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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Progression of fibrosis following recurrent hepatitis C virus (HCV) infection is frequent after liver transplantation (LT). Histology remains the gold standard to assess fibrosis, but the value of hepatic venous pressure gradient (HVPG) is being explored. We evaluated patients with recurrent HCV infection after LT to assess whether HVPG correlates with liver histology, particularly fibrosis. A total of 90 consecutive patients underwent 170 HVPG measurements concomitant with transjugular liver biopsy (TJB), with 31.5 (range, 6–156) months of follow up. Median biopsy length was 22 mm and total portal tract count was 12 (complete 6, partial 6). Median HVPG was 4 mmHg: 38% of patients ≥6 mmHg (portal hypertension, PHT), 13% ≥10 mmHg. HVPG correlated with Ishak stage (r = 0.73, P < 0.001) for mild (0–3) and severe fibrosis (4–6), and grade score (r = 0.47, P < 0.001), but neither correlated with interval from LT nor biopsy length. HVPG was ≥10 mmHg in 15 patients: 12 had stage 5 or 6, and 3 severe portal expansion. HVPG was repeated in 49, between 7 and 60 months with weak correlation to fibrosis score (r = 0.30, P = 0.045). A total of 12 patients with HVPG ≥6 mmHg had fibrosis score ≤3, while 8 patients had normal HVPG but fibrosis stage ≥4. These discrepancies were mostly associated with specific histological features such as perisinusoidal fibrosis rather than errors in measuring HVPG. In 29 with HVPG <6 mmHg at 1 yr, none decompensated compared to 4 of 13 (31%) with PHT. In conclusion, HVPG correlates with fibrosis and its progression, due to recurrent HCV infection, assessed in TJB. Liver Transpl 13:1305–1311, 2007. © 2007 AASLD.

The severity of portal hypertension (PHT) correlates with the severity of liver disease and cirrhosis, both functionally and histologically1 and also with the Model for End-Stage Liver Disease,2 such that it has independent prognostic value separate from clinical and laboratory assessment.2, 3

Hepatic vein catheterisation4 was modified by Groszmann et al.5 using a balloon catheter. The measurement of hepatic venous pressure gradient (HVPG) (the difference between wedge hepatic venous pressure [WHVP] − free hepatic venous pressure) is reproducible6 and is the preferred technique for evaluating PHT, correlating 1:1 with the direct measurement of portal vein pressure in patients with sinusoidal and postsinusoidal causes of cirrhosis,7, 8 particularly alcoholic and viral-related cirrhosis. Normally HVPG ranges from 1 to 5 mmHg; pressures ≥6 mmHg indicate PHT.6

WHVP increases with progression of chronic hepatitis and PHT, before histologically detectable cirrhosis.9 A gradient >5 mmHg was always associated with significant changes in liver biopsy in 1 study, although a normal gradient did not completely rule out cirrhosis,10 suggesting that WHVP could provide supplementary information to liver biopsy, with a higher predictive value for assessing stage and activity of chronic liver disease, than routine biochemical tests.10 Other studies have correlated HVPG both with severity and etiology of cirrhosis,3, 7, 11 with only 1 study documenting a difference between HCV and alcoholic cirrhosis.12

A significant correlation has been shown between antiviral response and HVPG changes in HCV chronic hepatitis,13, 14 and between HVPG and histological features of cirrhosis.15 HVPG >10 mmHg predicts the development of complications of HCV cirrhosis.16 HVPG has been put forward as a test that would reflect progression during both precirrhotic and cirrhotic stages of HCV liver disease and be an end point in antiviral therapy, irrespective of antiviral response.17 Fibrosis associated with recurrent HCV infection after liver transplantation (LT).18–20 progresses faster to cirrhosis and decompensation compared to the pretransplantation HCV setting.21

Transjugular liver biopsy (TJB)22 enables multiple cores of tissue to be obtained23 and is easily combined with hemodynamic evaluations. The potential utility of HVPG as a hemodynamic marker related to HCV progression can be assessed providing due attention is paid to sampling of liver biopsies, as poor samples can lead staging and grading errors, particularly in HCV infection.24 A recent study did not evaluate HVPG in relation to TJB specimens (average length was only 1 cm,25) whereas HVPG was correlated with percutaneous liver biopsies taken 12 months after transplantation, with an average length of 1.5 cm. The latter is below the optimum for grading and staging.24

We performed a prospective study in patients receiving transplantion for HCV cirrhosis, correlating HVPG, which was routinely measured at the time of TJB, with histological stage and grade, and also quality of the specimens. We aimed to assess whether HVPG is a reliable measurement in the post-LT setting, thus helping to identify those patients with more severe recurrence and to assess potential benefit from antiviral treatment.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Patient Inclusion and Characteristics (Table 1)

From January 2002 to January 2006, we evaluated prospectively a series of 90 patients (65 males, 25 females) who had routine hepatic venography and pressure measurement at the time of TJB. Selection criteria were: 1) cadaveric whole liver orthotopic LT with primary diagnosis of HCV cirrhosis, 2) age >18 yr old, 3) at least 6 months post-LT. The study protocol conformed to the ethical guidelines of the Declaration of Helsinki. All patients gave written informed consent. Repeated measurements were made in 49 patients, mostly yearly in conjunction with protocol biopsies, unless an earlier biopsy was indicated. Regarding pretransplantation concomitant etiology, 3 with hepatitis B virus infection were hepatitis B virus DNA–negative post-LT under hepatitis B immunoglobulin and lamivudine. Among 10 with concomitant alcoholic etiology, 2 at follow-up biopsy were misusing alcohol. A total of 8 had received antiviral treatment before the first HVPG and 2 had sustained virological response, whereas 2 had relapsed and 4 did not respond or had discontinued therapy.

Table 1. Characteristics of the Cohort Population
  1. Abbreviations: ALD, alcoholic liver disease; HBV, hepatitis B virus; HDV, hepatitis D virus; HCC, hepatocellular carcinoma; FK, tacrolimus; AZA, azathioprine; MMF, mycophenolate mofetil; CsA, cyclosporine A; SIR, sirolimus; NA, not available.

Patient number90
 Male:female65:25
Age (yr) [median (range)]55 (36–74)
Months from transplant [median (range)]31.5 (6–156)
Pretransplantation concomitant etiology (number of patients) 
 ALD14
 HBV3
 HDV2
 HCC16
Genotypes (% of patients) 
 121%
 1b33%
 26%
 325%
 412%
 51%
 NA2%
Maintenance immunosuppression (% patients) 
 FK30%
 FK/AZA15%
 FK/MMF10%
 CsA15%
 CsA/AZA10%
 SIR7%
 SIR/MMF5%
Number of HVPG evaluations and liver biopsies190
Number of patients with multiple evaluations49
HVPG value (mmHg) [median (range)]4 (1–24)
Biopsy specimen length (mm) [median (range)]22 (6–46)
Number of fragments [median (range)]4 (1–9)
Median number of portal tracts 
 Complete + partial (range)12 (0–23)

TJB and Hemodynamic Study

All procedures were performed in the X-ray suite by experienced personnel (D.P., D.S., U.T., M.M., M.S.) after a 6-hours fast, under local anesthesia (lignocaine 1%, 5–10 mL subcutaneously); 70% of patients received intravenous sedation with 5–10 mg diazepam (Diazemulus; Dumex). The procedure has been detailed elsewhere23 using a 19G Tru-cut type biopsy needle (Quick core; Cook, William Cook Europe, Denmark). We performed 3 or 4 passes through the same hepatic vein wall (right or middle) to ensure that sufficient liver tissue was obtained. Hepatic vein pressures were measured using a 5-F balloon catheter (Royal Flush plus Straight Visceral Angiographic Beacon tip catheter-Cook-William Cook Europe) using the technique described by Groszmann and Wongcharatrawee.6 Three sets of measurements were taken using monitor DATASCOPE MEDICAL 2000A 6189-L7, setting the external 0 point at the mid-axillary line. A difference ≤ 1 mmHg of the free hepatic pressure gradient with the measured inferior vena cava pressure was considered acceptable. WHVP was measured for at least 1 minute each time. If there was movement from the patient or breathing artifacts, measurements were repeated. HVPG was calculated as the mean of the 3 gradients, the difference between WHVP minus free hepatic pressure gradient.

Biopsy Specimen Study

Liver biopsy samples were formalin fixed, paraffin-embedded, and stained with hematoxylin and eosin. Gordon and Sweet staining for reticulin, and chromotrope anilin blue or MSB staining were used to assess fibrosis. Each biopsy sample was evaluated histologically according to Ishak et al.26 for stage (fibrosis; 0–6) and necroinflammatory activity (grade: after combining the scores for piecemeal necrosis 0–4, confluent necrosis 0–6, focal necrosis 0–4, portal inflammation 0–4). We excluded 3 biopsies in which confluent necrosis was present. A stage score of 4 or more was considered as severe fibrosis (any portal tract with fibrosis outside it) and represented an easily defined dividing point from stage 3, which is solely fibrosis confined to the portal tract.

We recorded the number of liver fragments in each biopsy and its total length (lengths of each fragment summed), and the number of portal tracts per fragment and in total. Portal tracts were defined according to Crawford et al.27 i.e., “focus of connective tissue containing at least 2 luminal structures (either/or bile duct, portal vein or hepatic artery)”. A portal tract was considered complete, when its full circumference was visible, or when at least three-quarters of the circumference and 3 luminal structures were visible. A portal tract was considered partial when its circumference was incomplete but contained at least 2 luminal structures. Portal tracts were not counted in biopsies with severe distortion of the liver architecture, such as in cirrhosis or severe nodular expansion, because it is impossible to recognize and count individual portal tracts. For the purpose of the study we assumed there would be a normal WHVP and HVPG if the fibrosis was solely confined to portal tracts (presinusoidal PHT) and a raised HVPG if there was stage 4 or more. We planned a subgroup analysis of potentially discrepant results to evaluate factors, such as lobular inflammation, which could affect this.

Statistical Analysis

All data were analyzed using the statistical package SPSS (version 13.0; SPSS Inc, Chicago, IL). The chi-squared test was used for comparing quantitative variables. Quantitative variables normally distributed were expressed as mean values ± 1 standard deviation and nonnormally distributed as median values (range). Significance testing was 2 sided and set to <0.05. The correlation between HVPG and stage, grade, and total Ishak score was evaluated by Spearman correlation. Comparisons were made between first and last (paired) biopsies for stage, grade, and HVPG using Mann Whitney test; for the correlation between Δ(stage) vs. Δ(HVPG) we used Spearman's correlation. In the subgroup of paired biopsies, the proportions of patients with or without the presence of severe fibrosis (stage 0–3 vs. 4–6) and severe PHT (HVPG <6 vs. ≥10) were evaluated.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

There were 170 procedures in 90 patients, 49 of whom had repeated biopsies with a median of 24 months between the first and last (range, 7–60). All but 4 patients had HVPG and biopsy performed after 12 months from transplantation; all were stage ≤2. In the entire cohort the median HVPG was 4 mmHg (range, 1–24) and HVPG was ≥6 mmHg in 38% (n = 37 patients) of measurements; median free hepatic pressure gradient was 9 mmHg (range, 0–18) and median WHVP was 14 mmHg (range, 3–30). A total of 15 patients (22 procedures, 13%) had a clinically significant increase of HVPG (≥10 mmHg). In 12, the first biopsy was associated with stage 5 Ishak (n = 7) or established cirrhosis (n = 5). In the remaining 3 patients, all had Ishak stage 3 but with severe expansion of the portal tracts; there was no lobular inflammation. Of the 15 patients, 9 had repeat biopsies: 1 stage 3-patient had stage 5, whereas in the others, stage 5 (n = 2) and cirrhosis (n = 6) were again seen.

The median length of the liver biopsies was 22 mm (range, 6–46) and the number of fragments was 4 (range, 1–9). The median number of complete portal tracts was 6 (range, 0–23) and the number of partial portal tracts was 6 (range, 0–15). In cirrhotic patients and in those with severe portal expansion, the portal tract count was not performed (58 biopsies; i.e., 34% of the total). The median Ishak stage was 3 (range, 0–6) and grade was 4 (range, 0–9).

There were no major complications apart from 1 episode of supraventricular tachycardia, which disappeared with repositioning of the guidewire.

Correlation between the Hepatic Venous Pressure Measurements and Histology

Total Cohort

There was a significant correlation between Ishak stage (fibrosis) score and HVPG (Spearman's r = 0.73, P < 0.001) (Fig. 1). HVPG was also separately correlated with mild (portal) fibrosis (Ishak 0–3) or severe fibrosis, i.e., expansion with bridging (Ishak 4–5), and probable or definite cirrhosis (Ishak 6). Thus the relationship with HVPG held across the range of fibrosis. HVPG maintained its correlation with stage of fibrosis: Ishak 0–3, r = 0.47 (P < 0.001) and advanced fibrosis or cirrhosis, Ishak 4–6, r = 0.32 (P = 0.011).

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Figure 1. Ishak stage (fibrosis) score significantly correlates with HVPG (P < 0.001) in the entire patient cohort.

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HVPG correlated with Ishak grade score (r = 0.47, P < 0.001), piecemeal necrosis (r = 0.45, P < 0.001), focal necrosis (r = 0.40, P < 0.001), and portal inflammation (r = 0.33, P < 001). Total Ishak score also correlated with HVPG (r = 0.63, P < 0.0001). There was no correlation between the interval from transplantation and HVPG. Similarly, there was no correlation between HVPG and the total biopsy length, portal tract number, stage, or grade. In addition, no significant correlation was detected between fibrosis stage or grade and biopsy length or interval from transplantation.

There were 42 patients who had been measured at 12 months: 13 had PHT (HVPG ≥6 mmHg)—4 decompensated later (3 ascites, 1 variceal bleeding); in the 29 without PHT, none have decompensated as yet.

Patients with repeated biopsies.

Among the 49 patients who had repeated biopsies, 24 patients had 2 procedures, 19 patients had 3 procedures, and 6 patients had 4 or more procedures. The change in HVPG (Fig. 2) (expressed as difference between the last and first measurement) had a weak correlation with changes in fibrosis score (r = 0.30, P = 0.045). However, no significant correlation was found between change in grade and HVPG (P = 0.042) and median HVPG did not change (5 mmHg; range, 1–14). Regarding the whole paired group, the mean of the first evaluations for HVPG was 5.31 ± 2.9 vs. 6.29 ± 4.5 for the last (P = 0.82); when evaluating those with PHT at first measurement, a better correlation was found, with mean first HVPG at 8.4 ± 2.3 vs. 10 ± 5 for the last HVPG (P = 0.076).

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Figure 2. HVPG (first and last [second]) in patients with paired biopsies, according to normal (0–6), portal hypertension (6–9), and significant portal hypertension (>9).

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In the last biopsies 47% had severe fibrosis (score 4–6) compared to 34% in the first biopsies in this group of patients (Fig. 3). The median fibrosis score was 2 (range, 0–6) in the first biopsy vs. 3.5 (range, 0–6) in the last biopsy (P = 0.07). In 5, the last evaluation was done after termination of pegylated interferon and ribavirin without antiviral response: in 2, Ishak fibrosis score was stable (12 and 18 months after the end of treatment) but in the other 3 fibrosis had worsened (treatment stopped between 2 and 4 months before the last biopsy).

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Figure 3. Ishak stage (fibrosis) score divided as mild (0–3) vs. severe fibrosis (4–6) in patients with paired biopsies (first and last [second]). More patients in the last biopsies showed severe fibrosis.

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Patients with defined discrepancies between histology and pressure measurements.

There were 25 pressure evaluations (18 patients) that fulfilled our definition of potentially discrepant results with respect to the expected fibrosis stage or HVPG. The median biopsy length of the entire “discrepant” group was 22 mm (range, 13–30) and the number of fragments was 3.5 (range, 2–8) similar to the population as a whole. In the discrepant group, 56% of biopsies did not show severe nodularity/cirrhosis with 4 (range, 1–9) complete portal tracts and 8 (range, 2–13) partial portal tracts.

There were 16 measurements with fibrosis score <4 and HVPG ≥6 mmHg (range, 6–14 mmHg) (Group I) in 12 patients; 3 patients had a single evaluation and 9 had repeat evaluations 10 and 36 months after the first. In 6, severe fibrosis/cirrhosis was diagnosed, suggesting that underlying fibrosis was underdiagnosed in the first biopsy and may have accounted for most of the discrepancies in this group; in 2 histological evaluation was unchanged and in 1 mild fibrosis was seen, with HVPG being <6 mmHg. In the first biopsy, 8 of the 12 patients had pericellular/perisinusoidal fibrosis (no alcohol history) and 2 had sinusoidal changes with enlarged vacuolated macrophages. Inflammatory grade ≥4 was present in 80% of measurements.

In Group II, with normal HVPG but fibrosis score ≥4, there were 8 patients (9 measurements) and 3 had repeat evaluation. Two patients had less fibrosis, implying that there might have been an overestimation of the stage in the first biopsies, while 1 with a history of alcohol misuse had pericellular fibrosis in both biopsies and had no change in fibrosis score. In this group, the inflammatory grade was ≥4 in 78% of the measurements.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In this prospective study, hemodynamic evaluation of hepatic venous pressures was performed at the time of TJB in patients receiving LT for HCV cirrhosis, to assess the correlation with histological features as assessed by Ishak score. As the natural history of HCV is compressed and there can be rapid progression to cirrhosis within a few years, this transplant population is ideal for such a study. The need for histological follow-up allowed us to exploit the TJB, which is ideal to obtain sufficiently adequate samples.23

In the 90 patients, 38% showed at least 1 measurement with HVPG ≥6 mmHg. Clinically significant PHT (HVPG >10 mmHg),28 was present in 15 patients (17%) (22 assessments): in 20 there was cirrhosis, whereas in 2 assessments (2 patients who had resumed drinking alcohol) pericellular fibrosis with ballooned hepatocytes compatible with alcoholic-type injury was present and may have contributed to PHT.29

We used the widely accepted histological scoring system by Ishak et al.;26 one of its advantages is an easily recognizable difference between stage 3 and 4, and another advantage is that a precirrhotic stage (fibrosis stage 5) is allowed for, with the highest stage 6 representing probable or definite cirrhosis. In our cohort, followed between 6 months to 15 years, Ishak fibrosis score was significantly correlated with HVPG. Importantly, this correlation existed across the range from mild fibrosis (score 0–3) to advanced fibrosis (4–6). This confirms that in precirrhotic liver disease, at least due to HCV infection, portal pressure increases are reflected by HVPG measurement. Recently, in 23 alcoholic-related and 25 HCV-related patients with cirrhosis, HVPG correlated with small nodularity and increasing thickness of fibrous septae.15 Given that progression of fibrosis at different sites of the liver may be heterogeneous, the average pressure measured over a large area of stagnant flow (by occlusion of the balloon) may reflect fibrosis better than the comparatively small area analyzed by liver biopsy17; this means that HVPG may be a better measure to assess in repeated evaluations, as the error may be less than assessing changes in fibrosis stage.

The necroinflammatory activity, expressed as Ishak grade score, was also significantly correlated with HVPG; and as expected, so did the total Ishak score. Interestingly, each of the components of inflammation making up the Ishak grade score correlated with HVPG, suggesting that they also contribute to HVPG. The fact that the interval after transplantation did not have a correlation with HVPG and WHVP is an important one, suggesting that the pressure measurements are not related to other features, which may have a temporal relationship with the interval from LT, and that HVPG is sensitive to both early and late progression of recurrent HCV infection.

Although sampling error24, 30 always remains a potential bias in this type of study, we followed a protocol with 3 or 4 passes with a TJB to obtain sufficient tissue.23 We have shown that 3 passes results in a median length of 22 mm, CPT of 8, and PPT of 5,23 and that the evaluation of 3 cores is always better than 1.31 Microarchitectural variability at the liver periphery is greater than at deeper sites within the liver,27 so this could favor assessing fibrosis in liver biopsy cores obtained by TJB, if sampling is adequate. There was no correlation between HVPG and biopsy length, so that sampling error was minimized and thus the pressure correlations described are far more reliable. Indeed, the median specimen length was 22 mm, with a median 12 portal tracts (6 complete and 6 partial), both measurements similar to the best percutaneous liver biopsy studies.32–34

Optimal liver biopsies are crucial to any study correlating fibrosis to another parameter. In the recent study by Blasco et al.,25 which evaluated paired procedures (51 patients at 3 months and 65 patients at 12 months post–orthotopic LT) the average length was 10 mm (with TJB, 16-G needle) and 15 mm with percutaneous liver biopsy (14-G needle), with diagnostic agreement at histology between the 2 types of biopsy, with a total portal tract number of 7 (TJB) and 9 (percutaneous liver biopsy). This is the expected number of total portal tracts from the length of specimen.34 The authors did not differentiate whether complete, partial portal tracts, or both, were recorded. No biopsies beyond 1 yr were evaluated. A significant association between fibrosis stage and HVPG was found at 1 yr, the correlation was made with percutaneous liver biopsy and not TJB because of their small size, which was likely to be due to an aspiration technique, in contrast to Trucut biopsies as used in our study.34 A recent systematic review of TJB series from our group35 showed that compared to Menghini needle, specimens obtained with Trucut (using a similar number of passes) were longer (14.5 mm vs. 9.5 mm; P = 0.008), less fragmented (11.4% vs. 31.7%; P < 0.001), and had greater diagnostic adequacy (97.4% vs. 93.2%; P < 0.001). Importantly, despite apparent good correlation, they too report some discrepant results, attributing most of these to sampling error, but also to sinusoidal fibrosis in absence of alcohol intake.25 A study by Carrion et al.,36 based on an overlapping population of patients, but not biopsies, showed a correlation between HVPG and transient elastography. The latter, being a noninvasive test, will allow good monitoring of the progression of HCV disease if further studies show good correlation with HVPG.

In our cohort, 49 patients had 81 repeated measurements ranging from 7 to 60 months after the first procedure (median 24 months) (Figs. 2 and 3). Changes in HVPG were statistically correlated (P = 0.045) with changes in Ishak fibrosis score, even though 16 measurements were defined as discrepant. These results were not influenced by antiviral therapy as only 8 patients were treated, and only 1 had sustained virological response.

Our discrepant results occurred despite the optimal use of balloon occlusion and adequate sample size of biopsy. The majority of the discrepancies were associated with PHT despite mild fibrosis (<4) (Group I), with zone 3 changes: 8 biopsies had perisinusoidal/pericellular fibrosis and 3 had obstruction of sinusoids from foamy cells or vacuolated macrophages, which could account for raised HVPG. Moreover, among 9 who had a subsequent biopsy, 6 showed fibrosis ≥4, while 2 had the same pattern of HVPG/fibrosis. This again suggests that sampling variability and specific histological features,25 and not the variability in pressure measurements, accounts for most of the discrepancies.

However, there were 9 assessments in 8 patients with fibrosis ≥4 and a lower HVPG value than expected (Group II). Although a normal gradient does not completely rule out cirrhosis10 or severe fibrosis, this is rare. Qualitatively, the biopsies were similar to Group I biopsies. No significant pericellular fibrosis was seen; inclusion of the connective tissue normally seen in large (septal) portal tracts is responsible for overestimating fibrosis in chronic viral hepatitis.37 Therefore, this might account for some of this group's discrepancies.

It has been said that cirrhosis can be considered a vascular disease of the liver38 and that the hemodynamic parameters, splanchnic and renal, can describe severity. In this study we have shown that HVPG is a hemodynamic marker6 that can be used as a marker of fibrosis progression before cirrhosis, and, together with TJB, can be performed with an adequate technique to yield adequate samples.23 We recommend repeat histological sampling when there appear to be discrepant results. In agreement with Blasco et al.,25 we confirmed a correlation between HVPG and histological fibrosis stage at 1 yr and also in biopsies up to 5 yr. We also found, as did Blasco et al.,25 that if PHT was present at 1 yr (HVPG ≥6 mmHg), decompensation occurred: in our cohort 4 of 13 (31%) decompensated, compared to none of 29 without PHT. HVPG measurement can give additional information to the liver biopsy39 after LT for HCV cirrhosis, which may also be useful in the nontransplantation situation.2, 3, 7, 15–17, 40

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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