QJM Advance Access originally published online on April 25, 2008
QJM 2008 101(6):493-501; doi:10.1093/qjmed/hcn037
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Hepatic encephalopathy after transjugular intrahepatic portosystemic shunt insertion: a decade of experience
From the 1Liver Unit and 2Department of Radiology, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, UK
Address correspondence to Steven Masson, The Liver Unit, Freeman Hospital, Freeman Road, Newcastle Upon Tyne, NE7 7DN, UK. email: steven_masson{at}hotmail.com
Received 9 April 2007 and in revised form 12 September 2007
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Summary |
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Background: Since its introduction, transjugular intrahepatic portosystemic shunt (TIPS) has been extensively used for treatment of portal hypertension. We report a decade of experience with particular emphasis on characterizing post-TIPS hepatic encephalopathy (HE).
Aim: To determine the frequency of clinically evident or minimal HE post-TIPS, identify predisposing factors and determine the impact of minimal HE on quality of life.
Design: Prospective data collection and retrospective case notes analysis.
Methods: Of 197 patients referred for TIPS insertion, 136 patients who survived the procedure by more than 4 weeks were available for assessment. Data collected at TIPS insertion was supplemented by case note analysis. Psychometric testing was performed and health profile questionnaires administered on patients still attending.
Results: Most patients had alcoholic liver disease (62.4%) and bleeding varices unresponsive to endoscopic therapy (86%). Clinically evident post-TIPS HE developed in 34.5% of patients, was of similar frequency in the groups treated with polytetrafluoroethylene covered and uncovered stents, and the only significant predictor was pre-TIPS HE. Post-TIPS HE necessitating liver transplant or contributing to death occurred in only 14 (10.3%) patients. Minimal encephalopathy (abnormal psychometry) was present in 49% of patients at 26 (3–123) months after TIPS but this frequency was similar in a cohort of cirrhotics being assessed for liver transplant. However, patients with abnormal psychometry had significantly lower quality of life scores than those with normal psychometry.
Conclusions: Although, HE is relatively common after TIPS insertion, with careful selection of patients it is usually short-lived and easily managed. Minimal HE is no more prevalent than expected in a cirrhotic population without TIPS.
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Introduction |
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In recent years, transjugular intrahepatic portosystemic stent-shunts (TIPS) have been increasingly used for the treatment of the complications of portal hypertension. Meta-analysis of randomized controlled trials confirms the superiority of TIPS over endoscopic treatments in prevention of variceal rebleeding but without any improvement in mortality.1–4 Additionally, TIPS is effective in the resolution of refractory ascites in some patients5–9 but it remains unclear as to whether there is any survival advantage.10,11
One of the main drawbacks of TIPS is the development of hepatic encephalopathy (HE). The incidence of new or worsening HE after TIPS is reported to be around 30%,12–14 yet its clinical spectrum and the identification of risk factors for its development remain ill-defined. The diagnosis of HE typically relies on a clinical classification,15 which is insufficiently sensitive to detect lesser degrees of impairment. However, psychometric testing has a much higher sensitivity for these more subtle changes and has allowed the detection of ‘sub-clinical’ or ‘minimal HE’ representing the lower end of this neuropsychiatric spectrum.16,17 While the clinical significance of minimal HE has been a matter of controversy in recent years, clinical experience and scientific data have emerged on which to base a current consensus which highlights its importance.18 Skills involving motor performance or speed are impaired in minimal HE,19 with particular concern about fitness to drive20 and the occurrence of minimal HE may predict the development of subsequent overt HE.21 However, it remains unclear as to the extent that minimal HE develops after TIPS insertion. Additionally, while the development of HE after TIPS insertion undoubtedly results in significant morbidity, the extent to which it affects quality of life and perceived health status has never been clarified.
The other principal disadvantage of TIPS is the development of shunt dysfunction. Early clinical experience revealed that around half of TIPS patients would require shunt revision within the first year.22 For this reason, Polytetrafluoroethylene (PTFE) covered stent-grafts, thought to decrease dysfunction rates by reducing pseudo-intimal hyperplasia within the stent, were developed.23 Initial clinical trials revealed a marked improvement in shunt patency24 and worries concerning the likelihood of increased frequency of encephalopathy because of this were not sustained. The actuarial rates of encephalopathy in the groups being treated with covered and uncovered prostheses were similar.24
TIPS was first used in Newcastle in 1992 and more than 50 procedures were undertaken prior to the time period covered by the study reported below. Here, we report our experience of using both PTFE covered and ‘bare stent’ TIPS in almost 200 patients over a 10-year period, with particular emphasis on assessing post-TIPS HE as a complication. In addition to presenting observational data regarding the development of clinically evident HE, we hypothesized that TIPS insertion would be associated with the development of minimal HE and that this would lead to a reduced quality of life. To clarify this, we studied psychometric responses in those TIPS patients still attending, administered health questionnaires to measure quality of life and correlated the significance of this neuropsychiatric impairment with perceived health status. Therefore, the aim of this study was to determine the frequency of clinically evident or minimal HE after TIPS insertion, identify predisposing factors and determine the impact of minimal HE on quality of life. This study was approved by the Newcastle and North Tyneside Health Authority Joint Ethics Committee.
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Patients
Between January 1995 and December 2004, 197 patients were referred for TIPS to the Regional Liver Unit within our hospital. In this series, TIPS was used as a rescue procedure for variceal bleeding unresponsive to endoscopic therapy (continued bleeding despite two endoscopic treatments) or ascites requiring repeated therapeutic paracentesis. Data was collected prospectively at the time of TIPS insertion and during surveillance portography. In addition, case notes were analysed retrospectively. Data was available for 192 patients.
Procedure
TIPS insertion was performed by an experienced interventional radiologist. Because of the recognized complication of HE, the aim of the procedure in our centre was to decrease portal pressure gradient (PPG) to just <12 mmHg25 using stents dilated to 8, 10 or 12 mm according to the reduction in pressure gradient achieved; only seven patients required a 12 mm shunt to achieve this pressure reduction. The index TIPS was created using bare stents (principally Wallstent), mainly during the first 5 years, or a PTFE covered stent (Viatorr) in the latter half of the decade. Shunt patency was checked using a combination of Doppler ultrasonography and portography. Shunt dysfunction during haemodynamic evaluation was treated with balloon dilatation and/or additional stenting. Shunt dysfunction was identified by an increase in PPG to above the threshold for gradient reduction, evidence of luminal narrowing, or by a reduction in Doppler peak velocity with subsequent confirmation of insufficiency on portography. The decision to intervene was tailored according to these findings and the clinical situation of each patient.
Follow-up
Patients were followed at 3–6 month intervals with clinical, biochemical and haematological assessment, until death, liver transplantation, or loss to follow-up. Portography was performed initially at 3 months, then yearly when possible. At other times, portography was performed when clinically indicated. Clinically evident HE was assessed prior to TIPS and during follow-up; its definition, presence and evaluation of severity was based on modified West Haven criteria for semi-quantitative grading of mental status.15
Psychometric testing
A test battery for the detection of minimal HE, the psychometric hepatic encephalopathy score (PHES), was performed on patients still attending follow-up. The battery score varies between +6 and –18. The score is a summation of the number of SDs (+1 to –3) from the age corrected mean of each test from six paper and pencil tests: number connection tests A and B, digit symbol test, line tracing test time and errors, and serial dotting. Values of –5 to –18 are considered abnormal.26 In patients where the cirrhosis was due to alcohol, all had been abstinent for several months prior to testing. Exclusion of continued alcohol ingestion was checked for by use of a questionnaire. All patients attended as out-patients and were tested on the programmed investigation unit. Venous blood was collected on the day of testing for Child/Pugh and MELD score and whole blood ammonia. The latter was measured within 1 min of collection using the Ammonia Checker (Ammonia Checker II, Kyoto Daiichi Kaguku Co Ltd). Shunt patency was confirmed in the 6 months prior to or after psychometric testing in 65% of patients.
Computerized psychometry (CDR) was also undertaken within 1 week of the paper and pencil tests. Both assessments were carried out according to a standardized schedule by the same operator (HM). The CDR battery subtests, in order of administration were: simple reaction time, number vigilance, choice reaction time, spatial working memory, numeric working memory, delayed word recall and recognition, and picture recognition. The individual CDR subtest measures were combined into composite scores to reflect the five cognitive domains identified previously by factor analysis:27 power of attention; continuity of attention; speed of memory; quality of working memory and quality of episodic memory. Scores for the CDR factors were calculated in 5-year age bands from the CDR Normative database (ranging from n = 55 controls in the 71–75 age band, up to 1370 controls in the 18–25 age band).27
Administration of health profile questionnaire
Patients who had undergone psychometric testing were asked to complete two health profile questionnaires. A generic instrument, the Short Form 36 (SF-36), thought to provide a global assessment of health-related quality of life applicable to all types of chronic disease28,29 along with a more recently derived disease-specific instrument, the chronic liver disease questionnaire (CLDQ)30,31 were utilized.
SF-36 is constructed of 36 multiple-choice questions covering four domains in the area of physical health (physical functioning, role limitation-physical, bodily pain and general health) and four domains in the area of mental health (role limitation-emotional, vitality, mental health and social functioning). CLDQ is designed to be more responsive to changes in quality of life, which specifically pertain to patients with chronic liver disease. It presents 29 multiple-choice questions covering the six domains of abdominal symptoms, fatigue, systemic symptoms, activity, emotional function and worry.
Statistical analysis
Descriptive statistics are provided as the mean (±SD), median and range or percentage for quantitative and qualitative variables, respectively. Comparisons between groups were performed with the chi-squared, unpaired Student's t-test or Mann–Whitney U test as appropriate. P-values <0.05 (two tailed) were considered significant.
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Patient characteristics
Patient characteristics are presented (Table 1). Most patients were male (62.4%) with alcoholic liver disease (65.0%) and bleeding varices (86.0%). Ages ranged from 21 to 79 years (mean 51.6 ± 11.6 years).
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Procedure
Technical success was achieved in 184 of 192 patients (95.8%). In the remainder, TIPS insertion was not completed due to portal venous occlusion (n = 3), inability to access the portal circulation (n = 3), intraperitoneal haemorrhage from portal venous tear (n = 1) or low portal pressure at the time of the procedure (n = 1).
Mortality
There were no deaths during the TIPS procedure but there were two deaths later on the same day. These were due to further variceal haemorrhage (n = 1) and severe cardiac failure (n = 1). Death occurred within 4 weeks of the procedure in 35 patients (18.2%) including one patient who developed severe cardiac failure secondary to pulmonary hypertension. There were 93 deaths (50.5%) out of 184 patients, with most deaths due to end-stage liver failure and/or sepsis. A Kaplan-Meier plot of mortality in all patients is shown (Figure 1) which shows that 40% survived 5 years.
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Follow up
Patients were followed until death (n = 93; mean time to death 17.3 ± 25.1 m), orthotopic liver transplantation (n = 20; mean time to transplantation 12.0 ± 16.5 m), or are still attending (n = 59; mean follow-up 41.9 ± 36.1 m). The remainder have been lost to follow-up (n = 12; mean follow-up 14.6 ± 15.2 m). Overall, the mean follow-up was 34.0 ± 30.4 m. A profile of patient follow-up is shown (Figure 2).
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In those patients in whom TIPS was successfully inserted (n = 184), no further analysis on the development of encephalopathy was possible in 48. They were excluded because of early mortality (n = 35), liver transplantation during the same admission (n = 5), or failure to attend any follow-up, usually in patients referred from other hospitals (n = 8). A profile of those analysed is shown (Figure 3).
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Clinically evident HE
Clinical evidence of HE was identified in 52 patients (38.2%), although persistent alcohol abuse was thought to be responsible for confusion in some of these (n = 5) giving an actual incidence of 34.5% (n = 47). HE was classified as new or a deterioration of pre-existing portosystemic encephalopathy. Of the patients included in analysis (n = 136), 19.4% of patients had evidence of encephalopathy prior to TIPS insertion. Of those with HE after TIPS insertion 69.2% developed new encephalopathy and 30.8% had a worsening of pre-existing HE. Further analysis revealed pre-existing HE to be the only significantly predictive variable in determining the subsequent development of HE after TIPS insertion (Table 2).
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In terms of onset, HE most commonly developed within 3 months of TIPS insertion (n = 26) or within the first year (n = 35). Rarely, did it develop later than 3 years (n = 3). In some patients, HE resolved completely within the first 3 months (n = 10) or within the first year (n = 12). The severity of HE after TIPS insertion was stage 1 (n = 24) or stage 2 (n = 16) in the majority with only a small number of stage 3 (n = 3) or stage 4 (n = 4). In those patients whose pattern of HE was episodic (n = 23), the median number of episodes was 1 (1–5).
Of those developing HE after TIPS insertion the outcomes were as follows. In the majority, HE resolved with conservative management (withdrawal of diuretics or psychotropic medication or the commencement of lactulose) (n = 20), the use of antimicrobials (n = 5) and the treatment of rebleeding (n = 1). In an attempt to resolve HE the TIPS was radiologically occluded (n = 3) but none of these improved prior to death. HE contributed to the decision to transplant in three patients. In eight patients, HE persisted and the patients died from end-stage liver failure. In a further six patients, HE was a feature only of the terminal illness.
Covered stents vs. uncovered stents
TIPS was created using a covered stent-graft in 58 patients and a bare stent in the remainder (n = 78). Successful portal pressure reduction was achieved in all patients and was similar in the two groups (Table 2). In patients who had surveillance portography, primary patency (shunt sufficiency avoiding the need for intervention) at 1 year was 86.7% vs. 53.4% for the covered and bare stents, respectively (P 
0.01, 
2). More patients required intervention for shunt dysfunction in the uncovered stent group [35 (44.8%) of 78 patients vs. 5 (8.6%) of 58 patients]. A total of 60 vs. 8 procedures were required during a follow-up period of 43.2 ± 35.0 vs. 19.8 ± 13.1 months (covered vs. bare). This included five patients with dysfunction of uncovered prostheses in whom covered stents were subsequently inserted during follow-up. HE occurred with equal frequency after both covered (37.9%) and bare stents (39.4%).
Psychometric testing
Those patients known to be still attending were invited to attend for psychometric testing. PHE scores were available in 35 patients (Table 3). The remainder were not tested because of concomitant neurological or psychiatric diagnoses (n = 4), continued alcohol ingestion (two patients were inebriated when they attended) or did not attend. The median length of time between TIPS insertion and psychometric testing was 26.0 (range 3–123) months. Child/Pugh,32 MELD and blood ammonia values in this group are shown (Table 3).
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The paper and pencil PHE score was abnormal (–5 to –18) in 17 patients (49% of those who attended). Over half of these (n = 11) had been identified as having clinically evident HE during follow-up, but the rest (n = 6) had not. PHE score was normal (–4 to 2) in 18 patients. A small number of these (n = 2) had been identified as having clinical evidence of HE, but in each case this was one episode of HE soon after TIPS insertion, which was short-lived and had resolved long before the psychometric testing. Repeat testing was carried out in five patients, two of whom improved after more than 3 years’ follow-up while one was unchanged and two deteriorated. The computerized CDR score (Table 3) was significantly lower in those with abnormal PHE scores (P < 0.01, Mann–Whitney U test) and was in the normal range (–3 to +5) in only 14 of the 36 tests performed (39%).
Quality of life questionnaires
Of 35 patients who had undergone psychometric testing, 19 (54%) completed the quality of life questionnaires within 8–20 weeks of psychometric testing. In both the SF-36 and CLDQ questionnaires, the total scores for patients with abnormal psychometric test results (HE score –5 to –18) were significantly lower than that for patients with normal psychometric test results (HE score –4 to 6) (P < 0.05, Mann–Whitney U test) (Table 4). This difference was significant in the domains covering physical health in the SF-36 questionnaire and in the domains of fatigue, systemic symptoms and activity in the CLDQ.
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The survival from variceal bleeding has progressively improved over the past two decades, with in-hospital mortality falling from 42.6% in 1980 to 14.5% in 2000.33 This was associated with a decrease in rebleeding from 47 to 13%, with endoscopic therapy and antibiotic prophylaxis being independent predictors of mortality. These improvements were achieved without the introduction of TIPS, only 6% of patients being treated by this procedure in the latter decade. In our centre in the past 10 years, we have only used TIPS for bleeding patients failing endoscopic therapy and this explains the high 30 day mortality (18.2%), such patients usually dying from multiorgan failure. Nevertheless, TIPS now has a well-established role in the management of portal hypertension and our experience over the last decade reflects that of similar units in terms of technical success and rates of complications.34,35
With respect to clinically evident HE developing after TIPS insertion, our rate of 34.5% is similar to other reports with the caveat that the criteria used for the diagnosis of post-procedure HE varies significantly in reported studies.4 Nevertheless, it is clearly a common complication. However, in our population, in most cases this is low-grade, transient and episodic, often related to a specific precipitant. These episodes tend to occur soon after TIPS insertion and can usually be easily managed conservatively, resolving thereafter. It has been suggested that this temporal relationship relates to cerebral adaptation to gut-derived neurotoxins, which may occur within a few months of the TIPS procedure.36 Less frequently, more persistent encephalopathy develops, relating either to subsequent progression of the underlying liver disease or associated with pre-terminal illness. In extreme cases, radiological intervention can be undertaken to resolve refractory spontaneous HE. However, this occurs at the expense of a predictable recurrence of portal hypertension, which can be problematic especially in the presence of progressive underlying liver disease. For this reason, in our series, shunt occlusion was rarely undertaken in keeping with previously reported rates of intentional occlusion to reverse HE (
5%).37 In a recent study from Edinburgh38 post-TIPS HE resistant to conventional treatment and requiring shunt modification was present in 38 of 733 patients. In this group the median age was 11 years greater and the pressure gradient reduction slightly greater (6.9 ± SD 3.2 vs. 7.6 ± 2.2; Table 2) than in our patients.
In our population, those patients who developed clinically evident HE were significantly more likely to have a past history of encephalopathy and tended to be male. Past history of encephalopathy12,34 along with increasing age13 have previously been identified as important variables increasing the risk of post-TIPS HE. This could imply that TIPS is inappropriate for patients who remain, or have been, severely encephalopathic. However, in practice this salvage therapy is often the only therapeutic option available. Additionally, if the encephalopathy has been precipitated by variceal bleeding, then arrest of the bleeding can improve the encephalopathy. Notably, we did not find any difference in the PPG after the procedure in those who developed HE and those who did not. It has previously been suggested that post-TIPS HE is associated with a lower PPG25 implying that effective portal decompression increases the risk of HE. Others factors that have been associated with an increased risk of post-TIPS HE include female sex and an aetiology other than alcoholic liver disease,14 which our results did not support. However, given the small numbers of patients with aetiologies other than alcohol, our sample size is probably too small to exclude the cause of cirrhosis or course of underlying disease as being important determinants in post-procedure HE. Additionally, as TIPS was carried out as an emergency procedure for variceal bleeding unresponsive to endoscopic treatment in 86% of our patients we have not attempted to correlate post-TIPS HE with Child or MELD scores at the time of the procedure as these rapidly change in haemodynamically unstable patients.
Electrophysiological studies by the Vienna Group showed a decrease in P300 latency 6 months after TIPS.39 The abnormality was persistent and bore no obvious temporal relationship to the TIPS insertion. There was significant burden of neuropsychiatric impairment in many of our patients, which was not identified clinically. However the abnormal PHE and CDR scores in 49 and 61% of the patients tested were not significantly different from a cohort of patients we have tested, who were being evaluated for liver transplantation with similar MELD but without TIPS where abnormal results were present in 50% (PHE) and 48% (CDR) of patients. Ideally, we would have presented data with regard to the degree of minimal HE prior to TIPS insertion and the lack of such data is clearly a limitation of our study. However, the majority of our patients were treated with TIPS as an emergency for bleeding varices so it was not possible to obtain meaningful pre-TIPS psychometric data.
By the administration of the health questionnaires, we have quite explicitly demonstrated the impact of psychometric impairment on daily life. These patients clearly have a globally diminished level of functioning with significant impairments in dimensions of both physical and mental health. Minimal HE is therefore, an important determinant of perceived and actual quality of life. More generally, we would advocate the need to adopt a more widespread approach to the diagnosis of these more subtle impairments especially as it has been suggested that patients with minimal HE should be treated.40
The use of coated stents dramatically decreased the rate of shunt dysfunction which, in turn, reduced the number of re-interventions. This real-life clinical experience confirms the results of a recent randomized clinical trial.24 Notably, the incidence of HE was not more frequent in those with covered stents. These findings have direct implications for cost effectiveness of the TIPS procedure in terms of surveillance, re-intervention and hospitalization due to clinical relapses. Previously, there have been some concerns raised about the cost-effectiveness of the TIPS procedure and that in addition to the cost of the TIPS itself, the cost per bleed seems most sensitively related to the costs involved with shunt dysfunction.41 Given our experience with covered stents, this should be re-evaluated as we have now changed our clinical practice and routine surveillance is by colour Doppler alone rather than with portal venography.
In conclusion, HE is relatively common after TIPS insertion. However, in our cohort, in whom we aimed for a PPG reduction to only just below the 12 mmHg threshold required to prevent rebleeding, clinically evident HE was usually short-lived and easily managed conservatively. Minimal encephalopathy was not more prevalent in TIPS patients than cirrhotics being evaluated for liver transplant but when present was associated with decreased quality of life. Clinical necessity will often dictate that this procedure is undertaken even in those patients at greatest risk. However, older patients and those with a previous history of HE should be carefully assessed so that the risk of HE does not outweigh the benefit.
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Dr Brian Saxby of Cognitive Drug Research, Goring-on-Thames, UK kindly computed the CDR scores.
Conflict of interest: None declared.
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References |
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