PMID: 7737629

20 Nonami T, Yokoyama I, Iwatsuki S, Starzl TE. The incidence of portal vein thrombosis at liver transplantation. Hepatology 1992;16:1195-1198. PMID: 1427658

21 Sakugawa H, Nakasone H, Nakayoshi T, Kawakami Y, Yamashiro T, Maeshiro T, et al. Clinical characteristics of patients with cryptogenic liver cirrhosis in Okinawa, Japan. Hepatogastroenterology 2003;50:2005-2008. PMID: 14696453

22 Tarantino L, Francica G, Sordelli I, Esposito F, Giorgio A, Sorrentino P, et al. Diagnosis of benign and malignant portal vein thrombosis in cirrhotic patients with hepatocellular carcinoma: color Doppler US, contrast-enhanced US, and fine-needle biopsy. Abdom Imaging 2006;31:537-544. PMID: 16865315

23 Ando E, Tanaka M, Yamashita F, Kuromatsu R, Yutani S, Fukumori K, et al. Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis: analysis of 48 cases. Cancer 2002;95:588-595. PMID: 12209752

24 Connolly GC, Chen R, Hyrien O, Mantry P, Bozorgzadeh A, Abt P, et al. Incidence, risk factors and consequences of portal vein and systemic thromboses in hepatocellular carcinoma. Thromb Res 2008;122:299-306. PMID: 18045666

25 Amitrano L, Guardascione MA. Management of portal vein thrombosis in cirrhotic patients. Mediterr J Hematol Infect Dis 2009;1:e2009014. PMID: 21415954

26 Sogaard KK, Astrup LB, Vilstrup H, Gronbaek H. Portal vein thrombosis; risk factors, clinical presentation and treatment. BMC Gastroenterol 2007;7:34. PMID: 17697371

27 Janssen HL, Wijnhoud A, Haagsma EB, van Uum SH, van Nieuwkerk CM, Adang RP, et al. Extrahepatic portal vein thrombosis: aetiology and determinants of survival. Gut 2001;49:720-724. PMID: 11600478

28 Li MX, Zhang XF, Liu ZW, Lv Y. Risk factors and clinical characteristics of portal vein thrombosis after splenectomy in patients with liver cirrhosis. Hepatobiliary Pancreat Dis Int 2013;12:512-519. PMID: 24103282

29 Manzanet G, Sanjuán F, Orbis P, López R, Moya A, Juan M, et al. Liver transplantation in patients with portal vein thrombosis. Liver Transpl 2001;7:125-131. PMID: 11172396

30 Dumortier J, Czyglik O, Poncet G, Blanchet MC, Boucaud C, Henry L, et al. Eversion thrombectomy for portal vein thrombosis during liver transplantation. Am J Transplant 2002;2:934-938. PMID: 12482145

31 Delgado MG, Seijo S, Yepes I, Achécar L, Catalina MV, García-Criado A, et al. Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein thrombosis. Clin Gastroenterol Hepatol 2012;10:776-783. PMID: 22289875

32 Primignani M. Portal vein thrombosis, revisited. Dig Liver Dis 2010;42:163-170. PMID: 19766546

33 Lendoire J, Raffin G, Cejas N, Duek F, Barros Schelotto P, Trigo P, et al. Liver transplantation in adult patients with portal vein thrombosis: risk factors, management and outcome. HPB (Oxford) 2007;9:352-356. PMID: 18345318

34 Selvaggi G, Weppler D, Nishida S, Moon J, Levi D, Kato T, et al. Ten-year experience in porto-caval hemitransposition for liver transplantation in the presence of portal vein thrombosis. Am J Transplant 2007;7:454-460. PMID: 17229075

35 Bach AM, Hann LE, Brown KT, Getrajdman GI, Herman SK, Fong Y, et al. Portal vein evaluation with US: comparison to angiography combined with CT arterial portography. Radiology 1996;201:149-154. PMID: 8816536

36 Chou CK, Mak CW, Tzeng WS, Chang JM. CT of small bowel ischemia. Abdom Imaging 2004;29:18-22. PMID: 15160748

37 Francoz C, Belghiti J, Vilgrain V, Sommacale D, Paradis V, Condat B, et al. Splanchnic vein thrombosis in candidates for liver transplantation: usefulness of screening and anticoagulation. Gut 2005;54:691-697. PMID: 15831918

38 Englesbe MJ, Kubus J, Muhammad W, Sonnenday CJ, Welling T, Punch JD, et al. Portal vein thrombosis and survival in patients with cirrhosis. Liver Transpl 2010;16:83-90. PMID: 20035521

39 Rodríguez-Castro KI, Porte RJ, Nadal E, Germani G, Burra P, Senzolo M. Management of nonneoplastic portal vein thrombosis in the setting of liver transplantation: a systematic review. Transplantation 2012;94:1145-1153. PMID: 23128996

40 Wang SP, Yan XP, Xue F, Dong DH, Zhang XF, Ma F, et al. Fast magnetic reconstruction of the portal vein with allogeneic blood vessels in canines. Hepatobiliary Pancreat Dis Int 2015;14:293-299. PMID: 26063031