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Volume: 17 Issue: 5 October 2019

FULL TEXT

ARTICLE
Single-Center Retrospective Study of Clinical and Laboratory Features That Predict Survival of Patients With Budd-Chiari Syndrome After Liver Transplant

Objectives: Budd-Chiari syndrome is a rare but critical condition that can progress to liver failure and death. For severe cases, orthotopic liver transplant remains the only curative option. The present study aimed to identify predictive parameters to assess outcomes of liver transplant.

Materials and Methods: Medical records of 33 indi-viduals with Budd-Chiari syndrome who received orthotopic liver transplant were retrospectively assessed. Twenty-seven eligible patients were identified and grouped by outcome (survived/deceased) after transplant for Budd-Chiari syndrome. Demographic, clinical, and serum parameters taken at the time of Budd-Chiari syndrome diagnosis were evaluated for prognostic value.

Results: Differences between patients who survived and those who died were found for nausea/vomiting (P < .01) and splenomegaly (P < .01), which were both more common in patients who died after transplant. In addition, patients in the deceased group exhibited significantly lower serum cholinesterase levels (P < .01) and higher alkaline phosphatase levels (P < .01). Scoring systems to assess liver status or Budd-Chiari syndrome severity (Model for End-Stage Liver Disease and Child-Pugh scores, Rotterdam score, and the transjugular intrahepatic portosystemic shunting prognostic index) did not differ between groups.

Conclusions: Nausea/vomiting, splenomegaly, low serum cholinesterase, and high alkaline phosphatase were associated with adverse outcomes after orthotopic liver transplant for Budd-Chiari syndrome. These factors may be surrogate markers for a severely impaired health status at time of diagnosis and should be evaluated prospectively in larger cohorts.


Key words : Alkaline phosphatase, Cholinesterase, Nausea, Predictive value, Splenomegaly

Introduction

Budd-Chiari syndrome (BCS) is a rare and potentially life-threatening disorder. This syndrome arises from a hepatic venous outflow obstruction that can be located at any level from the small hepatic veins to the junction of the inferior vena cava with the right atrium.1,2 Hepatic outflow obstruction secondary to cardiac or pericardial diseases and sinusoidal obstruction syndrome are excluded from this definition.1

Depending on the underlying cause, BCS can be classified as primary BCS, when the obstruction is located endoluminally (eg, due to thrombosis), or secondary, when the obstruction is located outside the hepatic veins (eg, due to tumor or cyst).2

Prothrombotic conditions and hereditary diseases can lead to the development of primary BCS. The most frequent underlying prothrombotic conditions are myeloproliferative diseases, such as polycythemia vera, essential thrombocytosis, and idiopathic myelo-fibrosis.3 Other common causes are hereditary thrombophilia, including factor V Leiden, protein C/S deficiency, and G20210A prothrombin gene mutation.4 Further risk factors are acquired conditions, such as antiphospholipid syndrome, hyperhomocysteinemia, paroxysmal nocturnal hemoglobinuria, and use of oral contraceptives.5 Almost half of the patients affected by BCS have multiple underlying prothrombotic risk factors.4 Interestingly, in Asian populations, BCS is most often due to a membranous obstruction of the vena cava or primary inferior vena cava thrombosis.6 Data from China have described endoluminal aberrations caused by unknown factors (possibly related to environmental factors and infection) resulting in BCS.7 In the present study, only cases with BCS from the West were included; therefore, our study may not be applicable in BCS patients of Asian origin.

The clinical presentation of BCS depends on the rate of hepatic venous outflow obstruction and whether the pressure can be reduced by formation of decompressing collaterals. These 2 factors lead to highly variable disease courses that range from asymptomatic patients to fulminant liver failure.2,8 Most commonly, patients present with 3 main symptoms: ascites, abdominal pain, and hepatomegaly.5,8 Less common symptoms include nausea and vomiting, which are more often seen in fulminant forms.6 Splenomegaly, peripheral edema, caput medusae, gastrointestinal bleeding, and hepatic encephalopathy are more often seen in the chronic form.2,6,8

The diagnosis of BCS is mostly based on imaging methods such as Doppler ultrasonography, computed tomography, or magnetic resonance imaging (MRI). These techniques can show the hepatic venous outflow tract obstruction.9 There are no data available with regard to the diagnostic superiority of MRI over computed tomography, and MRI is not as effective as Doppler ultrasonography in documenting intrahepatic collaterals.10 The diagnosis can be challenging due to the heterogenous clinical presentation of individual patients, a nonspecific combination of laboratory analyses, and a range of possible differential diagnoses.11 Thus, BCS often remains undiagnosed until clinical presentation worsens.

Treatment options for BCS comprise antico-agulation, decompression therapies (such as throm-bolytic therapy), portosystemic shunting, transjugular intrahepatic portosystemic shunt (TIPS), and orthotopic liver transplantation (OLT), when the clinical condition deteriorates and other therapies fail.5

In this study, our aim was to identify early prognostic markers that can predict overall mortality in BCS patients after OLT. For this, data from 27 BCS patients who underwent OLT in our institution were retrospectively analyzed, with emphasis on clinical presentation and laboratory features at time of first diagnosis.

Materials and Methods

Patient cohort and study design
From the Eurotransplant database, we identified 33 patients with BCS (12 men, 21 women), who underwent OLT at the University Hospital Essen between July 1989 and March 2016. During this period, 2426 total patients had received liver transplant procedures at the University Hospital Essen. Among these were 261 living-donor transplant procedures. Data were collected retrospectively from the database and by analyses of patient medical records. Four patients were excluded due to incomplete clinical data. Among patients who survived until the end of follow-up, 2 required retransplant procedures and were excluded due to this severe event. In one case, organ failure due to a cholangitis occurred with retransplant 9 days after the first OLT. In the other case, liver cirrhosis developed, with retransplant occurring 8 years after the first transplant. The final cohort thus comprised 27 patients (Figure 1).

Demographic and clinical data, as well as serum parameters taken at the time point of first diagnosis, were evaluated. Time from diagnosis to OLT, patient survival, and causes of death were recorded. Serum parameters included leukocyte counts and C-reactive protein (CRP) levels as markers of inflammation. Parameters reflecting synthesis capacity of the liver included coagulation parameters (international normalized ratio, activated partial thromboplastin time, thrombin time, and antithrombin levels), albumin, and cholinesterase. Because cholinesterase was not routinely detected over the whole period of retrospective recruitment, for 7 patients, no cholinesterase measurements were available. Serum parameters usually associated with damage of liver parenchyma (alanine aminotransferase, aspartate aminotransferase) and markers of cholestasis (total/direct bilirubin, alkaline phosphatase, and gamma-glutamyltransferase levels) were evaluated. Renal function was estimated via creatinine serum concentrations. In addition, various prognostic scores were calculated, including Model for End-Stage Liver Disease (MELD) score, Child-Pugh score, BCS TIPS prognostic index, and the Rotterdam index, to identify or confirm a possible predictive value for overall mortality of patients after OLT.

This study was performed in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines and was approved by the local insti-tutional review board (Ethik-Kommission am Universitätsklinikum Essen, 16-7045-BO). Because of the retrospective nature of this study, the institutional review board waived the requirement for written informed consent.

Statistical analyses
Categorical data are presented as numbers and percent, and continuous data are shown as means and standard error or median and range. To identify prognostic parameters for prediction of mortality in BCS patients after OLT, the patient cohort was divided into 2 groups. Group 1 contained all patients who survived after OLT (18 patients), and group 2 contained all patients who died within follow-up after OLT (9 patients).

Differences between the groups were assessed with two-tailed unpaired t tests (continuous data) and the Fisher exact test (categorical data). Statistical significance was assumed at P < .05. Patient survival after OLT was evaluated using Kaplan-Meier curves.Statistical analyses were performed using Excel 2007 version 12 for Windows (Microsoft Corporation, Redmond, WA, USA), Prism version 5 for Windows (GraphPad Software, La Jolla, CA, USA), and QuickCalcs (GraphPad Software, San Diego, CA, USA).

Results

Patients with Budd-Chiari syndrome who survive after transplant are younger
The median age of the 27 patients with BCS who underwent OLT was 35 years (range, 15-63 y); 18 (66.7%) were women, and 9 (33.3%) were men. The survival group included 18 patients who survived until end of follow-up (median follow-up duration was 49.2 mo; range, 0.3-287.5 mo). Group 2 included 9 patients (33.3%) who died after OLT. Causes of death were liver failure (n = 2), sudden death due to heart failure (n = 2), cholangitis with abscess (n = 1), sepsis with multiorgan failure (n = 1), intracerebral hemorrhage (n = 1), and pneumonia (n = 1). Cause of death was unknown in 1 patient. Median time between diagnosis and OLT was 2 months (range, 0.07-119.8 mo), and median time between OLT and death was 14.1 months (range, 0.3-211.4 mo). The 1-year, 5-year, and 10-year survival rates were 85.2%, 74.1%, and 74.1%, respectively (Figure 2).

Patients in group 2 were on average older than patients in group 1 (39 ± 4 vs 34 ± 2 years old; P > .05). The mean body mass index of the total cohort was 25.5 ± 0.7 kg/m2, which did not differ significantly between the groups (25.4 ± 0.8 kg/m2 in group 1 vs 25.8 ± 1.5 kg/m2 in group 2; P = .88).

Cause of Budd-Chiari syndrome does not affect survival after transplant
Twenty-five patients (92.6%) developed primary BCS due to any prothrombotic risk constellation. Secondary BCS occurred in 2 patients; with 1 caused by an angiosarcoma and the other caused by echinococcosis. Of the 25 patients affected by primary BCS, 16 patients (64%) presented with at least 1 prothrombotic risk factor, 7 patients (28%) had a combination of 2 to 4 risk factors, and 4 patients (16%) did not have any risk factor with the prothrombotic constellation. None of the observed risk constellations were associated with mortality after OLT in patients with BCS. The exact distribution of individual prothrombotic risk factors is given in Table 1.

Nausea/vomiting and splenomegaly at diagnosis are associated with death after transplant
The initial clinical presentation of the cohort is presented in Table 2. The most common symptoms were ascites (77.8%), abdominal pain (74.1%), and hepatomegaly (33.3%). Other symptoms were nausea and vomiting (29.6%), esophageal varices (29.6%), fatigue (22.2%), icterus (22.2%), splenomegaly (14.8%), pleural effusion (11.1%), peripheral edema (11.1%), fever (11.1%), renal insufficiency (7.4%), and hepatic encephalopathy (7.4%). Group 2 had significantly more incidences of nausea and vomiting (P = .006) and palpable splenomegaly (P = .007). Thus nausea and vomiting and palpable splenomegaly might have a prognostic value for survival after OLT for BCS.

Prognostic scores for Budd-Chiari syndrome are not predictive for survival after liver transplant
Several prognostic scores, which have been suggested as predictive for survival in liver diseases or BCS, were calculated for the study cohort to identify a possible prognostic value to predict mortality of BCS patients after OLT. The BCS TIPS prognostic index, Rotterdam index, and MELD and Child-Pugh scores were evaluated. Patients in group 2 had higher and therefore potentially worse scores than group 1, although the differences did not reach statistical significance (Table 3).

Alkaline phosphatase and cholinesterase differed significantly between Budd-Chiari syndrome patients who survived or died after liver transplant
Routine laboratory parameters from the time of first diagnosis were compared between group 1 and group 2 (Table 4). On average, patients presented with elevated leukocyte counts (15.38 ± 1.81/nL) and elevated CRP (6.76 ± 1.2 mg/dL) as possible inflammation reactions. Coagulation parameters reflecting the synthesis capacity of the liver were above the normal range, indicating impaired liver function. Antithrombin and albumin levels, which are synthesized in the liver and therefore represent synthesis capacity of the liver, were below standard values. Serum concentrations of markers for liver damage, including aspartate aminotransferase (567.82 ± 262.07 U/L) and alanine aminotransferase (510.95 ± 223.96 U/L), were greatly above reference ranges. Concentrations of serum markers for cholestasis (gamma-glutamyltransferase and bilirubin) were elevated over reference ranges. Mean creatinine serum concentration as a surrogate marker of renal function was within the normal range. None of these factors differed between group 1 and group 2 (Table 4).

Serum concentrations of the cholestasis marker alkaline phosphatase were elevated above the normal range in our study group (247.46 ± 35.29 U/L), and concentrations of the liver synthesis marker cholinesterase (3.75 ± 0.47 U/mL) were reduced (Figure 3). Patients in group 2 had significantly higher levels of alkaline phosphatase (389.86 ± 54.35 U/L; P = .009) and significantly lower levels of cholinesterase (2.17 ± 0.26 U/mL; P = .004) compared with group 1 (185.87 ± 37.75 U/L and 4.61 ± 0.66 U/mL, respectively). High alkaline phosphatase and low cholinesterase serum concentrations early during the BCS course could have a predictive value for survival of BCS patients after OLT.

Discussion

In this retrospective study, we analyzed 27 patients who underwent OLT for liver failure due to BCS. Demographic, clinical, and diagnostic data were evaluated with special emphasis on serum parameters and prognostic scores at time of first diagnosis. Our aim was to identify parameters predictive of patient outcomes after OLT. The analyzed prognostic scores did not differ significantly between patients who survived and patients who died, which is in line with a study of 248 BCS patients who had OLT; that study demonstrated no prognostic value for the Rotterdam index for outcome after OLT.12 Nausea and vomiting and palpable splenomegaly at time of BCS diagnosis were significantly different between our outcome groups after OLT. Low serum concentrations of cholinesterase and high alkaline phosphatase serum levels were associated with adverse outcomes after OLT for BCS. The demographic characteristics of the presented cohort were quite similar to cohorts published in European and American studies.4,12-16 In addition, our 1-, 5-, and 10-year survival rates were similar to other studies and indicated that OLT provided good outcomes for treatment of BCS.12-14

The risk factors or causes of BCS found in our study were similar to previously published series.3,4 None of the prothrombotic risk factors seemed to have a negative impact on survival, which has been suggested previously.3,17 Demographic data versus risk factors of the presented BCS cohort were also similar to these previously published cohorts.

For patients with BCS, the most common symptoms are ascites (76%-100%), abdominal pain (45%-86%), and hepatomegaly (43-83%).18 Less common symptoms include palpable splenomegaly. Interestingly, patients in our study who presented with this symptom at first diagnosis had increased mortality after OLT, which to our knowledge has not been previously observed. A possible explanation for this finding based on pathophysiology of BCS may be portal hypertension as underlying cause of sple-nomegaly.3,19 It could be possible that splenomegaly is an early sign of an undiagnosed portal hyper-tension, which negatively affects survival.20 Other often disregarded clinical symptoms are nausea and vomiting. However, patients in our study who had nausea and/or vomiting at first diagnosis had a worse outcome after OLT. Nausea and vomiting are usually unspecific symptoms and can be due to multiple reasons. Organomegaly or massive ascites can lead to gastrointestinal compression, which can cause nausea and vomiting.21 Ascites has been described as a negative prognostic factor in BCS patients.4 In our study, we could not distinguish between massive or moderate ascites. Nausea and vomiting could be the result of massive ascites or indicative of increased gastrointestinal compression. Patients in our study with splenomegaly and nausea/vomiting at first diagnosis showed adverse outcomes after OLT for BCS. These symptoms might be surrogate signs for a more severe cause or already present consequences of BCS, which cannot be detected otherwise.

Routine laboratory parameters showing impaired liver synthesis capacity generally indicate a com-promised health status at the time of first diagnosis. Leukocytosis and elevated CRP levels suggest an acute phase reaction,22 although leukocytosis could also have been a consequence of myeloproliferative diseases present in 40.7% of our cases. Deficiency of coagulation factors leads to the observed prolongation of thrombin time and activated partial thromboplastin time, which reflect an impairment of liver synthesis capacity. This is supported by low levels of antithrombin, albumin, and cholinesterase as these are also synthesized in the liver.22,23 In addition, elevated markers of liver injury and cholestasis can be detected.22,23 Compared with previously published data, our present cohort exhibited higher levels of liver and cholestasis markers,4,15,24-28 whereas albumin was similar to other cohorts.4,15,25,26 Generally, our present cohort seemed to have more severe liver damage with similar capacity of synthesis compared with other published cohorts. The observed differences may be a consequence of our limitation to BCS patients who underwent OLT.

The most important aim of the presented study was to find predictive factors for survival after OLT. Serum concentrations of cholinesterase were significantly lower and alkaline phosphatase was significantly higher in patients who died compared with those who survived. Cholinesterase is an α-glycoprotein synthesized in the liver29 and has been identified as a prognostic factor after OLT in patients with cirrhosis, hepatitis B and C virus, and primary sclerosing cholangitis.30 Low cholinesterase levels are associated with negative prognosis in patients with cervical and pancreatic carcinoma.29 Severe liver damage presenting with reduced protein synthesis, massive liver cell death, or malnutrition can result in reduced cholinesterase.23,29 Although the body mass index shown in our cohort did not indicate malnutrition, more than 80% of patients had ascites, which can affect body mass index and complicate interpretation. Low cholinesterase could be a sign of malnutrition, which can lead to high postoperative mortality.30 Furthermore, serum concentrations of cholinesterase are negatively correlated with interleukin 6 and tumor necrosis factor α. Although these cytokines were not measured in our study cohort, increased inflammatory signaling would be in line with the observed leukocytosis and elevated CRP.

Alkaline phosphatase is a glycoprotein produced in several tissues (liver, biliary duct, and kidney).31 A negative impact of high alkaline phosphatase levels on prognosis of patients with hepatocellular, gastric, pancreatic, and colorectal cancer has been previously shown.32 High activities of alkaline phosphatase correlating with CRP are also present in inflam-mation.33 High alkaline phosphatase activities can lead to atherosclerosis,34 which could facilitate progression of BCS and aggravate the clinical situation. Portal hypertension also leads to elevated alkaline phosphatase activities, which has been identified to have a negative impact on survival.20 Together, low cholinesterase and high alkaline phosphatase levels pretransplant in patients with BCS suggest a more severe situation, possibly as indirect markers of inflammation, malnutrition, or progressive vascular damage. Our findings need to be interpreted with care due to the retrospective nature over a long period of time, affecting diag-nostic procedures and data availability. Budd-Chiari syndrome is a rare condition, and the analysis was restricted to patients who received OLT, leading to a limited number of patients. However, rigorous statistical analysis was applied to minimize the effects of these limitations.

Conclusions

Early pretransplant clinical features and serum concentrations of cholinesterase and alkaline phos-phatase may be able to assist in estimating survival of BCS patients after OLT. A larger prospective study could confirm whether a combination of palpable splenomegaly, nausea and vomiting, elevated alkaline phosphatase, and low cholinesterase might improve prediction of outcomes of OLT in patients with BCS.


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Volume : 17
Issue : 5
Pages : 665 - 672
DOI : 10.6002/ect.2018.0274


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From the 1Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany; the 2Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany; the 3Department of Power Transmission and Storage, University of Duisburg-Essen, Duisburg, Germany; and the 4Department of General, Visceral and Transplantation Surgery, University Hospital, University Duisburg-Essen, Essen, Germany
Acknowledgements: The authors have no funding or conflicts of interest to declare. *Barbara Jeschke and Aline Gottlieb contributed equally to this work.
Corresponding author: Ali Canbay, Hepatology and Infectious Diseases, Otto-von-Guericke University, Leipzigerstr. 44, 39120 Magdeburg, Germany
Phone: +49 391 67 13100
E-mail: ali.canbay@med.ovgu.de