Recurrence of nonviral liver diseases after liver transplantation.

Many nonviral diseases that cause liver failure may recur after liver transplantation. Although most studies have shown that a recurrent disease does not negatively affect patient and graft survival in the intermediate postoperative course, there is growing evidence that, especially in patients with primary sclerosing cholangitis and in patients with recurrent abusive alcohol drinking, disease recurrence is a significant risk factor for graft dysfunction and graft loss. Therefore, the recurrence of nonviral diseases has become a clinically important and prognostically relevant issue in the long-term management of recipients of liver transplantation.

Acute-on-chronic liver failure: excellent outcomes after liver transplantation but high mortality on the wait list.

Acute-on-chronic liver failure (ACLF) is characterized by high short-term mortality. Liver transplantation (LT) is a potential therapy for patients who do not improve with supportive measures, but the efficacy of LT has not been shown. The aim of this study was to investigate the feasibility of LT and to determine the postoperative outcomes of patients with ACLF. All patients referred to our liver unit between 2002 and 2010 were registered in a database. The diagnosis of ACLF was made in accordance with the Asian Pacific Association for the Study of the Liver consensus. The post-LT outcomes were compared with the outcomes of a cohort of patients with chronic liver disease who underwent transplantation for other indications during the same period. One hundred forty four of 238 patients fulfilled the ACLF criteria. In an intention-to-treat analysis, the median transplant-free survival time was 48 days. Multiorgan failure was the most common cause of death. Ninety-four patients (65%) were evaluated for LT, 71 patients (49%) were listed, and 33 patients (23%) finally underwent deceased donor LT; this resulted in a wait-list mortality rate of 54%. Patients who developed infectious complications (particularly pneumonia and/or sepsis) and patients who received renal replacement therapy or mechanical ventilation were less likely to undergo LT. The 1- and 5-year survival rates of 87% and 82% were comparable to the rates for non-ACLF patients. In conclusion, this study shows that LT remains the only therapeutic option for the vast majority of patients with ACLF. However, LT was feasible in less than one fourth of the patients with a 5-year survival rate greater than 80%.

Early viral load and recipient interleukin-28B rs12979860 genotype are predictors of the progression of hepatitis C after liver transplantation.

There have been few detailed studies of viral kinetics after liver transplantation (LT), and conflicting data have been reported on viral loads and the severity of recurrent hepatitis C virus (HCV) disease. This long-term study aimed to examine (1) the impact of HCV RNA levels at specific points in time within the first year and (2) the influence of interleukin-28B (IL-28B) genotypes on patient outcomes and the severity of recurrent HCV disease. The viral loads were measured 2, 4, 12, 24, and 48 weeks after LT, and the recipient/donor IL-28B genotypes of 164 patients were determined. A Cox regression analysis showed that the viral load at week 2 was an independent negative predictor of recipient outcomes. A week 2 viral load ≥ 6.0 log(10) IU/mL was significantly associated with reduced patient survival. After a mean follow-up of 6.5 years, 21 of 164 patients (12.8%) developed a cholestatic type of HCV recurrence and/or rapidly progressed to cirrhosis within 1 year. A multivariate binary regression analysis showed that HCV viremia at week 2 and a non-C/C recipient IL-28B genotype were independent risk factors for cholestatic recurrent HCV. No predictive factors could be found for the occurrence of recurrent liver cirrhosis 5 and 10 years after LT. Our study shows that the HCV RNA level at week 2 and the recipient IL-28B genotype are independent, statistically significant risk factors for post-LT cholestatic HCV, and it emphasizes the importance of viral load monitoring and IL-28B genotyping for identifying HCV recipients at risk for severe HCV recurrence.

Coronary computer tomographic angiography for preoperative risk stratification in patients undergoing liver transplantation.

The assessment of the cardiovascular risk profile in patients with end-stage liver disease is essential prior to liver transplantation (LT) as cardiovascular diseases are major causes of morbidity and mortality in the posttransplant course. The aim of this study was to evaluate the accuracy of a 64-slice coronary computed tomographic angiography (CTA) and coronary calcium scoring (CCS) to predict the postoperative cardiovascular risk of patients assessed for LT. In this single center, observational study we included 54 consecutive patients who were assessed for LT and consequently transplanted. Twenty-four patients (44%) presented with a high CCS above 300 and/or a significant stenosis (>50% percent narrowing due to stenotic plaques) and were further referred to coronary angiography. Three of these patients had a more than 70% LAD stenosis with subsequent angioplasty (n=1) or conservative therapy (n=2). The other patients showed only diffuse CAD without significant stenosis. The remaining 30 patients with normal CTA findings were listed for LT without further tests. None of the 54 patients developed cardiovascular events peri- and postoperatively. This study indicated that CTA combined with CCS is a useful non-invasive imaging technique for pre-LT assessment of coronary artery disease and safe tool in the risk assessment of peri- and postoperative cardiovascular events in patients undergoing LT.

The clinical challenges of acute on chronic liver failure.

Acute on chronic liver failure (ACLF) encompasses patients with previously well-compensated liver disease in whom an acute decompensation of liver function occurs because of a precipitating event. There are emerging data on the presentation and course of patients with this profile of liver disease; a clear definition based on precise diagnostic criteria, however, remains difficult to establish. In a high percentage of patients, ACLF is associated with the development of multi-organ failure leading to high in-hospital mortality despite costly intensive care therapy. Liver transplantation remains the only curative therapeutic option for the majority of these patients. Therefore, early identification of the precipitating events inducing ACLF and better understanding of the underlying mechanism are key issues for the prevention and treatment of ACLF. However, although there is increasing evidence that cytokines play a major role in the development of ACLF, the pathophysiology remains complex and poorly understood.

Live donor liver transplantation for primary sclerosing cholangitis: is disease recurrence increased?

PURPOSE OF REVIEW: There is convincing evidence that primary sclerosing cholangitis (PSC) recurs after deceased donor liver transplantation with an incidence of about 20% after 5 years. This review summarizes data regarding recurrent disease in the setting of live donor liver transplantation. RECENT FINDINGS: End-stage liver disease secondary to PSC accounts for less than 3% of all live donor liver transplantations worldwide. Therefore, there are only few data regarding recurrent disease in this setting available, mainly from Japanese transplant centers. Based on these studies, however, only including a small number of patients, recurrent disease was diagnosed in 25-67% of transplant recipients after a mean follow-up of 34 months following transplantation. Cytomegalovirus infection in the early postoperative phase and biologically related donors were found to be statistically significant risk factors for disease recurrence. More than one third of patients with recurrent disease either died or developed graft failure. SUMMARY: These data suggest that patients with PSC undergoing live donor liver transplantation, especially with biologically related donors, may have a higher risk to develop recurrent disease compared with the deceased donor setting. However, this fact has to be interpreted with great caution, primarily due to the rather small number of patients. Further studies analyzing pooled data of all transplant centers performing live donor liver transplantations are needed to confirm these findings.

Saccadic latency in hepatic encephalopathy: a pilot study.

Hepatic encephalopathy is a common complication of cirrhosis. The degree of neuro-psychiatric impairment is highly variable and its clinical staging subjective. We investigated whether eye movement response times-saccadic latencies-could serve as an indicator of encephalopathy. We studied the association between saccadic latency, liver function and paper- and pencil tests in 70 patients with cirrhosis and 31 patients after liver transplantation. The tests included the porto-systemic encephalopathy (PSE-) test, critical flicker frequency, MELD score and ammonia concentration. A normal range for saccades was established in 31 control subjects. Clinical and biochemical parameters of liver, blood, and kidney function were also determined. Median saccadic latencies were significantly longer in patients with liver cirrhosis when compared to patients after liver transplantation (244 ms vs. 278 ms p < 0.001). Both patient groups had prolonged saccadic latency when compared to an age matched control group (175 ms). The reciprocal of median saccadic latency (µ) correlated with PSE tests, MELD score and critical flicker frequency. A significant correlation between the saccadic latency parameter early slope (σ(E)) that represents the prevalence of early saccades and partial pressure of ammonia was also noted. Psychometric test performance, but not saccadic latency, correlated with blood urea and sodium concentrations. Saccadic latency represents an objective and quantitative parameter of hepatic encephalopathy. Unlike psychometric test performance, these ocular responses were unaffected by renal function and can be obtained clinically within a matter of minutes by non-trained personnel.

Extensive surveillance promotes early diagnosis and improved survival of de novo malignancies in liver transplant recipients.

The aim of our study was to examine whether an extensive surveillance protocol will promote early diagnosis and improved survival in patients with de novo cancer following liver transplantation (LT). Of 779 consecutive LT recipients, 96 (12.3%) developed 105 malignancies. The cumulative risk for the development of de novo cancer was 10%, 24%, 32% and 42% at 5, 10, 15 and 20 years after LT, respectively. The most frequent tumor types were skin (17%), lung (16%), oropharyngeal (11%) and prostate cancer (11%). The overall standard incidence ratio as compared to that of the general population was 1.9 (95% CI: 1.5-2.3). The median survival of patients with de novo non-skin cancers was 3.1 years after diagnosis. Only patients with skin cancers and solid tumors, diagnosed at early stages, showed an excellent outcome. After introducing an intensified surveillance protocol, the detection rate of de novo cancers increased from 4.9% to 13% and more de novo malignancies were diagnosed in earlier stages. For non-skin cancers, the median tumor-related survival significantly improved from 1.2 to 3.3 years as well as the median overall survival post-LT. This study indicates that an extensive tumor surveillance program is highly recommendable in LT recipients.

Transjugular intrahepatic portosystemic shunt in liver transplant recipients.

AIM: To evaluate the efficacy of transjugular intrahepatic portosystemic shunts (TIPSs) after liver transplantation (LT). METHODS: Between November 1996 and December 2005, 10 patients with severe recurrent hepatitis C virus infection (n = 4), ductopenic rejection (n = 5) or portal vein thrombosis (n = 1) were included in this analysis. Eleven TIPSs (one patient underwent two TIPS procedures) were placed for management of therapy-refractory ascites (n = 7), hydrothorax (n = 2) or bleeding from colonic varices (n = 1). The median time interval between LT and TIPS placement was 15 (4-158) mo. RESULTS: TIPS placement was successful in all patients. The mean portosystemic pressure gradient was reduced from 12.5 to 8.7 mmHg. Complete and partial remission could be achieved in 43% and 29% of patients with ascites. Both patients with hydrothorax did not respond to TIPS. No recurrent bleeding was seen in the patient with colonic varices. Nine of 10 patients died during the study period. Only one of two patients, who underwent retransplantation after the TIPS procedure, survived. The median survival period after TIPS placement was 3.3 (range 0.4-20) mo. The majority of patients died from sepsis with multiorgan failure. CONCLUSION: Indications for TIPS and technical performance in LT patients correspond to those in non-transplanted patients. At least partial control of therapy-refractory ascites and variceal bleeding could be achieved in most patients. Nevertheless, survival rates were disappointing, most probably because of the advanced stages of liver disease at the time of TIPS placement and the high risk of sepsis as a consequence of immunosuppression.

Living donor liver transplantation.

Initially living donor liver transplantation (LDLT) was almost exclusively performed in infants and children. Adult LDLT programmes were initiated several years later. In the west this programme was introduced in view of a critical shortage of deceased donors and a constant increase in waiting list mortality. At present, this procedure is accepted as a therapeutic option for patients with end-stage liver disease to make up for the shortage of donor organs from dead patients. In Asia, however, LDLT has become the predominant means of liver transplantation as donor organs from the diseased cannot be used for religious and ethical reasons. Although there have been significant improvements in surgical techniques and consequently in recipient outcome over recent years, the LDLT procedure is still associated with donor morbidity and even mortality. The overall reported donor mortality was 0.2% and donor morbidity ranged between 0% and 100%. Biliary complications and infections were the most commonly reported donor complications. Therefore, a thorough medical as well as psychological evaluation of the donor and recipient are necessary prior to this procedure. To date, LDLT comprises less than 5% of adult liver transplantations in Europe and in the United States. Recipient and graft survival are almost identical to those seen with liver transplantations from deceased donors (DD). Biliary and vascular complications are more often seen in the LDLT setting. So far, no studies have focussed on the impact of LDLT on waiting list mortality. There is international consensus that this procedure should be restricted to centres with large experience in deceased donor liver transplantations as well as in hepatobiliary surgery. Ethical issues, optimal utility and application of adult LDLT and optimal recipient and donor characteristics have yet to be defined.

Response to preoperative chemoembolization correlates with outcome after liver transplantation in patients with hepatocellular carcinoma.

Patients with small hepatocellular carcinoma (HCC) can be cured by liver transplantation (LT). However, many patients drop out during the waiting time as a result of tumor progression. We prospectively investigated the effect of transarterial chemoembolization on long-term survival of 116 patients with HCC listed for LT. Intention-to-treat analysis revealed that patients with either complete or partial response to therapy (no vital tumor or devascularization of > or =30%, respectively) as assessed by computed tomographic scan before LT had far better 1-, 2-, and 5-year survival rates (100, 93.2, and 85.7%; and 93.8, 83.6, and 66.2%, respectively) compared with those with no response or with tumor progression (82.4, 50.7, and 19.3%). Posttransplant survival analysis showed a marked survival benefit according to transarterial chemoembolization response: patients with complete or partial response had 1-, 2-, and 5-year survival rates of 89.1, 85.1, and 85.1%, and 88.6, 77.4, and 63.9%, respectively, compared with 68.6, 51.4, and 51.4% for patients whose disease did not respond to therapy. Subgroup analysis, however, showed that these benefits were only seen in patients whose disease met the Milan criteria, but not in disease exceeding the Milan criteria but fitting the expanded University of California at San Francisco criteria. These patients were also more likely to drop out as a result of tumor progression while waiting for LT (dropout rate 12.1 vs. 2.9%) and to develop recurrent HCC (21.6 vs. 7.6%). Downstaged patients did even worse, with a dropout rate of 26.7% and a 5-year survival rate of only 25%. In conclusion, the response to preoperative chemoembolization may predict long-term outcome after LT.

Bactobilia after liver transplantation: frequency and antibiotic susceptibility.

After liver transplantation (LT), bactobilia occurs frequently in patients, leading in some cases to cholangitis and biliary sepsis. The present study is the first to investigate bactobilia after LT, and it gives an overview of predisposing factors for bactobilia, the microbial spectrum in the bile of LT patients, and the antibiotic susceptibility. A total of 172 endoscopic retrograde cholangiography (ERC) procedures were performed in 66 LT patients between 1 month and 5.8 years after LT. Bile samples were examined microbiologically. Sixty-eight nontransplanted patients without cholestasis, but requiring ERC for other reasons served as a control group. Of 172 samples obtained from LT patients, 126 (73.3%) were positive for microbes. A total of 236 organisms were isolated: 114 (48.3%) gram-positive bacteria, 92 (39.0%) aerobic gram-negative, 8 (3.4%) anaerobes, and 22 (9.3%) fungi. Ciprofloxacin and amoxycillin/clavulanic acid showed the best susceptibility results among oral antibiotics and piperacillin/tazobactam and imipenem/cilastatin among intravenous preparations. In contrast, only 15.7% of non-LT patients showed bactobilia. In conclusion, our study shows that bactobilia is a problem in patients after LT and that it is not only a contamination from endoscopic intervention. Mechanical obstruction, plastic stents, gallstones, and papillotomy increase the risk of bactobilia significantly. In our cohort we had the best antibiotic susceptibility results for positive cultures in LT patients with piperacillin/tazobactam, ciprofloxacin, or amoxycillin/clavulanic acid.

Small bowel adenocarcinoma in Crohn's disease: a case report and review of literature.

Small bowel adenocarcinomas are remarkable for their rarity, difficult diagnosis and poor prognosis. Here we report an unusual case of a 33-year-old patient in whom infiltrative adenocarcinoma of the small bowel was diagnosed after a 10-year history of Crohn's disease. In most previously reported cases, detection of Crohn's disease was subsequent to that of carcinoma of the small bowel or the patients involved had an even longer history of the disease. Our literature review suggests that the risk of small bowel adenocarcinoma is higher in patients with Crohn's disease than in the overall population. We present details on epidemiology as well as clinical and diagnostic aspects of this rare disease entity.

Long-term outcome of endoscopic treatment of biliary strictures after liver transplantation.

Biliary strictures are one of the most common complications following liver transplantation (LT), with an incidence of 5.8-34%. Endoscopic techniques have been successfully used to treat biliary complications; however, the long-term efficacy and safety of this treatment option has not yet been fully elucidated. This prospective study was performed to determine the efficacy and safety of endoscopic management of biliary complications after LT and its impact on long-term patient and graft survival. Biliary strictures were suspected in the presence of elevated liver parameters and/or abnormal abdominal sonography and subsequently diagnosed by endoscopic retrograde cholangiography (ERC). The mean follow-up was 39.8 (range, 0.3-98.2) months after first ERC. Between October 1992 and December 2003, a total of 515 patients underwent LT. Biliary complications were diagnosed in 84 patients (16.3 %). Anastomotic strictures (AS) alone were found in 65 (12.6%) and nonanastomotic strictures (NAS) in 19 patients (3.7%). Long-term success was observed in 77% of patients with AS. In patients with NAS, partial long-term responses could be achieved in 63% of patients. Five patients (6.2%) required a percutaneous and 6 (7.4%) patients a surgical approach. In conclusion, the long-term outcome for patients with post-liver transplant biliary strictures after endoscopic treatment is excellent, especially for patients with AS. Development of NAS reduces graft but not patient survival after endoscopic therapy.

Motor dysfunction in patients with liver cirrhosis: impairment of handwriting.

Motor dysfunction is an important clinical finding in patients with liver cirrhosis and mild forms of hepatic encephalopathy. The mechanisms and clinical appearance of motor impairment in patients with liver cirrhosis are not completely understood. We studied fine motor control in forty four patients with advanced liver cirrhosis (excluding those with hepatic encephalopathy grade II) and 48 healthy controls using a kinematic analysis of standardized handwriting tests. We analysed parameters of velocity, the ability to coordinate and the level of automatisation of handwriting movements. Furthermore, we studied the association between impairment of handwriting and clinical neuro-psychiatric symptoms. As compared with control subjects, patients showed a statistically significant reduction of movement peak velocity in all handwriting tasks as well as a substantial increase of number of velocity inversions per stroke. Using a z-score based assessment we found impairment of handwriting in fourteen out of forty four patients (31.8 %). The deterioration of handwriting was associated with clinical symptoms of motor dysfunction, such as bradykinesia, adiadochokinesia, dysmetria of upper extremities and gait ataxia. This is the first study that quantitatively investigates impairment of handwriting in patients with liver cirrhosis. Our findings suggest the application of kinematic analysis of handwriting for diagnostics of motor dysfunction in patients with mild forms of hepatic encephalopathy.

Multidimensional assessment of neuro-psychiatric symptoms in patients with low-grade hepatic encephalopathy: a clinical rating scale.

AIM: To evaluate the feasibility of a new clinical rating scale for a standardized assessment of cirrhosis-associated neuro-psychiatric symptoms. METHODS: Forty patients with liver cirrhosis (LC, with or without low-grade hepatic encephalopathy) were invest-igated using a clinical neuro-psychiatric rating scale based on a comprehensive list of neurological, psychomotor, cognitive, affective, behavioral symptoms, and symptoms of disturbed bioregulation. RESULTS: The analysis revealed that the majority of cirrhotic patients showed, besides characteristic neurological symptoms of hepatic encephalopathy, various psychomotor, affective and bioregulatory symptoms (disturbed sleep and sexual dysfunction). Patients were impaired in the following subscales: sleep and biorhythm disorder (75.0% of patients), Parkinsonoid symptoms (25.0%), affective symptoms (17.5%), and psychomotor retardation (12.5%). The increase of total neuro-psychiatric clinical score was significantly associated with the degree of hepatic enceph-alopathy. CONCLUSION: This study suggests that a substantial number of patients with LC and low-grade hepatic encephalopathy manifest various clinical neuro-psychiatric symptoms. The use of a rating scale, which explores clinical dimensions of hepatic encephalopathy, would improve the management of patients with LC.

Alendronate in combination with calcium and vitamin D prevents bone loss after orthotopic liver transplantation: a prospective single-center study.

Bone loss is a common complication in patients before and after liver transplantation (LT). The aim of this study was to investigate the efficacy of prophylactic treatment with bisphosphonates after LT in preventing progressive bone loss in LT patients. We included 136 patients with end-stage liver diseases awaiting LT. Bone mineral density (BMD) (by dual X-ray absorptiometry) and markers of bone metabolism were determined before, and 4, 12, 24, 36, and 48 months after LT. All patients received vitamin D and calcium supplementation before and after LT, those with osteopenia or osteoporosis prior to LT were additionally treated with alendronate following LT. Decreased BMD was seen in a high percentage of patients undergoing LT (osteopenia 48.5%, osteoporosis 23.5%). Reduced BMD before LT was not related to gender, underlying liver disease, or Child-Turcotte-Pugh classification. Body mass index (BMI) prior to LT, however, correlated significantly with the fracture risk. Alendronate prevented the ubiquitously observed bone loss after LT in patients with osteoporosis and osteopenia and, in addition, led to an increase in BMD in patients with osteoporosis within 24 months after LT. In conclusion, our study suggests that alendronate is efficacious in preventing the natural course of bone loss associated with LT.