Non-cirrhotic Portal Fibrosis Research Articles

Reliability of splenic stiffness in prediction of variceal bleeding and high-risk varices in non-cirrhotic portal fibrosis (NCPF)

Reliability of splenic stiffness in prediction of variceal bleeding and high-risk varices in non-cirrhotic portal fibrosis (NCPF)

Role of splenic hepatic elastography ratio in differentiating non-cirrhotic portal fibrosis and chronic liver disease in children and adolescents.

Differentiation of Non-cirrhotic Portal Fibrosis (NCPF) from chronic liver disease (CLD) in children and adolescents with portal hypertension (PHT) is challenging especially in cases where liver stiffness measurement (LSM) and hepatic venous pressure gradient are higher. This objective of the current study was to evaluate the diagnostic accuracy of the splenic stiffness measurement (SSM)/LSM ratio in the diagnosis of NCPF. From January 2019 to December 2023, consecutive children and adolescents of 6months to 18years of age with PHT (CLD and NCPF) were prospectively enrolled. Transient elastography (TE) for SSM and LSM, upper gastrointestinal endoscopy (UGIE), liver biopsy/trans-jugular liver biopsy, abdominal imaging, and laboratory evaluation were done. The relationship of TE parameters for diagnosis of NCPF and CLD was evaluated. Receiver-operating characteristic (ROC) statistics were applied using R Studio-4.2.2 statistical software. One hundred and forty seven with CLD and 27 patients with NCPF were evaluated. Median age was 10.0 (IQR 2.4-14.0) years; 68.4% were males. The AUROC of SSM/LSM ratio was better (0.992, 95%CI 0.982-1.0001) than LSM (0.945, 95%CI0.913-0.977) and SSM (0.626, 95%CI0.258-0.489) for the diagnosis of NCPF. SSM/LSM ratio cut-off of 3.67 predicted NCPF with an excellent sensitivity (100%), specificity (95.9%), and diagnostic accuracy (95.91%). The AUROC of SSM/LSM ratio was excellent and outperformed other TE parameters in the subgroups, i.e., LSM between 10 and 20kPa (0.982, 95%CI 0.947-1.000), without clinically significant varices (CSV) (1.000, 95%CI 1.000-1.000) and with CSV (0.993, 95%CI 0.983-1.000). Diagnostic performance of SSM/LSM Ratio was better than LSM for discriminating NCPF from CLD using McNemar test (p = 0.01). The SSM/LSM ratio is an excellent tool in differentiating NCPF from CLD.

Hepatic Cirrhosis with Esophageal Varices: A Case Report

Background: In adults, portal hypertension is generally caused by hepatic cirrhosis, whereas in children it is more commonly caused by extrahepatic abnormalities with normal liver function. Portal hypertension causes hemodynamic abnormalities. Gastrointestinal bleeding is the most severe clinical manifestation of portal hypertension in both children and adults. Pathogenetically, increased pressure in the portal vein can be caused by increased vascular resistance and increased portal blood flow. The site of obstruction can be prehepatic (portal vein obstruction), intrahepatic (presinusoidal: eg congenital hepatic fibrosis; para sinusoidal: cirrhosis, hepatotoxic drug therapy, vitamin A hepatotoxicity; post sinusoidal: venocclusive disease) and/or post hepatic (Budd-Chiari syndrome, constrictive pericarditis). Case presentation: The study reports the results of observations of a case of a boy, FAA, aged 12 years and 2 months who came to the emergency room at Dr. M. Djamil General Hospital Padang with the main complaint of hematemesis and splenomegaly from physical examination. Non cirrhotic portal fibrosis is a cause that is not uncommon in the population in the early second decade of life. Some children with non-cirrhotic portal fibrosis as adults can end up with end stage liver disease. Conclusion: Patients with noncirrhotic or cirrhotic portal hypertension can be assessed using the Child Pugh instrument as an instrument that is still used to determine the survival rate if patients with portal hypertension.

Idiopathic Portal Hypertension: A Case Report of an Adult Indian Rural Female of “Banti Syndrome”

Non-cirrhotic portal fibrosis (NCPF)/idiopathic portal fibrotic hypertension (IPH) is one of the major diseases that include a group of diseases caused by increased portal venous pressure which is thought to be due to intrahepatic or prehepatic lesions in the absence of liver cirrhosis. In the present case a 35-year-old female presented with abdominal fullness and pain in the upper abdomen for the past two months which was not associated with the consumption of water or food, nausea, or vomiting. When we investigated it was seen that she had severe anemia with pancytopenia with no malarial parasite on peripheral smear, liver renal and liver function tests were within the normal range. The diagnosis of Banti’s syndrome was made. However, the patient was then vitally stable and was started on propranolol and was advised for splenectomy due to refractory anemia. The present study provides easy and conventional diagnostic techniques for clinical diagnosis and proves the radiological technique.

Machine learning can guide suitability of consultation and patient referral through telemedicine for hepatobiliary diseases.

Telemedicine is an evolving tool to provide health-care services. We evaluated the suitability of telemedicine to deliver effective consultation for hepatobiliary disorders. In this prospective study spanning over a year, we interviewed hepatologists delivering the teleconsultations through a pre-validated questionnaire. A consult was deemed suitable based on the physician's judgment in the absence of unplanned hospitalization. We evaluated factors determining the suitability through inferential statistics and machine learning models, namely, extreme gradient boosting (XGB) and decision tree (DT). Of 1118 consultations, 917 (82.0%) were deemed suitable. On univariable analysis, patients with skilled occupation, higher education, out-of-pocket expenses, and diseases such as chronic hepatitis B, C, and non-alcoholic fatty liver disease (NAFLD) without cirrhosis were associated with suitability (P<0.05). Patients with cirrhosis (compensated or decompensated), acute-on-chronic liver failure (ACLF), and biliary obstruction were likely unsuitable (P<0.05). XGB and DT models predicted suitability with an area under the receiver operating curve of 0.808 and 0.780, respectively. DT demonstrated that compensated cirrhosis with higher education or skilled occupation with age <55years had 78% chance of suitability whereas hepatocellular carcinoma, decompensated cirrhosis, and ACLF patients were unsuitable with a 60-95% probability. In non-cirrhotic liver diseases, hepatitis B, C, and NAFLD were suitable, with a probability of 89.7%. Biliary obstruction and previous failure of teleconsultation were unsuitable, with a probability of 70%. Non-cirrhotic portal fibrosis, dyspepsia, and dysphagia not requiring intervention were suitable (probability: 88%). A simple decision tree can guide the referral of unsuitable and the management of suitable patients with hepatobiliary diseases through telemedicine.

Prevalence of Celiac Disease in adult patients with Non-Cirrhotic Portal Fibrosis

Prevalence of Celiac Disease in adult patients with Non-Cirrhotic Portal Fibrosis

Porto-sinusoidal vascular disorder.

It is well established that portal hypertension can occur in the absence of cirrhosis, as reported in patients with immune disorders, infections and thrombophilia. However, similar histological abnormalities primarily affecting the hepatic sinusoidal and (peri)portal vasculature have also been observed in patients without portal hypertension. Thus, the term porto-sinusoidal vascular disorder (PSVD) has recently been introduced to describe a group of vascular diseases of the liver featuring lesions encompassing the portal venules and sinusoids, irrespective of the presence/absence of portal hypertension. Liver biopsy is fundamental for PSVD diagnosis. Specific histology findings include nodular regenerative hyperplasia, obliterative portal venopathy/portal vein stenosis and incomplete septal fibrosis/cirrhosis. Since other conditions including alcohol-related and non-alcoholic fatty liver disease, or viral hepatitis, or the presence of portal vein thrombosis may occur in patients with PSVD, their relative contribution to liver damage should be carefully assessed. In addition to histology and clinical diagnostic criteria, imaging and non-invasive tests such as liver and spleen stiffness measurements could aid in the diagnostic workup. The introduction of PSVD as a novel clinical entity will facilitate collaborative studies and investigations into the underlying molecular pathomechanisms encompassed by this term.

Maternal and perinatal outcome in pregnancies complicated with portal hypertension: a systematic review and meta-analysis.

Portal hypertension is secondary to either cirrhotic or non-cirrhotic causes, and complicating pregnancy poses a challenge to the treating team. A systematic review was performed to determine maternal and perinatal outcomes in women with portal hypertension. Outcomes were compared among those with cirrhotic (CPH) with non-cirrhotic portal hypertension (NCPH) as well as non-cirrhotic portal fibrosis (NCPF) with extra-hepatic portal vein obstruction (EHPVO). Medline and EMBASE databases were searched for studies reporting outcomes among pregnant women with portal hypertension. Reference lists from relevant papers and reviews were hand-searched for appropriate citations. Data were extracted to describe maternal complications, obstetric and neonatal outcomes. A random-effects model was used to derive pooled estimates of various outcomes, and final estimates were reported as percentages with a 95% confidence interval (CI). Cumulative, sequential and sensitivity analysis was studied to assess the temporal trends of outcomes over the period. Information on 895 pregnancies among 581 patients with portal hypertension was included from 26 studies. Portal hypertension was diagnosed during pregnancy in 10% (95% CI 4-24%). There were 22 maternal deaths (0%, 95% CI 0-1%), mostly following complications from variceal bleeding or hepatic decompensation. Variceal bleeding complicated in 14% (95% CI 9-20%), and endoscopic interventions were performed in 12% (95% CI 8-17%) during pregnancy. Decompensation of liver function occurred in 7% (95% CI 3-12%). Thrombocytopenia was the most common complication (41%, 95% CI 23-60%). Miscarriages occurred in 14% (95% CI 8-20%), preterm birth in 27% (95% CI 19-37%), and low birth weights in 22% (95% CI 15-30%). Risk of postpartum hemorrhage was higher (RR 5.09, 95% CI 1.84-14.12), and variceal bleeding was lower (RR 0.51, 95% CI 0.30-0.86) among those with CPH compared to NCPH. Risk of various outcomes was comparable between NCPF and EHPVO. One in ten pregnancies complicated with portal hypertension is diagnosed during pregnancy, and thrombocytopenia is the most common complication. Hepatic decompensation and variceal bleeding remain the most common cause of maternal deaths, with reduced rates of bleeding and its complications reported following the introduction of endoscopic procedures during pregnancy. CPH increases the risk of postpartum hemorrhage, whereas variceal bleeding is higher among NCPH.

A Case of Acquired Hepato-Cerebral Degeneration after Splenorenal Shunt from Ethiopia

Acquired hepato-cerebral degeneration (AHD) is a neurologic syndrome caused by liver dysfunction and long-standing portosystemic shunting. There is scarce and conflicting information regarding the clinical course of AHD. We report the case of a 25-year-old male who underwent splenectomy and splenorenal shunt for recurrent UGIB 20 to Esophageal varices 20 to Non-Cirrhotic portal hypertension 20 to Non-Cirrhotic portal fibrosis and hypersplenism, in Mumbai, India. He presented with slow movement, hypophonia, gait instability, and rigidity of the lower extremities. In this paper, we discuss the patient’s case with literature review.

Use of caudal pancreatectomy as a novel adjunct procedure to proximal splenorenal shunt in patients with noncirrhotic portal hypertension: A retrospective cohort study.

Backgrounds/AimsProximal splenorenal shunt (PSRS) is considered a one-time treatment for noncirrhotic portal hypertension (NCPH) to prevent recurrent upper gastrointestinal (UGI) hemorrhage and long-term complications. Long-term shunt patency is necessary to achieve these. The lie of the shunt is a contributing factor to early shunt thrombosis. We investigated the role of resection of the distal tail of pancreas (caudal pancreatectomy [CP]) in improving the lie of shunt and decreasing shunt thrombosis.MethodsThis was a retrospective cohort study of patients with NCPH who underwent PSRS between 2014-2020 in JIPMER, Puducherry, India. CP was performed in patients with a long tail of pancreas, with the tip of pancreatic tail extending up to splenic hilum on preoperative CT. Perioperative parameters and shunt patency rate of patients who underwent PSRS with CP (Group A) were compared with patients undergoing conventional PSRS (Group B). Statistical analysis was performed using the Mann-Whitney U test and χ2 test.ResultsEighty four patients with NCPH underwent PSRS (extrahepatic portal vein obstruction = 39; noncirrhotic portal fibrosis = 45). Blood loss was lower (p = 0.002) and post-shunt fall in portal pressure higher (p = 0.002) in Group A. Shunt thrombosis rate was lower (p = 0.04) while rate of complete variceal regression (p = 0.03) and biochemical pancreatic leak (p = 0.01) were higher in Group A.There was no clinically relevant pancreatic fistula in either group.ConclusionsCP is a safe and useful technique for reducing shunt thrombosis after PSRS in patients with NCPH by improving the lie of shunt.

Ultrasound and Computed Tomography Features of Non Cirrhotic Portal Hypertension caused due to Non Cirrhotic Portal Fibrosis and Extrahepatic Portal Vein Obstruction: A Retrospective Study

Introduction: Non Cirrhotic Portal Hypertension (NCPH) encompasses a wide range of disorders that are characterised by increased portal pressure with the absence of cirrhosis of liver. The disorders are classified anatomically based on the site of blood flow obstruction into prehepatic, hepatic and posthepatic causes. These numerous and variable aetiological factors and the lack of standardised diagnostic criteria, makes NCPH under-recognised both clinically and pathologically and often being falsely labelled as cryptogenic cirrhosis. Therefore, it is important for radiologists to be aware of the imaging features that constitute NCPH for its early recognition, so that appropriate management can be carried out. Aim: To assess the distinct ultrasound and Computed Tomography (CT) features of the two main causes of NCPH: Non Cirrhotic Portal Fibrosis (NCPF) and Extrahepatic Portal Venous Obstruction (EHPVO). Materials and Methods: This retrospective observational study included all radiologically diagnosed cases of NCPH who underwent ultrasound and CT examination at the Institution between June 2020-June 2021. A total of 10 patients met the inclusion criteria. The various imaging features of NCPF and EHPVO were analysed and tabulated. Results: The study showed male predominance with males and females being seven and three, respectively. The mean age of the patients in the study was 35.1 years. The common cause in both NCPF and EHPVO was idiopathic. The most characteristic imaging finding in EHPVO was cavernous transformation of the portal vein seen in all cases and that in NCPF being dilatation of the spleno-portal axis and mural thickening of the main portal vein seen in all the cases. Conclusion: The present study demonstrated the characteristic imaging features of NCPF and EHPVO which are leading cause of NCPH, facilitating radiologist to identify the conditions and not label cases with Portal Hypertension (PHT) as cryptogenic cirrhosis.

Pediatric non-cirrhotic portal hypertension: Endoscopic outcome and perspectives from developing nations.

Non-cirrhotic portal hypertension (NCPH) forms an important subset of portal hypertension in children. Variceal bleed and splenomegaly are their predominant presentation. Laboratory features show cytopenias (hypersplenism) and preserved hepatic synthetic functions. Repeated sessions of endoscopic variceal ligation or endoscopic sclerotherapy eradicate esophageal varices in almost all cases. After variceal eradication, there is an increased risk of other complications like secondary gastric varices, cholangiopathy, colopathy, growth failure, especially in extra-hepatic portal vein obstruction (EHPVO). Massive splenomegaly-related pain and early satiety cause poor quality of life (QoL). Meso-Rex bypass is the definitive therapy when the procedure is anatomically feasible in EHPVO. Other portosystemic shunt surgeries with splenectomy are indicated when patients present late and spleen-related issues predominate. Shunt surgeries prevent rebleed, improve growth and QoL. Non-cirrhotic portal fibrosis (NCPF) is a less common cause of portal hypertension in children in developing nations. Presentation in the second decade, massive splenomegaly and patent portal vein are discriminating features of NCPF. Shunt surgery is required in severe cases when endotherapy is insufficient for the varices. Congenital hepatic fibrosis (CHF) presents with firm palpable liver and splenomegaly. Ductal plate malformation forms the histological hallmark of CHF. CHF is commonly associated with Caroli’s disease, renal cysts, and syndromes associated with neurological defects. Isolated CHF has a favourable prognosis requiring endotherapy. Liver transplantation is required when there is decompensation or recurrent cholangitis, especially in Caroli’s syndrome. Combined liver-kidney transplantation is indicated when both liver and renal issues are present.

Safety, Feasibility, Yield, Diagnostic and Prognostic Implications of Transjugular Liver Biopsy in Children and Adolescents.

The objectives of the study were to evaluate the indications, feasibility, complications and clinical implications of transjugular liver biopsy (TJLB) in children. Data of all TJLB performed in children <18 years old was retrieved from the computerized hospital information system. TJLB was done using a 19 G quick-core needle biopsy system with 20 mm throw length. Hepatic venous pressure gradient was additionally measured in children with portal hypertension. A single pathologist reviewed all the biopsies again and provided structured information. A total of 102 children, including 5 with acute liver failure underwent TJLB with technical success in 101 (99%). A mean of 2.3 ± 0.9 passes (range: 1-5) was taken for the biopsy. The most common indications for TJLB in our cohort were elevated international normalized ratio >1.5 (66, 64.7%), ascites (46, 45.1%) and thrombocytopenia (platelet count < 60,000/mm3) (42, 41.2%). Mean size of the tissue received was 14.5 ± 5.6 mm with an average of 10.2 ± 4.7 portal tracts. Only one child developed major (category D) complication (hemobilia) and 12 (11.8%) developed minor complications post-procedure. Etiological diagnosis could be made in a total of 64 (63.9%) children undergoing TJLB, the most common diagnosis being autoimmune hepatitis (n = 31), non-cirrhotic portal fibrosis (n = 16) and drug-induced liver injury (n = 4). TJLB is well tolerated, feasible and helps make a diagnosis in close to 64% children allowing timely medical and/or surgical intervention. It is especially useful for diagnosis of autoimmune liver diseases, drug-induced liver injury and non-cirrhotic portal fibrosis.

Guidewires as Embolic Agents? Embolotherapy of Large Splenic Artery Aneurysms

AbstractSplenic artery aneurysms are among the more frequently diagnosed intra-abdominal aneurysms and are not infrequent in patients with raised portal venous pressure often requiring endovascular or surgical therapy. A 36-year-old female patient with Non-cirrhotic portal fibrosis and portal hypertension was diagnosed with multiple large splenic artery aneurysms for which she was initially operated which resulted in substantial blood loss during dissection that required embolotherapy. Initial attempts at coil embolization proved unsuccessful due to the wide aneurysmal neck and flow characteristics. Following which the aneurysmal sac was packed with multiple guidewires to act as a scaffold for further coil embolization. Subsequently, hemostasis was achieved and the patient underwent splenectomy later thereby demonstrating that embolization of large aneurysms can be accomplished with reasonable efficacy using guidewires.

Liver involvement in patients with coeliac disease: proof of causality using IgA/anti-TG2 colocalisation techniques

AimsDespite clinical evidence of liver involvement in patients with coeliac disease (CeD), there is a lack of a method to prove this association.MethodsOf 146 treatment-naive patients with CeD, 26 had...

English

Massive splenomegaly presenting with hypersplenism, pancytopenia and portal hypertension, without any underlying known cause is known as Banti’s syndrome. There are various causes of splenomegaly. When all the known causes of portal hypertension are ruled out, it is termed as Banti’s syndrome. This syndrome was discovered by Guido Banti in 1882 and is named after him. Banti’s syndrome is also known as idiopathic portal hypertension or non-cirrhotic portal fibrosis.1 Banti’s syndrome is commonly found in India and Japan than in the West. 2 There is absence of any haematologic cause, primary hepatic cause or any tumour or mass lesion involving the spleen. Banti had stated that the primary organ involved was spleen and not the liver leading to secondary splenomegaly. Other features include normal liver function tests, varices seen in endoscopy, cytopenia of one or more cell lines, absence of cirrhosis, patent hepatic veins and elevated portal pressure with multiple collaterals. The complications include rupture of varices and massive bleeding. 3 We report a case of a 20-year-old male who presented to us with a history of fever for 7 days and one-episode of hematemesis on the day of admission. All known causes of hypersplenism were ruled out and he was diagnosed to have idiopathic massive splenomegaly with portal hypertension and hypersplenism.

New Classification of Gastric Varices: A Twenty-Year Experience

Abstract Objectives Gastric varices (GV) have been classified by the Sarin classification for over two decades. However, a subset of these varices does not fit into this classification. We share our experience on GV in past 20 years and propose a modification. Materials and Methods Consecutive patients with portal hypertension (PHT) posted for esophagogastroduodenoscopy were screened for GV between 1996 and 2016 at a tertiary-care hospital. GV were categorized as gastroesophageal varices (GOV1, GOV2) and isolated gastric varices (IGV1, IGV2) by Sarin’s classification. Patients with varices in esophagogastric region as well as distally in the stomach or duodenum, thus having efferent drainage into the superior as well as inferior vena cava simultaneously, remain unclassified and were coined as GOV3. Statistical Analysis Descriptive data was represented as mean (standard deviation) or median (interquartile range) or number (percentage). Chi-squared test, t-test, and logistic regression were done to compare groups and identify outcomes of interest. Results GV were recognized in 400 (11.5%) of 3,476 patients with PHT. Underlying disease was cirrhosis in 301 (75.2%), extrahepatic portal venous obstruction in 78 (19.5%), noncirrhotic portal fibrosis in 18 (4.5%) and Budd–Chiari syndrome in 3 (0.75%) patients with GV. GOV1, GOV2, IGV1, IGV2, and combined GOV1 with GOV2 were seen in 170 (42.5%), 154 (38.5%), 17 (4.3%), 5 (1.3%), and 12 (3.0%) patients; respectively. GOV3 were identified in 42 (10.5%) patients. Ninety-three patients with GV presented with gastrointestinal bleed and frequency of GOV2 was higher and GOV1 and GOV3 were lower among bleeders than non-bleeders. Conclusions A significant proportion of patients with GV remain uncategorized by current classification among PHT patients. Addition of GOV3 in Sarin’s classification will make it more comprehensive, uniform, and reproducible for future studies.

Histological analyses of trucut liver biopsies from patients with noncirrhotic portal fibrosis and extra-hepatic portal vein obstruction.

Both noncirrhotic portal fibrosis (NCPF) and extrahepatic portal venous obstruction (EHPVO) are important causes of noncirrhotic portal hypertension (PH) in the Asian region. In this study, we analyzed the histopathological changes of liver needle-core biopsies from patients with NCPF and EHPVO. The patients were diagnosed as per the Asia Pacific Association for the Study of Liver (APASL) criteria. Minimum adequacy criteria for liver core biopsies were defined, and finally, 69 liver biopsies from patients with NCPF and 100 liver biopsies from patients with EHPVO were analyzed. All histological parameters were predefined, and three experienced pathologists analyzed the biopsies after reaching consensus. Institute ethics committee clearance was taken. Although some histological features were overlapping, phlebosclerosis of intra-hepatic branches of the portal vein (PV), periportal aberrant vascular channels, remnant portal tracts, and hepatic fibrosis beyond the portal tracts without the formation of complete hepatic nodules (P < 0.001 for all) were common histological characteristics of NCPF on core-needle liver biopsies; while maintained lobular architecture, nonspecific dilatation of PV branches, absence of intra-hepatic PV phlebosclerosis, aberrant vascular channels, and significant fibrosis were characteristics of EHPVO. Despite the considerable histological overlap between NCPF and EHPVO, careful histological evaluation, supplemented by clinical features, radiological and biochemical findings can help in making a conclusive diagnosis. Patients with NCPF and EHPVO with clinical jaundice show transaminitis, high serum alkaline phosphatase level, more variceal bleed, and histological evidences of nodular regenerative hyperplasia.

Caput medusae in a patient with non-cirrhotic portal fibrosis: Clinical images

Caput medusae in a patient with non-cirrhotic portal fibrosis: Clinical images

Proximal Splenorenal Shunt Surgery for Bleeding Gastric Varices in Non-Cirrhotic Portal Hypertension.

BackgroundThe optimal management of gastric variceal bleeding in patients with non-cirrhotic portal hypertension (NCPH) is debatable due to the lack of data from large randomized controlled trials. Here we present our experience on proximal splenorenal shunt (PSRS) surgery in NCPH patients with bleeding gastric varices.MethodsOver a five-year period, a total of 25 PSRS surgeries were performed and data was collected prospectively. Nineteen extrahepatic portal vein obstruction (EHPVO) and six non-cirrhotic portal fibrosis (NCPF) patients with bleeding fundic or isolated gastric varices and normal liver function were included. The collected data was analyzed retrospectively.ResultsOf the 25 patients who underwent PSRS five were lost to follow-up. Twenty patients (80%) were followed up for a median of 3.4 (1-5) years. Gastric variceal regression was noted in all 20 patients with the disappearance of varices in eight patients. On follow-up, shunt thrombosis was noted in four (20%) patients of whom, two had rebleeding between six months and three years after shunt surgery.ConclusionPSRS was effective in controlling gastric variceal hemorrhage in 92% (23 of 25) of patients with preserved liver function.