Assessment of adult patients with chronic liver failure for liver transplantation in 2015: who and when?

In 2015, there are a few absolute contraindications to liver transplantation. In adult patients, survival post-liver transplant is excellent, with 1-year survival rate >90% and 5-year survival rates >80% and predicted median allograft survival beyond 20 years. Patients with a Child-Turcotte Pugh score ≥9 or a model for end-stage liver disease (MELD) score >15 should be referred for liver transplantation, with patients who have a MELD score >17 showing a 1-year survival benefit with liver transplantation. A careful selection of hepatocellular cancer patients results in excellent outcomes, while consideration of extra-hepatic disease (reversible vs irreversible) and social support structures are crucial to patient assessment. Alcoholic liver disease remains a challenge, and the potential to cure hepatitis C virus infection together with the emerging issue of non-alcoholic fatty liver disease-associated chronic liver failure will change the landscape of the who in the years ahead. The when will continue to be determined largely by the severity of liver disease based on the MELD score for the foreseeable future.

Pouch adenomas in Familial Adenomatous Polyposis after restorative proctocolectomy.

INTRODUCTION: Australian Clinical Practice Guidelines suggest six to twelve-monthly endoscopic pouch surveillance in patients after restorative proctocolectomy for Familial Adenomatous Polyposis (FAP). There are several reports of adenomas and carcinomas forming within the ileum, ileal pouch mucosa or residual rectal mucosa. A retrospective clinical study was performed to audit pouch endoscopic surveillance at a large Sydney tertiary referral Hospital. The aim was to evaluate adenoma development after restorative proctocolectomy for FAP and the adherence rate to published clinical guidelines. METHODS: Thirty-nine patients who had restorative proctocolectomy for FAP from 1985 to 2011 were identified. Demographic data, details of surgery, original histopathology and details of follow-up pouch endoscopy and pathology findings were obtained. RESULTS: Of the thirty-nine patients, twenty-seven patients were included in this study. Adenomas were found in twelve of 27 (44%) patients. Mean time to first polyp formation was 88 months and median time was 72 months (range 18-249 months). All polyps were either tubular or tubulovillous in histology. One polyp had high grade dysplasia. The remainder had mild or moderate dysplasia. Polyps were excised either endo-anally or during pouchoscopy. None of the five patients who had a hand-sewn ileal pouch-anal anastomosis (IPAA) developed polyps on follow-up, compared with 12 of the 22 (55%) with a double stapled anastomosis (fishers exact test; p=0.047 (two-tailed)). Of those who developed pouch adenomas, eight (67%) developed further pouch adenomas on follow-up. CONCLUSIONS: This study supports guidelines recommending lifelong pouch surveillance after restorative proctocolectomy for FAP. Those who develop pouch adenomas may be at greater risk of developing further adenomas. Residual rectal mucosa at the pouch-anal anastomosis should be carefully examined.

Terlipressin therapy for moderate-to-severe hyponatraemia in patients with liver failure.

BACKGROUND: Hyponatraemia in liver failure is associated with increased morbidity and mortality. Improving serum sodium in liver failure has been observed in patients receiving terlipressin. METHODS: We assessed the response of hyponatraemia in patients with liver failure to terlipressin using comparative retrospective analysis. RESULTS: Twenty-three patients received terlipressin for hyponatraemia after failed conservative management (median age 52 years (27-67), model for end-stage liver disease score 28 (16-38)). The median therapy was 7 days (1-27), with an average total dose of 25 mg (4-90) and a mean follow up of 51 days (5-1248). These patients were compared with 11 hyponatraemic patients managed conservatively during the same period with comparable age, baseline serum sodium and follow up. After 1 week of terlipressin therapy, serum sodium increased from a median of 120 (115-128) to 129 mmol/L (121-144) (P < 0.001), and at the end of terlipressin therapy, the serum sodium had increased significantly to 131 mmol/L (120-148) (P < 0.001). In comparison, in the conservatively managed group, the serum sodium did not increase significantly from the baseline of 123 (117-127) mmol/L. Adverse events occurred in 26% of patients receiving terlipressin, which predominantly pulmonary oedema. Importantly, more hyponatraemic patients treated with terlipressin (48%) were alive compared with the conservative group (18%), despite the latter having a significantly lower baseline median MELD score of 21 (16-30) (P = 0.008). Moreover, the transplant-free survival was higher in the terlipressin (30%) compared with the conservative group (0%). CONCLUSIONS: Terlipressin is effective in treating hyponatraemia in liver failure. Importantly, terlipressin use results in better transplant-free survival but also more adverse events.

Increasing liver transplantation waiting list mortality: a report from the Australian National Liver Transplantation Unit, Sydney.

BACKGROUND: We aimed to describe the demand for liver transplantation (LTx) and patient outcomes on the waiting list at the Australian National Liver Transplantation Unit, Sydney over the last 20 years. METHODS: We performed a retrospective analysis with the data divided into three eras: 1985-1993, 1994-2000 and 2001-2008. RESULTS: The number of patients accepted for LTx increased from 320 to 372 and 548 (P < 0.001) with the number of LTx being performed increasing from 262 to 312 and 452 respectively (P < 0.001). The median adult recipient age increased from 45 to 48 and 52 years (P < 0.001) while it decreased in children from 4 to 2 and 1 years respectively (P = 0.001). In parallel, the deceased donor offers decreased from 1003 to 720 and 717 (P < 0.001). Methods to improve access to donor livers have been used with the use of split livers, extended criteria and non-heart beating donors, resulting in increased acceptance of deceased donor offers by 65% and 115% in the second and third eras when compared with the first era (P < 0.001). However, the adult median waiting time has increased from 23 to 41 and 120 days respectively (P < 0.001). This was associated with increased adult mortality on the waiting list from 23 to 40 and 122 respectively (P < 0.001). CONCLUSIONS: Despite the increasing proportion of donor offers being used, the waiting list mortality is increasing. A solution to this problem is an increase in organ donation to keep pace with the escalating demand for LTx.

Improved cognitive function as a consequence of hepatitis C virus treatment.

OBJECTIVE: The aim of the study was to investigate the impact of treatment-related clearance of hepatitis C virus (HCV) on cognitive function. METHODS: A prospective study was conducted in 19 HCV-monoinfected and 15 HIV/HCV-coinfected individuals undergoing pegylated interferon alpha-2a and ribavirin therapy between April 2003 and August 2005. Neuropsychological, mood, and health-related quality of life (HRQOL) effects were assessed using computer-based battery, Trail Making Tests, Depression Anxiety Stress Scales and the Short Form-36 health survey. RESULTS: Pretreatment cognitive function, mood status, and HRQOL were similar between the HCV patient groups. Sustained virological response (SVR) rates were similar between HCV-monoinfected (68%) and HIV/HCV-coinfected (73%) groups. SVR was associated with significant improvements in some measures of cognitive function, independent of HRQOL improvement. CONCLUSIONS: Our findings provide evidence to support cognitive effects of HCV independent of mood status and HRQOL profiles.

p53 and DCC immunohistochemistry in curative rectal cancer surgery.

BACKGROUND AND AIMS: In rectal cancer altered expression of p53 or DCC may be indicative of poor patient prognosis. This study determined by immunohistochemistry the tumour status of p53 protein and DCC protein in patients with rectal cancer who had a curative resection and were followed-up prospectively and examined the correlation to clinical and pathology variables. PATIENTS AND METHODS: The study included 171 who had a curative resection for rectal cancer: 88 at Concord Hospital (CH) followed up for a mean of 11 years and 83 at Royal Prince Alfred Hospital (RPAH) followed up prospectively for a mean of 4.3 years. Specimens were assessed by immunohistochemical assay of p53 expression ( n=170) and of DCC expression ( n=168). RESULTS: p53 over-expression was demonstrated in 58% of CH tumours and 59% of RPAH tumours. Absence of normal DCC expression was demonstrated in 66% of CH tumours and 52% of RPAH tumours. On both separate and combined analysis of these groups there were no significant associations by univariate analysis between p53 expression or DCC expression or combinations of p53 and DCC expression and the pathology variables: extent of penetration through bowel wall, lymph node involvement, presence of venous invasion, and tumour differentiation. CONCLUSION: The immunohistochemical p53 and DCC status of rectal tumours was not associated with other clinical or pathology variables, nor predictive of outcome.

p53, DCC and thymidylate synthase as predictors of survival after resection of hepatic metastases from colorectal cancer.

BACKGROUND: Hepatic metastasis from colorectal cancer is a common problem. Hepatic resection offers the only chance of cure. Prognosis of patients following hepatic resection is currently based on clinicopathological factors (of both the primary cancer and the hepatic metastasis), which do not accurately predict the subsequent behaviour of the tumour. The aim of this study was to evaluate three molecular genetic markers - p53, DCC (deleted in colonic cancer) and thymidylate synthase - in both the primary colorectal tumour and the resected hepatic metastases, and to determine their correlation, if any, with survival in patients with resected hepatic metastases from colorectal cancer. METHODS: Sixty-three patients with hepatic metastases and 40 corresponding colorectal primary tumours were studied using immunohistochemical staining for p53, DCC and thymidylate synthase, as well as p53 gene mutations using polymerase chain reaction-single-stranded conformational polymorphism (PCR-SSCP) analysis. The results were correlated with survival. RESULTS: There was no correlation between p53, DCC or thymidylate synthase immunohistochemical staining, or between p53 PCR-SSCP analysis, and survival for either hepatic metastases or the colorectal primary tumour. CONCLUSION: Prediction of prognosis in patients having resection of hepatic metastases from colorectal cancer continues to be problematic. Other genetic markers or combination of markers need to be evaluated.

Hepatocellular carcinoma: current approaches to diagnosis and management.

Hepatocellular carcinoma, frequently associated with chronic viral hepatitis, is the fourth most common cancer worldwide. The incidence in Western countries is rising rapidly. Recent developments in diagnostic imaging allow for identification of small lesions amenable to curative therapy. Effective therapy of advanced hepatocellular carcinoma remains a major clinical problem.

Histological tumour response to pre-operative combined modality therapy in locally advanced rectal cancer.

BACKGROUND: Pre-operative combined modality therapy (CMT) is used in locally advanced rectal cancer. Its use affects the clinicopathological staging based on the resected specimen. Assessment of the tumour response in the resected specimen may provide prognostic information. This study was undertaken to determine the histological response to pre-operative chemoradiation and to assess the interobserver reliability of a newly developed tumour response grading system for rectal cancer. METHODS: Pre-operative biopsy specimens and the resected specimens of 21 patients with low rectal cancer were assessed. The patients underwent pre-operative CMT consisting of radiotherapy (45 Gy) with 5-FU either as a continuous infusion or as a bolus intravenous infusion with leucovorin. After four to six weeks tumour response was assessed by comparing pre-operative transrectal ultrasound (TRUS) findings (uT1-4, uN0-1) with postoperative histopathological assessment (pT1-4, pN0-1) using UICC TNM characteristics. Tumour response was defined as a decrease in T status. The histological response to CMT was based on the tumour regression grade (TRG) and ranged from fibrosis extending through the rectal wall with no residual cancer (TRG 1), to no evidence of tumour response (TRG 5). Inter-observer reliability was assessed using weighted and unweighted kappa statistics. RESULTS: Local downstaging was demonstrated in 11/21 (52%) of patients. Three of 21 patients had a TRG 1 response. Thirteen of 21 (62%) patients had TRG 1-3 responses to CMT. There was no significant correlation between local downstaging and TRG. The interobserver correlation coefficient for assessment of TRG was 0.88 (unweighted kappa). CONCLUSIONS: Local downstaging by pre-operative CMT can be demonstrated if pre-operative TRUS staging is compared to standard pathology staging in patients with rectal cancer. Local downstaging is not directly related to histologic response as assessed by TRG. Inter-observer reporting of tumour regression grade (TRG) is reliable.

Inferior liver allograft survival from cadaveric donors >50 years of age?

The growing imbalance between the number of cadaveric organ donors and recipients has led to an increasing use of high-risk donors as an option to expand the donor pool. The aim of this study was to evaluate our experience with the use of older liver (donor>50 yr of age) allografts. The medical records, postreperfusion biopsies and laboratory results were reviewed of the 393 patients who underwent orthotopic liver transplantation between 1986 and 1997. The outcome of the 61 patients who received older livers (OL) was compared to that of the other 332 recipients. Increasing use of OL was evident from 1992 onwards. Recipients of OL were older than recipients of younger livers (YL, p<0.001) and more commonly had underlying chronic viral hepatitis (CVH) or fulminant hepatic failure (p<0.05). Patient and allograft survival were only slightly less in recipients of OL versus YL (p=NS). Although postperfusion biopsies showed more damage in OL than YL allografts (p<0.05), this was not associated with increased primary graft failure. OL allografts can be transplanted with acceptable results into recipients without the concern of early allograft loss. SUMMARY OF ARTICLE: This report of one centre's experience with 61 recipients of older donor liver allografts identifies recipient factors that may also have a negative impact on allograft outcome. These factors include a diagnosis of either CVH or fulminant hepatic failure at the time of transplantation. Postreperfusion biopsies of older donor allografts tend to show more damage, but this is not associated with primary non-function.

Familial adenomatous polyposis: more evidence for disease diversity and genetic heterogeneity.

Familial adenomatous polyposis (FAP) is characterised by the presence of profuse colonic carpeting of adenomas throughout the entire colon and rectum. The genetic basis of FAP has been shown to be primarily associated with germline mutations in the APC gene. Notwithstanding, several reports have been published indicating that there is genetic heterogeneity in FAP and that the most likely explanation is the existence of another gene. In this report we further delineate the genotype/phenotype correlation in families that harbour germline mutations in the APC gene and identify some previously unreported changes in the APC gene which predispose to an attenuated disease phenotype. From 53 index patients diagnosed with either FAP or attenuated FAP, 27 harboured changes in the APC gene. The remaining 26 patients were further subgrouped according to their colonic phenotype. There were nine patients with a mixed hyperplastic/adenomatous colonic phenotype and there were 17 patients with an adenomatous colonic phenotype. Evaluation of the disease characteristics of these patients and their families is presented which may aid in the identification of new genes associated with colonic polyposis.

Liver transplantation in patients with transjugular intrahepatic portosystemic shunts.

BACKGROUND: In patients with intractable oesophageal variceal bleeding, transjugular intrahepatic portosystemic shunts (TIPSS) are being used increasingly as a bridge to orthotopic liver transplantation (OLTx). There is little information in the literature concerning variations in the operative techniques of OLTx required because of the presence of TIPSS. METHODS: A retrospective review of patients treated by TIPSS prior to OLTx was undertaken. The aims were to assess the effectiveness of TIPSS in bridging patients to OLTx and to examine whether TIPSS influence the operative management of OLTx. RESULTS: Over a 4-year period eight adult patients underwent TIPSS insertion prior to OLTx in the Australian National Liver Transplant Unit (ANLTU). Transplantation was performed at a mean of 14.6 (0.3-53.8) months after TIPSS insertion. Prevention of major recurrent variceal haemorrhage prior to transplantation was achieved in six cases. In two patients the stents were predominantly intrahepatic and they did not interfere with OLTx. In five patients the stents extended into the portal vein, requiring removal during OLTx either by division of the stent with the recipient portal vein, followed by removal of the fractured stent wires from the portal veins (n = 3), or by 'endarterectomy' of the recipient portal vein, allowing removal of the intact stent (n = 2). In one case where the stent extended into the suprahepatic inferior vena cava, removal was achieved by traction without difficulty. All patients are alive at a mean of 24 (7-53) months post-transplant and none has portal vein abnormalities. When compared to 178 adult patients who had no TIPSS and underwent primary OLTx during the same study period, there was no difference in the length of operating time or the usage of blood products during OLTx. CONCLUSION: Transjugular intrahepatic portosystemic shunts offer a bridge to OLTx by providing effective control of variceal haemorrhage. In the present series TIPSS did not increase surgical morbidity or mortality, but emphasis is placed upon the need for optimal TIPSS placement within the liver to facilitate subsequent OLTx.