Portal vein thrombosis in hepatitis C virus-related cirrhotic patients: Prevalence and clinical characteristics in an Egyptian cohort

Abstract

Portal vein thrombosis is a catastrophe not uncommonly complicating hepatitis C virus-related liver cirrhosis. To estimate its prevalence and clinical characteristics, we investigated 1000 cirrhotic patients by abdominal ultrasound or Doppler study at least. Portal vein thrombosis was found in 21.6%, of whom 157 (72.7%) had malignancy. Complete portal vein thrombosis was found in 70.4%. Half of all these patients had at least one episode of portal hypertensive bleeding, a third had abdominal pain and a quarter presented with jaundice. Portal bilopathy was diagnosed in two cases (0.9%). There was significant association between severity of liver disease, ascites, male gender and site of segmental focal lesion and portal vein thrombosis.

Keywords

Portal vein thrombosis hepatocellular carcinoma hepatitis C virus liver cirrhosis

Introduction

Portal vein thrombosis (PVT) is reported as a relative risk occurring seven fold as often in cirrhosis compared with the normal population.¹ The role of the liver in blood homeostasis is undebatable, maintaining a crucial balance between pro- and anti-coagulants.² In cirrhosis, this balance is significantly kept till a critical point at which one supervenes resulting in either bleeding or, less likely, thrombosis.³ Poor production of coagulation factors, added to a substantial platelet deficiency would significantly lead to bleeding,⁴ whilst portal flow stasis is the main preliminary event preceding PVT.⁵ Elevated levels of factor VIII (a procoagulant), G20210A mutation of prothrombin, factor V Leiden, reduced levels of protein C, S, antithrombin III, endoscopic treatment of oesophageal varices and abdominal surgery were also found to be additional risks of PVT in liver cirrhosis.⁶ The relationship of liver cirrhosis and PVT is controversial, probably part consequential and part causal, in that once PVT occurs, a progressive degradation of the liver ensues.⁴

The diagnosis of PVT is dependent on imaging techniques, including ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI). Doppler ultrasound is the method of first choice, as it is widely available, rapid and cheap. The detection of a portal cavernoma is highly suggestive of chronic PVT.³

Based on the increase in the use of technically advanced non-invasive liver imaging modalities, PVT has been increasingly identified in patients with cirrhosis, with an estimated current prevalence of 0.6–26%.⁷ Hepatocellular carcinoma (HCC), especially in those with cirrhosis, is among malignancy with the highest correlation with PVT formation.⁸ This combination is an aggressive disease with extremely poor prognosis.⁹ Hepatitis C virus (HCV) infection is the leading cause of cirrhosis in Egypt. Because of a chronic inflammatory response to the virus, HCV-infected patients may be at a higher risk of venous thrombo-embolism.¹⁰

Patients and methods

Our cross-sectional study was conducted on 1000 consecutive Egyptian patients with HCV-related liver cirrhosis, admitted to the National Liver Institute Hospital, Menoufia University. Approval from the ethical committee of the Institute and an informed patient consent were prerequisites before commencing the study. Chronic HCV cases with either clinical, laboratory and or radiological evidence of liver cirrhosis were included.⁵ Patients presenting with either chronic HCV infection without cirrhosis, non-HCV-related liver cirrhosis (e.g. hepatitis B virus (HBV), autoimmune hepatitis, alcoholic hepatitis, etc.), or cirrhotic patients with HBV and HCV co-infection all were excluded.

All enrolled cases were investigated at least by abdominal ultrasound with Doppler verification, and or any superior modality such as triphasic CT scan or MRI, for the presence of hepatic focal lesions and PVT. Patients were classified into two groups (PVT and non-PVT). We studied demographic characteristics (age, sex), habit of smoking, presence of medical systemic disorders (diabetes mellitus and hypertension), history of prior similar thrombotic events, and of cirrhosis complications as encephalopathy, ascites or gastrointestinal (GIT) bleeding and the drug history. The diagnosis of chronic HCV infection was confirmed by detection of HCV antibodies by third generation enzyme immunoassay (ETI-AB-HCVK-3 kit; Sorine Biomedica, Suluggia, Italy) and polymerase chain reaction (PCR) of HCV RNA by One™ Real-Time PCR, Applied Biosystems, Life Technologies brand of Thermo Fisher Scientific Corporation 2007, USA. Liver and real function tests included serum bilirubin total and direct, aspartate aminotransferase, alanine aminotransferase, albumin and urea and creatinine which were measured using Cobas Integra 800 Auto analyser (Roche Diagnostics Ltd, Mannheim, Germany). Prothrombin activity and international normalised ratio were measured using BFT II Analyser (Dade Behring Marburg GmbH, Marburg, Germany). Complete blood count (CBC) was done by using Sysmex instrument KX-21, Sysmex Inc., Japan, to assess haemoglobin level, white blood cell count and platelets count. Serum α-fetoprotein (AFP) was performed by chemiluminescence, with Immulite AFP (1000) kit (Diagnostic Products Corporation, Los Angeles, CA, USA). The normal AFP level is up to 5 ng/ml¹¹ and AFP > 400 ng/ml is considered diagnostic for HCC.¹² All patients were scored according to the Child-Pugh-Turcotte¹³ and the Model of End-Stage Liver Disease (MELD).¹⁴ PVT was classified according to the new classification.³

Data were collected and entered using SPSS (Statistical Package for Social Science) programme for statistical analysis. Quantitative data were shown as mean, SD and range. Qualitative data were expressed as frequency and percent at 95% confidence interval (95% CI). χ² test was used to measure association between qualitative variables. Student t-test and Mann–Whitney test were done to compare means and SD of two sets of quantitative normally and not normally distributed data, respectively. The results of comparing the correlation between two continuous variables were indicated by the correlation coefficient (r) using correlation analysis. Probability (p) value was considered to be of statistical significance at < 0.05.

Results

The majority (71.8%) of all studied patients were male (Figure 1). PVT was found in 216 (182/718 males (25.3%) and 34/282 females (12.1%)), with an overall prevalence of 21.6% in patients with HCV-related liver cirrhosis. HCC was found in 157 (72.6%). Complete PVT was diagnosed in 70.4% and partial in 29.6%. The site of PVT was found limited to the portal vein trunk (type I) in 140 (68.8%), to one branch of the portal vein (type IIa) in 40 (18.5%) and in 3 (1.3%) in both branches of the portal vein (type IIb). Type III (thrombus limited to trunk and branches) was found in 33 (15.2%). PVT without any venous extension existed in 198 (91.7%) but extended to the superior mesenteric vein (SMV) in 8 (3.7%), to the splenic vein in 6 (2.7%), and both splenic and SMV in 4 (1.8%) (Table 1).

Table 1.

Frequency, nature and extension of PVT among all studied patients.

PVT	Number	Percent%
PVT prevalence	Frequency (n = 216 out of 1000 cirrhotic patients)	21.6
PVT type (n = 216)
Complete	152	70.4
Partial	64	29.6
PVT classification (n = 216)
Type I (PV trunk only)	140	64.8
Type II a (one branch of PV)	40	18.5
RT PV	19	47.5
LT PV	21	52.5
Type II b (both branches)	3	1.4
Type III (trunk and branches)	33	15.3
PVT extension (n = 216)
No extension	198	91.7
SV	6	2.8
SMV	8	3.7
SV + SMV	4	1.8
Nature of PVT (n = 216)	157	72.7
With HCC	59	27.3
Without HCC

PVT: portal vein thrombosis; PV: portal vein; SMV: superior mesenteric vein; SV: splenic vein.

The presence of PVT was significantly higher in patients with ascites than those without (p < 0.01). However, it was not significantly related to abdominal pain, jaundice, GIT bleeding nor hepatic encephalopathy (p = 0.672, 0.501, 0.384, 0.510), respectively. Portal cavernoma was detected in only 30 (13.8%), whilst bowel ischemia and portal biliopathy was limited to 0.9% (Table 2).

Table 2.

Clinical characteristics of patients with and without PVT.

Studied variables	PVT		X²	p-Value
	No	Yes
	Number	Number
Abdominal pain
Yes	253	73	0.18	0.672
No	531	143	0.18	0.672
Jaundice
Yes	200	60	0.5	0.501
No	584	156	0.5	0.501
Gastrointestinal bleeding
Yes	413	121	0.8	0.384
No	371	95	0.8	0.384
Hepatic encephalopathy
Yes	127	31	0.4	0.510
No	657	185	0.4	0.510
Ascites
Yes	446	164	25.8	<0.01
No	338	52	25.8	<0.01
Child Pugh score
A	196	32	10.2	<0.01
B	366	111
C	222	73
Focal lesion
Yes	216	157	147.5	<0.01
No	568	59	147.5	<0.01
Ischemia
Yes	0	2	7.3	<0.01
No	784	214	7.3	<0.01
Portal biliopathy
Yes	0	2	7.3	<0.01
No	784	214	7.3	<0.01
Portal cavernoma
Yes	0	30	102.9	<0.01
No	784	186	102.9	<0.01

There was a statistically significant association with elevated Child Pugh scores and the presence of PVT (p < 0.01). However, those with score B had the highest incidence than those with score C (Table 2). A higher mean MELD score was also detected in patients with PVT than those without (17.17 ± 7.04 and 16.15 ± 6.83; p = 0.05), respectively, and cutoff values 12.5 showing 70.8% sensitivity and 35.8% specificity in prediction of PVT. The sensitivity and specificity of AFP for predicting PVT was 86.64% and 80.46%, respectively, at cutoff 52 ng/ml with the area under curve 0.880 (p < 0.01).

Focal lesions in the right lobe of liver was commonest (72, 45.9%), whilst bi-lobar focal lesions were found in 66 (42%) and focal lesions in the left lobe in 19 (12.1%). The presence of PVT was significantly higher in patients with bi-lobar hepatic focal lesions (p = 0.036).

Male gender, site of hepatic focal lesion and ascites were thus the only independent predictors of PVT development in cirrhotic HCV patients (p = 0.022, 0.045, 0.038), respectively (Table 3).

Figure 1.

Relationship between the presence of portal vein thrombosis and gender distribution.

Table 3.

Backward stepwise logistic regression analysis of predictors of PVT development in cirrhotic HCV patients.

	B	SE	Wald test	Significance	OR	95% CI
	B	SE	Wald test	Significance	OR	LL	UL
Male gender	0.725	0.318	5.220	0.022*	2.066*	1.109	3.849
Presence of ascites	0.685	0.330	4.307	0.038*	1.984*	1.039	3.790
Site of focal lesion	0.477	0.239	4.004	0.045*	1.612*	1.010	2.572

B: unstandardised coefficients; SE: standard of error; OR: odds ratio; CI: confidence interval; LL: lower limit; UL: upper limit.

Statistically significant at p < 0.05.

Discussion

The prevalence of PVT in cirrhosis has been variably reported. Earlier studies had mentioned lower rates ranging from 0.6 to 16%.^11–15 Studying autopsies of 23,796 deaths in Malmo hospital over 12 years, much higher rates were discovered.¹ The wide discrepancy has also been attributed to the type of diagnostic tool used.¹⁶ Certainly, its prevalence related to the severity of liver disease being found in 25% of transplantation cases,² and with HCC up to 35%.¹⁷ In Egypt, which is cursed with the heaviest burden of HCV, an association with HCC substantially increases the risk of PVT.^17–21 HCC is four times more common in men than women.²² Moreover, wide variability in partial or complete thrombosis is reported.^22,23 Using a new classification of PVT, it was evident that most thromboses occurred in the main trunk of portal vein.^7,24 However, a direct relationship with severity of liver disease as measured by Child-Pugh^3,15,25–29 or MELD scores^20,29,30 is not seen.

There was no statistically significant difference in modes of presentation including GIT bleeding, jaundice and hepatic encephalopathy between both groups (p > 0.05)^23,24 with presence of PVT, though bleeding was found more often in one survey.⁷ Ascites, being the most common clinical presentation, was significantly worse in the PVT group.²⁵

Thus, in conclusion, PVT represents a serious, and not infrequent, complication of HCV-related cirrhosis in Egyptian patients with higher morbidity and mortality. Male gender, the site of focal hepatic lesion and ascites were the only independent predictors of PVT. Further research targeting this development to improve better strategies of prophylaxis and management is needed.

Footnotes

Authors’ contributions

Omkolsoum Alhaddad: initiated the project, designed and implemented the study for application and revised the paper; Maha Elsabaawy and Omar Elshaaraawy: analysed the data, drafted and revised the paper; Mohamed Elhalawany: monitored the data collection, analysed the data; Mohamed Mohamed Houseni: radiological examination and judgment, drafted and revised the paper and Eman Abdelsameea: analysed the data, drafted and revised the paper.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Maha Elsabaawy https://orcid.org/0000-0002-3110-1547 Eman Abdelsameea

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