Differences in Prognostic Factors and Recurrence Patterns After Curative-Intent Resection of Perihilar and Distal Cholangiocarcinomas.

BACKGROUND: Perihilar cholangiocarcinoma and distal cholangiocarcinoma arise from the same tissue but require different surgical treatment methods. It remains unclear whether these cholangiocarcinoma types have different outcomes, prognostic factors, and/or recurrence patterns. METHODS: This retrospective study evaluated patients who underwent curative-intent resection for perihilar cholangiocarcinoma or distal cholangiocarcinoma at a tertiary academic hospital during 2000-2015. Survival and prognostic factors were identified using Kaplan-Meier and Cox regression analyses. RESULTS: The 90-day mortality rates were 0% for perihilar cholangiocarcinoma (36 patients) and 4% for distal cholangiocarcinoma (47 patients). There were no significant differences between perihilar cholangiocarcinoma or distal cholangiocarcinoma in median overall survival (30.9 vs 40.4 months) or median disease-free survival (14.2 vs 21.4 months). Among perihilar cholangiocarcinoma patients, age > 65 years was an independent predictor of poorer overall survival (hazard ratio: 2.45, 95% confidence interval: 1.07-5.64), while requiring bile duct re-resection was an independent predictor of disease-free survival (hazard ratio: 2.76, 95% confidence interval: 1.01-7.51). Among distal cholangiocarcinoma patients, a pN1 category independently predicted poorer overall survival (hazard ratio: 3.40, 95% confidence interval: 1.14-10.11), while preoperative CA19-9 levels >30 U/mL (hazard ratio: 2.51, 95% confidence interval: 1.09-5.79) and pN1 category (hazard ratio: 2.51, 95% confidence interval: 1.09-5.79) predicted a shorter disease-free survival. Local recurrence was more common with perihilar cholangiocarcinoma (50% of recurrences), while multiple synchronous sites were more common for distal cholangiocarcinoma (41% of recurrences). CONCLUSION: Perihilar cholangiocarcinoma and distal cholangiocarcinoma patients have similar survival outcomes. However, local control appears to be more prognostic for perihilar cholangiocarcinoma patients, while positive lymph nodes are critical prognostic factor for distal cholangiocarcinoma patients.

Enhanced recovery protocol after liver resection.

BACKGROUND: Enhanced recovery protocols (ERPs) accelerate patient recovery and shorten hospital stay by optimization of perioperative care. However, experience with ERPs is still limited in liver surgery. METHODS: The implementation of a multimodal ERP was studied in patients who underwent open and laparoscopic liver surgery. An opioid-sparing pain treatment was chosen together with early mobilization and oral feeding, as well as restricted use of abdominal drains and catheters. Date to discharge, postoperative complications and patient satisfaction were assessed. A historical cohort of patients who underwent liver resection served as a control group. RESULTS: Some 134 liver resections (126 open, 8 laparoscopic) were performed between April 2013 and March 2014. Operations were carried out mostly for malignant liver tumours. One hundred and six (79.1 per cent) of the 134 patients were discharged by the fifth postoperative day. The median (range) postoperative hospital stay was 4 (2-11) days, compared with 6 (4-16) days for the control group (P < 0.001). Only four patients in the ERP group were readmitted and the 30-day mortality rate was zero. CONCLUSION: An ERP for perioperative care after liver surgery was introduced safely and effectively. Discharge within 4 days is achievable with no increase in adverse events and good patient satisfaction.

Long-term renal function deteriorates at a similar rate among liver transplant patients with preserved renal function at 1 year and in the general population: is chronic calcineurin inhibitor nephrotoxicity overrated?

BACKGROUND: Chronic calcineurin inhibitor (CNI) nephrotoxicity is associated with histologic kidney lesions, but the contribution of maintenance-dose CNI use to the decline over time in glomerular filtration rate (GFR) post liver transplantation (OLT) remains unclear. METHODS: We studied annual changes in estimated GFR >1 year posttransplant among 105 CNI-treated adult OLT patients with a GFR of 60-100 mL/min at 1 year during a mean follow-up of 7 years (20 years in 20 patients). RESULTS: The annual GFR decline >1 year posttransplant was 0.2 mL/min per year (SD 3.8). This decline rate was unaffected by the decade of OLT, follow-up period, or GFR at 1 year, and showed no correlation with CNI blood levels. Of the 13 (12%) patients with a GFR deterioration >3 mL/min per year, 77% presented with hypertension, diabetes, and/or dyslipidemia. The decline in GFR >1 year post-OLT did not exceed the decline of 0.5-0.8 mL/min per year reported in the general population. Declines faster than 3 mL/min per year, which occurred no more frequently among patients than in the general population, seemed attributable to coexistent vascular risk factors. CONCLUSIONS: Among OLT patients with preserved renal function at 1 year posttransplant, our findings challenge the clinical impact of chronic progressive CNI nephrotoxicity and highlight the importance of a tight control of blood pressures, glucose and lipid levels, and other modifiable risk factors in order to preserve long-term renal function.

Cholesterol metabolism altered and FGF21 levels high after pediatric liver transplantation despite normal serum lipids.

Liver transplantation (LT) predisposes to metabolic derangements and increases the risk for cardiovascular disease. We conducted a national cross-sectional study of all pediatric recipients who underwent LT between 1987 and 2007. We measured serum levels of noncholesterol sterols (surrogate markers of cholesterol synthesis and intestinal absorption) and fibroblast growth factor 21 (FGF21) in 49 patients (74% of survivors) at a median of 10 years posttransplant and in 93 controls matched for age and gender. Although serum cholesterol levels were similar in patients and controls, patients displayed increased whole-body synthesis and decreased intestinal absorption of cholesterol compared with controls (lathosterol to cholesterol ratio 129 ± 55 vs. 96 ± 41, respectively, p < 0.001; campesterol to cholesterol ratio 233 ± 91 vs. 316 ± 107, respectively; p < 0.001). Azathioprine (r =-0.383, p = 0.007) and low-dose methylpredisolone (r =-0.492, p < 0.001) were negatively associated with lathosterol/sitosterol ratio reflecting a favorable effect on cholesterol metabolism. FGF21 levels were higher in patients than in controls (248 pg/mL vs. 77 pg/mL, p < 0.001). In healthy controls, FGF21 was associated with cholesterol metabolism, an association missing in LT recipients. Normal serum lipids are achievable in long-term survivors of pediatric LT, but changes in cholesterol metabolism and increased FGF21 levels may explicate later cardiovascular risk.

General health, health-related quality of life and sexual health after pediatric liver transplantation: a nationwide study.

The long-term impact of pediatric liver transplantation (LT) and its complications on general health, health-related quality of life (HRQoL) and sexual health were assessed. We conducted a national cross-sectional study of all pediatric recipients who underwent LT between 1987 and 2007. Of 66 survivors, 57 participants (86%) were compared to randomly chosen healthy controls (n = 141) at 10.7 ± 6.6 years posttransplant. PedsQL4.0, SF-36, DISF-SR and AUDIT questionnaires for appropriate age groups were used. Patients and controls <7 years had similar HRQoL and 54% of patients aged over 7 scored within the controls' normal range on all HRQoL domains. In adult survivors, physical functioning and general health were decreased (p < 0.05). Biliary complications, reoperations and obesity were independently associated with reduced HRQoL (p < 0.05 for all). Still 64% of adult survivors considered their health excellent. Sexual health was similar to controls but LT recipients may experience problems with their orgasm strength (p = 0.050) and condom-based contraception was more common after LT than among controls (58% and 12%, p < 0.001). In conclusion, normal HRQoL and sexual health are achievable post-LT.

Treatment options in hepatocellular carcinoma today.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer related death worldwide. As over 90% of HCCs arise in cirrhotic livers preventive methods and surveillance policies have been adopted in most countries with high prevalence of hepatitis B or C infected people. Poor prognosis of HCC has shown some improvement during the last years. Targeted therapy with radiofrequency ablation (RFA), hepatic resection (HR), liver transplantation (LT), and transcatheter arterial chemoembolisation (TACE) seems to have an influence on this development. The heterogeneity of cirrhotic patients with HCC is still a big challenge. A patient with a small tumour in a cirrhotic liver may have a worse prognosis than a patient with a large tumor in a relatively preserved liver after "curative" HR. The choice of the treatment modality depends on the size and the number of tumours, the stage and the cause of cirrhosis and finally on the availability of various modalities in each centre.

Treatment of biliary complications after laparoscopic cholecystectomy.

The incidence of iatrogenic bile duct injury remains high despite increased awareness of the problem. This major complication following laparoscopic cholecystectomy (LC) has a significant impact on patient's well-being and even survival despite seemingly adequate therapy. The management of bile duct injury (BDI) includes education to avoid the insult, proper and early diagnosis and preferably early treatment. It is of utmost importance to involve experienced hepatobiliary surgeon early enough to perform corrective reconstruction or to plan other therapies with a multidisciplinary team including interventional radiologist and advanced endoscopist. The selection of correct therapy at the earliest possible phase has significant effect on patient outcome. The treatment options are surgery and endoscopy, either immediately or delayed. By constant and continuous analysis of the problem and information to the surgical community it should be possible to decrease the prevalence of iatrogenic BDI and even to avoid it.

Infectious complications more than 1 year after liver transplantation: a 3-decade nationwide experience.

Because few reports have addressed infections late (≥1 year) after liver transplantation (LT), we evaluated the incidence, risk factors and pathogens involved. Infection data were from the Finnish LT registry, with starting date, type and relevant pathogens for 501 Finnish adult LT patients surviving ≥1 year post-transplant. Follow-up end points were end of study, death or retransplantation. Logistic regression to assess risk factors was adjusted for age, gender and follow-up time. With 3923 person-years of follow-up, overall infection incidence was 66/1000 person-years; 155 (31%) suffered 259 infections, and two-thirds experienced only one infection. Cholangitis (20%), pneumonia (19%) and sepsis (14%) were most common. The most frequent bacteria were Enterococcus spp. and Escherichia coli, and the most frequent viruses cytomegalovirus and varicella zoster virus. Fungal infections were rare (n = 7). With 13 fatal infections, 17% of all late deaths involved infection. Primary sclerosing cholangitis (PSC) and Roux-en-Y-type biliary anastomosis were associated with cholangitis; 18% of PSC patients suffered late cholangitis. Late acute rejection was associated with sepsis. Age, gender or cytomegalovirus did not significantly influence late infections. In conclusion, although infection risk under maintenance immunosuppression therapy is relatively low, particular vigilance regarding cholangitis, pneumonia and sepsis seems appropriate.

Hepatic neutrophil activation during reperfusion may not contribute to initial graft function after short cold ischemia in human liver transplantation.

BACKGROUND: Experimental models of hepatic ischemia/reperfusion injury have implicated a pathophysiologic role for neutrophils in subsequent hepatocellular damage. In human liver transplantation, however, the effect of reperfusion-induced neutrophil activation on initial graft function is not clear. METHODS: In 38 patients undergoing liver transplantation, neutrophil CD11b and L-selectin expression, neutrophil count, and plasma lactoferrin levels were measured. To assess changes within the graft during initial reperfusion, samples of blood entering and leaving the graft were obtained simultaneously, and transhepatic ratio calculated (hepatic vein/portal vein; 1 denotes no change, <1 a decrease, and >1 an increase across the liver). Graft steatosis, postoperative liver function, and outcome were recorded. Associations between neutrophil activation markers and outcome measures were evaluated. RESULTS: Substantial hepatic neutrophil activation occurred during initial reperfusion, demonstrated by concomitant L-selectin shedding and CD11b upregulation (transhepatic ratios 0.9 [0.7-1.0]; 1.4 [0.9-1.9]; both P < .001; portal vs hepatic vein]. Simultaneously, hepatic neutrophil sequestration and lactoferrin release occurred (0.3 [0.2-0.5]; 1.7 [1.3-3.4]; both P < .001). Neither cold ischemic time (CIT; median 5 hours 36 minutes) nor hepatic neutrophil activation during reperfusion predicted early graft function, nor was there any association between CIT and neutrophil activation. CONCLUSIONS: Despite short CIT, extensive graft neutrophil activation and sequestration occurred. This, however, was not associated with impaired early graft function, suggesting short CIT may protect against severe neutrophil-mediated injury.

Successful liver-kidney transplantation in two children with aHUS caused by a mutation in complement factor H.

A 12-month-old boy and his 16-year-old aunt became acutely ill 6 months apart and were diagnosed to have atypical hemolytic uremic syndrome (aHUS). Genetic analysis revealed heterozygous R1215Q mutation in complement factor H (CFH) in both patients. The same mutation was found in five healthy adult relatives indicating incomplete penetrance of the disease. The patients developed terminal renal failure and experienced reversible neurological symptoms in spite of plasma exchange (PE) therapy. In both cases, liver-kidney transplantation was successfully performed 6 months after the onset of the disease. To minimize complement activation and prevent thrombotic microangiopathy or overt thrombotic events due to the malfunctioning CFH, extensive PE with fresh frozen plasma was performed pre- and perioperatively and anticoagulation was started a few hours after the operation. No circulatory complications appeared and all four grafts started to function immediately. Also, no recurrence or other major clinical setbacks have appeared during the postoperative follow-up (15 and 9 months) and the grafts show excellent function. While more experience is needed, it seems that liver-kidney transplantation combined with pre- and perioperative PE is a rational option in the management of patients with aHUS caused by CFH mutation.

Preoperative assessment of focal liver lesions: multidetector computed tomography challenges magnetic resonance imaging.

PURPOSE: To investigate prospectively multidetector computed tomography (CT) (MDCT) and magnetic resonance (MR) imaging (MRI) in the preoperative assessment of focal liver lesions. MATERIAL AND METHODS: Multiphasic MDCT and conventional gadolinium-enhanced MRI were performed on 31 consecutive patients prior to hepatic surgery. All images were blindly analyzed as consensus reading. Lesion counts and their relation to vascular structures and possible extrahepatic disease were determined. The data from the MDCT and MRI were compared with the results obtained by intraoperative ultrasound (IOUS) and palpation. Histopathologic verification was available. RESULTS: At surgery, IOUS and palpation revealed 45 solid liver lesions. From these, preoperative MDCT detected 43 (96%) and MRI 35 (78%) deposits. MDCT performed statistically better than MRI in lesion detection (P=0.008). Assessment of lesion vascular proximity was correctly determined by MDCT in 98% of patients and by MRI in 87%. Statistical difference was found (P=0.002). IOUS and palpation changed the preoperative surgical plan as a result of extrahepatic disease in 8/31 (26%) cases. In MDCT as well in MRI extrahepatic involvement was suspected in two cases. CONCLUSION: MDCT was superior to MRI and nearly equal to IOUS in liver lesion detection and in the determination of lesion vascular proximity. However, both techniques fail to reliably detect extrahepatic disease.

Toxic acute hepatitis and hepatic fibrosis after consumption of chaparral tablets.

In this report we describe a young, previously healthy woman who developed severe acute hepatitis after consumption of chaparral tablets, a commonly used herbal product. In this case, the elimination-rechallenge event and the exclusion of other possible aetiologic factors strongly supported true causality between the herbal product and the liver damage. Primary liver biopsy showed severe toxic hepatitis consistent with previous reports of chaparral-induced liver damage. Later, 6 months after the liver function tests had normalized, permanent hepatic fibrosis could still be seen.

Outcome following liver transplantation for primary sclerosing cholangitis in the Nordic countries.

BACKGROUND: Primary sclerosing cholangitis (PSC) is the most common indication for liver transplantation in the Nordic countries. Because these patients are difficult to evaluate with regard to timing of liver transplantation, it is important to establish predictors of post-transplant survival. METHODS: Data from two groups of patients receiving liver allografts during 1982-2001 were recorded: (a) PSC patients and (b) comparison patients. Outcome following transplantation has been recorded for all patients. Regression analyses have been performed for PSC patients to analyse predictors of patient and graft survival. RESULTS: A total of 245 PSC and 618 comparison patients received a first liver allograft in the period 1982 until the end of the study. The overall 1-, 3- and 5-year patient survival rates were 82%, 77% and 75%, and 80%, 77% and 74% in the PSC group and comparison group, respectively. Survival following transplantation has increased with time in both the PSC and the comparison group. Recent year of transplantation, no previous hepatobiliary surgery and a lower MELD score were predictors of survival following transplantation for PSC patients. PSC patients had a higher rate of re-transplantations (13% versus 8%, P = 0.01). Predictors of re-transplantation in PSC patients were an episode of early rejection and vascular thrombosis. CONCLUSION: In PSC patients, year of transplantation, previous hepatobiliary surgery and MELD score are predictors of survival following transplantation and these patients are more frequently in need of re-transplantation compared to the comparison group.

Liver transplantation in patients over 60 years of age.

Liver transplantation was previously only offered to patients under 60 years of age. We have analyzed the outcome after acceptance on the waiting list and after liver transplantation of patients over 60 years old. A total of 150 patients over 60 years old were listed for a first liver transplantation during 1990-1998. The annual number increased throughout the period. Primary biliary cirrhosis, primary sclerosing cholangitis, and acute hepatic failure were the most frequent diagnoses. A total of 119 patients received a first liver allograft. The patient 1-year survival was 75% and 3-year survival 62%, which was not significantly lower (P = 0.21) than that of the younger patients. When correcting for year of transplantation, the survival was, however, moderately but significantly lower than among the younger patients. Survival among those > 65 years (n = 38) did not differ from that of patients 60-65 years of age (n = 81). We conclude that an increasing number of patients over 60 years old can be listed for liver transplantation and receive a liver allograft with highly satisfying results.

Are diabetic patients in danger at renal transplantation? An invasive perioperative study.

It is assumed that diabetic patients with uraemia have more complications at renal transplantation than those who are not diabetic. We compared the preoperative ECGs, and invasive perioperative haemodynamic and oxygenation parameters in 15 diabetic and 15 non-diabetic uraemic patients undergoing renal transplantation. The number of patients with increased QT dispersion in the ECG was higher in diabetic than in non-diabetic patients (P<0.05). Before anaesthesia, heart rate and mean arterial pressure were higher (P<0.05) in the diabetic than in the non-diabetic group. After preanaesthetic volume loading all patients showed a hyperdynamic circulation, which subsided during anaesthesia. However, stroke volume index remained unchanged. Four patients in the diabetic group and six in the non-diabetic group needed additional oxygen therapy after surgery. No cardiac dysrhythmias were noted. However, the increased QT dispersion in diabetic patients calls for an adequate perioperative ECG monitoring for dysrhythmias. The diabetic and non-diabetic uraemic patients performed equally well at renal transplantation. In conclusion, renal transplantation for diabetics is justified.