Utility of scores to predict alcohol use after liver transplant (lt): take them with a grain of salt.

BACKGROUND AIMS: The Sustained Alcohol use post-Liver Transplant (SALT) and the High-Risk Alcohol Relapse (HRAR) scores were developed to predict return to alcohol use after liver transplant (LT) for alcohol associated liver disease (ALD). METHODS: A retrospective analysis of deceased donor LT 10/2018 to 4/2022 was performed. All patients (pts) underwent careful pre-LT psychosocial evaluation. Data on alcohol use, substance abuse, prior rehabilitation, and legal issues were collected. Post-LT, all were encouraged to participate in rehabilitation programs and underwent interval phosphatidylethanol (PeTH) testing. Pts with ALD were stratified by < or > 6 month sobriety prior to listing. Those with <6 month were further stratified as acute alcoholic hepatitis (AH) by NIAAA criteria and non-AH. The primary outcome was utility of the SALT (<5 vs. ≥5) and HRAR (<3 vs. ≥3) scores to predict return to alcohol use (+PeTH) within 1 year after LT. RESULTS: Of the 365 LT, 86 had > 6 month sobriety and 85 had <6 month sobriety; 41 with AH and 44 non-AH. In those with AH, the mean time of abstinence to LT was 58 days, and 71% failed prior rehabilitation. Following LT, return to drinking was similar in the AH (24%) compared to <6M non-AH (15%) and >6M ALD (22%). Only 4% had returned to heavy drinking. The accuracy of both the SALT and HRAR scores to predict return to alcohol was low (accuracy 61-63%) with poor sensitivity (46% and 37%), specificity (67-68%), positive predictive value (22-26%) with moderate negative predictive value (NPV) (81-83%), respectively with higher NPVs (95%) in predicting return to heavy drinking. CONCLUSIONS: Both SALT and HRAR scores had good NPV in identifying patients at low risk for recidivism.

Development of Clinical Algorithm Utilizing Vibration-Controlled Transient Elastography to Detect Advanced Hepatic Fibrosis in Liver Transplant Recipients.

INTRODUCTION: Vibration-controlled transient elastography (VCTE) based liver stiffness measurement (LSM) is an excellent 'rule-out' test for advanced hepatic fibrosis in liver transplant (LT) recipients, however, its ability to 'rule-in' the disease is suboptimal. The study aimed to improve diagnostic performance of LSM in LT recipients. METHODS: Adult LT recipients with a liver biopsy and VCTE were included (N = 150). Sequential covering analysis was performed to create rules to identify patients at low or high risk for advanced fibrosis (stage 3-4). RESULTS: Advanced hepatic fibrosis was excluded in patients with either LSM < 7.45 kPa (n = 72) or 7.45 ≤ LSM < 12.1 kPa and time from LT < 5.6 years (n = 25). Conversely, likelihood of advanced fibrosis was 95% if patients had LSM > 14.1 and controlled attenuation parameter > 279 dB/m (n = 21). Thus, 118 (79%) were correctly identified and 32 (21%) would have required a biopsy to establish the diagnosis. Compared to previously established LSM based cutoff values of 10.5 kPa (Youden index) and 13.3 kPa (maximized specificity), the false positive rates of sequential covering analysis was 1% compared to 16.5% with LSM ≥ 10.5 kPa and 8.3% with LSM ≥ 13.3 kPa. The true positive rates were comparable at 87% for sequential covering analysis, 93% for LSM ≥ 10.5 kPa and 83% for LSM ≥ 13.3 kPa. CONCLUSION: The proposed clinical sequential covering analysis allows for better risk stratification when evaluating for advanced fibrosis in LT recipients compared to LSM alone. Additional efforts are necessary to further reduce the number of patients with indeterminate results in whom a liver biopsy may be required.

Single incision simultaneous liver kidney transplantation: Feasibility and outcomes.

BACKGROUND: Traditionally, simultaneous liver kidney transplantation (SLK) has been performed using a subcostal incision for the liver allograft and a lower abdominal incision for kidney transplantation (dual incision, DI). At our institution, we performed SLK using a single subcostal incision (SI). The aim of this study was to report the outcomes of single versus dual incisions for SLK. METHODS: A retrospective cohort study of consecutive SLK procedures performed at our center from January 2015 to April 2021 was performed. The demographic characteristics, complications, intraoperative findings, and complications after SI and DI were statistically compared. RESULTS: A total 37 SLK were performed (19 DI and 18 SI). The age and indications for transplantation were comparable between the two groups. Patient in SI group had significantly higher MELD score (27.0 ± 1.5 vs. 31.7 ± 1.5, p = .038). The cold ischemic time of kidney transplantation (599 ± 26 min vs. 447 ± 27 min, p < .001) and the total surgical time (508 ± 21 min vs. 423 ± 22 min, p = .008) were significantly shorter in the SI group. The incidence of complications and post-transplant kidney function was comparable between the groups. A slightly higher incidence of surgical site complications was noted in the DI group without any statistically significance (p = .178). CONCLUSIONS: Single-subcostal incision SLK is technically feasible and has comparable outcomes to dual-incision SLK. SI was associated with shorter cold ischemic time for kidney transplant, as well as shorter overall operative time.

Liver transplantation for post-COVID-19 cholangiopathy: A case series.

BACKGROUND: Post-COVID-19 cholangiopathy is an emerging cholestatic liver disease observed in patients recovering from severe COVID-19 infection. Its prognosis is poor, necessitating liver transplantation in some cases. This study aimed to investigate the outcomes of liver transplantation for post-COVID-19 cholangiopathy. METHODS: Seven patients who underwent liver transplantation for post-COVID-19 cholangiopathy at three institutions between 2020 and 2022 were included in this retrospective multi-center case series. RESULTS: At the time of initial COVID-19 infection, all patients developed acute respiratory distress syndrome, and six patients (86%) required ICU admission. Median time intervals from the initial COVID-19 diagnosis to the diagnosis of post-COVID-19 cholangiopathy and liver transplantation were 4 and 12 months, respectively. Four patients underwent living donor liver transplantation, and three patients underwent deceased donor liver transplantation. The median MELD score was 22 (range, 10-38). No significant intraoperative complications were observed. The median ICU and hospital stays were 2.5 and 12.5 days, respectively. One patient died due to respiratory failure 5 months after liver transplantation. Currently, the patient and graft survival rate is 86% at a median follow-up of 11 months. CONCLUSIONS: Liver transplantation is a viable option for patients with post-COVID-19 cholangiopathy with acceptable outcome. Timely identification of this disease and appropriate management, including evaluation for liver transplantation, are essential.

Use of HCV-Positive Livers in HCV-Negative Recipients.

INTRODUCTION: There are only limited data on the survival outcomes after transplanting HCV RNA-positive liver into HCV RNA-negative recipients. The objective of our study was to determine whether there were graft and patient survival differences when HCV-negative patients received HCV RNA (nucleic acid amplification testing [NAT] positive)-positive liver grafts. METHODS: We queried the United Network for Organ Sharing data sets from January 2014 to December 2018, and recipients (N = 24,724) were stratified into 6 groups based on the status of HCV antibody and RNA of recipients and donors. The Cox proportional hazard regression was used to estimate the relationship between groups and 1-year post-LT graft or patient survival. RESULTS: During the study period, 1,358 recipients received NAT-positive liver grafts. Two hundred ten of the recipients were HCV negative. During the same period, 707 HCV antibody-positive but NAT-negative grafts were transplanted into 516 HCV-positive and 191 HCV-negative recipients. There were no differences in survival in HCV-positive recipients whether they received NAT-positive grafts (n = 1,148) or HCV antibody-negative/NAT-negative grafts (n = 6,321). Recipients of grafts from HCV antibody-positive/NAT-negative donors had similar survival whether recipients were HCV-negative patients (n = 191) or HCV-positive patients (n = 516), and their survival probabilities were similar to those of HCV-negative recipients (n = 6,321) receiving grafts from HCV antibody-negative/NAT-negative donors. Patient survival was lower (P = 0.049) when HCV-negative recipients (n = 210) received NAT-positive grafts compared with HCV-positive patients (n = 1,148) receiving NAT-positive grafts; however, when adjusted for recipient and donor characteristics, the difference was not significant. DISCUSSION: HCV-negative recipients receiving HCV-positive liver grafts (NAT positive) have excellent 1-year survival outcomes.

Extracorporeal membrane oxygenation support following liver transplantation-A case series.

BACKGROUND: Postoperative severe cardiopulmonary failure carries a high rate of mortality. Extracorporeal membrane oxygenation (ECMO) can be used as a salvage therapy when conventional therapies fail. METHODS: We retrospectively reviewed our experience with ECMO support in the early postoperative period after liver transplant between September 2011 and May 2016. RESULTS: Out of 537 liver transplants performed at our institution, seven patients required ECMO support with a median age of 52 and a median MELD score of 28. Veno-venous ECMO was used in four patients with severe respiratory failure while the rest required veno-arterial ECMO for circulatory failure. The median time from transplant to cannulation was 3 days with a median duration of ECMO support of 7 days. All patients except one were successfully decannulated. The median hospital length of stay was 58 days with an in-hospital mortality of 28.6%. CONCLUSION: Extracorporeal membrane oxygenation can be considered a viable rescue therapy in the setting of severe postoperative cardiopulmonary failure. Extracorporeal membrane oxygenation therapy was successful in saving patients who were otherwise unsalvageable.

Endovascular Reconstruction of the Hepatic Arterial System for the Management of Mycotic Pseudoaneurysm in a Liver Transplant Patient.

BACKGROUND: Hepatic artery pseudoaneurysm is a rare but very morbid complication after liver transplant. Treatment options include ligation or endovascular embolization, followed by revascularization. We describe a new endovascular approach by stent exclusion in a high-risk patient. RESULTS: A 62-year-old male who received a second liver transplant after failed allograft presented with hemobilia and was diagnosed with a hepatic artery pseudoaneurysm in the setting of infection. Given his hostile abdomen, an endovascular approach was sought. We excluded the mycotic pseudoaneurysm with multiple covered stent grafts extending from the common hepatic artery to the right and left hepatic arteries. He was discharged with long-term antibiotics. On his 6-month follow-up visit, his stent was patent and hepatic function was stable. CONCLUSIONS: Endovascular stent-graft placement for management of hepatic artery pseudoaneurysm after liver transplant should be considered as a lower morbidity alternative to surgical repair, even in the setting of infection.

Factors related to the self-application of insulin in subjects with diabetes mellitus. / Fatores relacionados à autoaplicação de insulina em indivíduos com diabetes mellitus.

OBJECTIVE: To identify the factors associated with the self-application of insulin in adult individuals with Diabetes Mellitus. METHOD: A cross-sectional study developed in the city of Viçosa-MG, which assessed 142 patients. The data collection was performed between April and July 2013 through an interview at the participant's home. Multiple logistic regression was used. RESULTS: The prevalence of the self-administration of insulin was of 67.6%, and it was associated with ages between 57 and 68 years old (OR = 0.3, 95% CI: 0.1-0.9), living with a partner and children (OR = 2.5, 95% CI: 1.1-5.0), 9 years or more of study (OR = 8.4, 95% CI: 1.9-37.9), living in an area not covered by the Family Health Strategy (FHS) (OR = 2.8, 95% CI: 1.1 - 7.0). CONCLUSION: The self-application of insulin was associated with age, schooling, marital status, and the FHS coverage. The recognition of these factors may contribute to the adherence to the self-application of insulin.

Resolution of donor non-alcoholic fatty liver disease following liver transplantation.

INTRODUCTION: Transplant surgeons conventionally select against livers displaying high degrees (>30%) of macrosteatosis (MaS), out of concern for primary non-function or severe graft dysfunction. As such, there is relatively limited experience with such livers, and the natural history remains incompletely characterized. We present our experience of transplanted livers with high degrees of MaS and microsteatosis (MiS), with a focus on the histopathologic and clinical outcomes. METHODS: Twenty-nine cases were identified with liver biopsies available from both the donor and the corresponding liver transplant recipient. Donor liver biopsies displayed either MaS or MiS ≥15%, while all recipients received postoperative liver biopsies for cause. RESULTS: The mean donor MaS and MiS were 15.6% (range 0%-60%) and 41.3% (7.5%-97.5%), respectively. MaS decreased significantly from donor (M=15.6%) to recipient postoperative biopsies (M=0.86%), P<.001. Similarly, MiS decreased significantly from donor biopsies (M=41.3%) to recipient postoperative biopsies (M=1.8%), P<.001. At a median of 68 days postoperatively (range 4-384), full resolution of MaS and MiS was observed in 27 of 29 recipients. CONCLUSIONS: High degrees of MaS and MiS in donor livers resolve in recipients following liver transplantation. Further insight into the mechanisms responsible for treating fatty liver diseases could translate into therapeutic targets.

Novel prokaryotic expression of thioredoxin-fused insulinoma associated protein tyrosine phosphatase 2 (IA-2), its characterization and immunodiagnostic application.

BACKGROUND: The insulinoma associated protein tyrosine phosphatase 2 (IA-2) is one of the immunodominant autoantigens involved in the autoimmune attack to the beta-cell in Type 1 Diabetes Mellitus. In this work we have developed a complete and original process for the production and recovery of the properly folded intracellular domain of IA-2 fused to thioredoxin (TrxIA-2ic) in Escherichia coli GI698 and GI724 strains. We have also carried out the biochemical and immunochemical characterization of TrxIA-2icand design variants of non-radiometric immunoassays for the efficient detection of IA-2 autoantibodies (IA-2A). RESULTS: The main findings can be summarized in the following statements: i) TrxIA-2ic expression after 3 h of induction on GI724 strain yielded ≈ 10 mg of highly pure TrxIA-2ic/L of culture medium by a single step purification by affinity chromatography, ii) the molecular weight of TrxIA-2ic (55,358 Da) could be estimated by SDS-PAGE, size exclusion chromatography and mass spectrometry, iii) TrxIA-2ic was properly identified by western blot and mass spectrometric analysis of proteolytic digestions (63.25 % total coverage), iv) excellent immunochemical behavior of properly folded full TrxIA-2ic was legitimized by inhibition or displacement of [35S]IA-2 binding from IA-2A present in Argentinian Type 1 Diabetic patients, v) great stability over time was found under proper storage conditions and vi) low cost and environmentally harmless ELISA methods for IA-2A assessment were developed, with colorimetric or chemiluminescent detection. CONCLUSIONS: E. coli GI724 strain emerged as a handy source of recombinant IA-2ic, achieving high levels of expression as a thioredoxin fusion protein, adequately validated and applicable to the development of innovative and cost-effective immunoassays for IA-2A detection in most laboratories.

Successful A2 to O Simultaneous Liver and Kidney Transplantation in the Setting of Pre-operative Positive HLA Crossmatch: A Case Report.

Simultaneous liver and kidney transplantation (SLKT) is possible for patients with high donor-specific HLA antibodies or with A2 donors to O recipients with high A2 titers. We report the first case of SLKT in a highly sensitized O recipient with organs from an A2 donor. The recipient is a 59-year-old woman with chronic kidney disease and liver failure due to autoimmune hepatitis and drug-induced liver injury. Immune work-up 8 days pre-transplant demonstrated a negative crossmatch and no HLA antibody (calculated panel reactive antibodies = 0%). Anti-A2 IgG levels were 512. The donor was a deceased 24-year-old man. One day before transplantation, serum from the recipient showed a significant increase in antibody reactivity (calculated panel reactive antibodies = 100%) attributable to blood product transfusion and memory response from previous pregnancies. Consequently, a crossmatch was positive for T and B cells with two newly detected HLA antibodies against the donor's antigens. On the day of surgery, the liver was transplanted first. Six hours and 37 minutes later, a repeat flow crossmatch was negative; donor-specific antibodies (DSAs) fell below the positive threshold, and anti-A2 IgG titer fell to 256. Thus, the kidney was transplanted after basiliximab induction therapy. Seven days post-transplant, non-donor-specific HLA antibodies were present but DSAs remain negative. The patient was discharged on postoperative day 57 with no signs of rejection at 4 months. This case illustrates a rapid and prolonged reduction in antibody titers (HLA and ABO) after SLKT. SLKT is feasible in patients with both DSA and high anti-A2 titer.

Robotic management of primary cholecystoduodenal fistula: A case report and brief literature review.

BACKGROUND: Cholecystoduodenal fistula (CDF) arises from persistent biliary tree disorders, causing fusion between the gallbladder and duodenum. Initially, open resection was common until laparoscopic fistula closure gained popularity. However, complexities within the gallbladder fossa yielded inconsistent outcomes. Advanced imaging and robotic surgery now enhance precision and detection. METHOD: A 62-year-old woman with chronic cholangitis attributed to cholecystoduodenal fistula underwent successful robotic cholecystectomy and fistula closure. RESULTS: Postoperatively, the symptoms subsided with no complications during the robotic procedure. Existing studies report favourable outcomes for robotic cholecystectomy and fistula closure. CONCLUSIONS: Our case report showcases a rare instance of successful robotic cholecystectomy with CDF closure. This case, along with a review of previous cases, suggests the potential of robotic surgery as the preferred approach, especially for patients anticipated to face significant laparoscopic morbidity.

Impact of Liver Transplantation on Adipose Tissue Compartments and Its Association With Metabolic Sequela.

BACKGROUND: Loss of skeletal muscle can be accompanied by an increase in adipose tissue leading to sarcopenic obesity. There are limited data on how liver transplantation (LT) might impact adipose tissue compartments, particularly among patients with metabolically active disease, such as nonalcoholic steatohepatitis (NASH) and subsequent metabolic sequela. METHODS: Skeletal muscle, visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) were measured using cross-sectional imaging performed in 190 patients pre-LT, 6 mo post-LT and 12 mo post-LT. Changes in adipose tissue and their impact on metabolic diseases were determined in patients transplanted for NASH versus non-NASH. RESULTS: Skeletal muscle, VAT, and SAT were similar in patients with NASH and non-NASH pre-LT despite a higher burden of metabolic diseases in patients with NASH. Following LT, no significant differences between skeletal muscle and SAT were observed in the entire cohort and among patients with NASH (versus non-NASH). LT recipients with the highest muscle mass pre-LT were at the greatest risk for muscle loss post-LT. A time-dependent increase in VAT was noted post-LT, which was more robust among patients with a history of NASH cirrhosis. In adjusted multivariate analysis, NASH versus non-NASH was a strong predictor of post-LT increase in VAT (ß-coefficient 3.00, P = 0.04). Pre-LT VAT was an independent predictor of post-LT serum triglycerides (ß-coefficient 5.49 ± 2.78, P = 0.05) and low-density lipoprotein cholesterol (ß-coefficient 1.80 ± 0.75, P = 0.02). A trend between pre-LT VAT and diabetes was noted but did not reach statistical significance. CONCLUSIONS: VAT but not SAT increases rapidly after LT, especially among patients transplanted for NASH cirrhosis and predicts future metabolic burden.

Robotic versus open mini-incision living donor nephrectomy: Single centre experience.

BACKGROUND: Robotic surgery is associated with less tissue manipulation and earlier recovery with minimal incision. The aim of this study was to compare the short-term clinical outcomes between robotic-assisted donor nephrectomy (RDN) and open mini-incision donor nephrectomy (ODN). METHODS: From 2016 to 2019, 141 cases involving RDN were analysed. Patient outcomes were compared with those of 191 patients who underwent ODN from 2010 to 2015. Demographics, operation factors, perioperative outcomes, and complications were retrospectively reviewed. RESULTS: The RDN group presented with less blood loss than the ODN group (p = 0.023). The length of hospital stay was significantly shorter in the RDN group than in the ODN group (p < 0.005). The overall rate of complications was low and there was no significant difference in complication rates between the groups. CONCLUSION: The robotic approach has benefits over the traditional open approach, including shorter length of hospital stay and reduced intraoperative blood loss.

Robotic management of huge hepatic angiomyolipoma: A case report and literature review.

Hepatic angiomyolipoma (HAML) is a rare, benign mesenchymal liver tumor encountered in Asia, primarily in females, and can be found within the right hepatic lobe, but also in other areas of the liver. Immunohistochemically, HAMLs are characteristically positive for human melanoma black-45 antigen (HMB-45) and can histochemically vary in the composition of angiomatous, lipomatous, and myomatous tissue, together with the presence of epithelioid cells. In this case report, we discuss a previously healthy patient presenting with bloating and previously documented concern of liver lesions, found to have HAML confirmed by surgical pathology. Surgery was decided, as HAMLs greater than 10 cm are at risk of rupture. This is one of the first documented cases of HAML resected through robot-assisted bisegmentectomy and cholecystectomy, and therefore, intraoperative images have been included to assist in the planning of future robotic cases.

Initial Experience With Robotic Liver Resection in the United States.

BACKGROUND: This study's aim was to show the feasibility and safety of robotic liver resection (RLR) even without extensive experience in major laparoscopic liver resection (LLR). METHODS: A single center, retrospective analysis was performed for consecutive liver resections for solid liver tumors from 2014 to 2022. RESULTS: The analysis included 226 liver resections, comprising 127 (56.2%) open surgeries, 28 (12.4%) LLR, and 71 (31.4%) RLR. The rate of RLR increased and that of LLR decreased over time. In a comparison between propensity score matching-selected open liver resection and RLR (41:41), RLR had significantly less blood loss (384 ± 413 vs 649 ± 646 mL, P = .030) and shorter hospital stay (4.4 ± 3.0 vs 6.4 ± 3.7 days, P = .010), as well as comparable operative time (289 ± 123 vs 290 ± 132 mins, P = .954). A comparison between LLR and RLR showed comparable perioperative outcomes, even with more surgeries with higher difficulty score included in RLR (5.2 ± 2.7 vs 4.3 ± 2.5, P = .147). The analysis of the learning curve in RLR demonstrated that blood loss, conversion rate, and complication rate consistently improved over time, with the case number required to achieve the learning curve appearing to be 60 cases. CONCLUSIONS: The findings suggest that RLR is a feasible, safe, and acceptable platform for liver resection, and that the safe implementation and dissemination of RLR can be achieved without solid experience of LLR.

'Burn and Push' technique: A novel robotic liver parenchymal transection technique.

BACKGROUND: Liver parenchymal transection during robotic liver resection (RLR) remains a significant challenge due to the limited range of specialised instruments. This study introduces our 'Burn and Push' technique as a novel approach to address these challenges. METHODS: A retrospective analysis was conducted on 20 patients who underwent RLR using the 'Burn and Push' technique at Virginia Commonwealth University Health System from November 2021 to August 2023. The study evaluated peri- and post-operative outcomes. RESULTS: The median operation time was 241.5 min (range, 90-620 min), and the median blood loss was 100 mL (range, 10-600 mL). Major complications occurred in one case, with no instances of postoperative bleeding, bile leak, or liver failure. CONCLUSIONS: The 'Burn and Push' technique is a viable and efficient alternative for liver parenchymal transection in RLR. Further research with larger sample sizes and consideration of the learning curve is necessary to validate these findings.

Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Rare Lymphoma with Isolated Hepatic Presentation.

Primary hepatic lymphoma (PHL) is extremely rare, accounting for less than 1% of all lymphomas, and is limited to the liver without extrahepatic involvement. A 30-year-old male was admitted in the Emergency Department complaining of weakness, fever, night sweats, significant weight loss, discrete ring alopecia, hepatomegaly, right axillary adenopathy and oedema of both legs. Laboratory evaluation showed normocytic normochromic anaemia, thrombocytosis, hyperbilirubinemia, cholestasis and increased international normalised ratio (INR). A computed tomography (CT) scan found an enlarged liver with a heterogeneous structure and moderate ascites. After admission in our ward further investigation revealed increased sedimentation velocity, ferritin and serum lactate dehydrogenase. A hepatic biopsy was performed which confirmed the diagnosis as a nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). The patient was transferred to a haematological ward and underwent chemotherapy with six cycles of R-CHOP. He is in complete remission after a year and half since the beginning of treatment. NLPHL, a very rare lymphoma, is more common in men between the third and fifth decades of life. Usually, the symptoms are very unspecific; a few patients have B symptoms at admission. This kind of presentation is also common in infectious, metabolic and autoimmune diseases, which were excluded in this case. Due to technical issues the final diagnosis was only possible due to the liver biopsy. Treatment with standard Hodgkin lymphoma protocols leads to complete remission in more that 95% of patients with NLPHL. LEARNING POINTS: Differential diagnosis of fever, especially in young patients, is very complex and complete investigation takes time, which can delay the diagnosis of malignancies such as primary hepatic lymphoma (PHL).PHL is very rare, and overlapping symptoms with other liver diseases can make the diagnosis very challenging.When the suspicion of PHL is very high, only the hepatic biopsy can lead to the correct diagnosis because the disease has no extrahepatic involvement.