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.

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.

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.

Neoplastic progression occurs through mutator pathways in hyperplastic polyposis of the colorectum.

AIM: Colorectal cancer has been described in association with hyperplastic polyposis but the mechanism underlying this observation is unknown. The aim of this study was to characterise foci of dysplasia developing in the polyps of subjects with hyperplastic polyposis on the basis of DNA microsatellite status and expression of the DNA mismatch repair proteins hMLH1, hMSH2, and hMSH6. MATERIALS AND METHODS: The material was derived from four patients with hyperplastic polyposis and between one and six synchronous colorectal cancers. Normal (four), hyperplastic (13), dysplastic (13), and malignant (11) samples were microdissected and a PCR based approach was used to identify mutations at 10 microsatellite loci, TGFbetaIIR, IGF2R, BAX, MSH3, and MSH6. Microsatellite instability-high (MSI-H) was diagnosed when 40% or more of the microsatellite loci showed mutational bandshifts. Serial sections were stained for hMLH1, hMSH2, and hMSH6. RESULTS: DNA microsatellite instability was found in 1/13 (8%) hyperplastic samples, in 7/13 (54%) dysplastic foci, and in 8/11 (73%) cancers. None of the MSI-low (MSI-L) samples (one hyperplastic, three dysplastic, two cancers) showed loss of hMLH1 expression. All four MSI-H dysplastic foci and six MSI-H cancers showed loss of hMLH1 expression. Loss of hMLH1 in MSI-H but not in MSI-L lesions showing dysplasia or cancer was significant (p<0.001, Fisher's exact test). Loss of hMSH6 occurred in one MSI-H cancer and one MSS focus of dysplasia which also showed loss of hMLH1 staining. CONCLUSION: Neoplastic changes in hyperplastic polyposis may occur within a hyperplastic polyp. Neoplasia may be driven by DNA instability that is present to a low (MSI-L) or high (MSI-H) degree. MSI-H but not MSI-L dysplastic foci are associated with loss of hMLH1 expression. At least two mutator pathways drive neoplasia in hyperplastic polyposis. The role of the hyperplastic polyp in the histogenesis of sporadic DNA microsatellite unstable colorectal cancer should be examined.

Case report: an inherited APC mutation in the first reported Australian case of Turcot's syndrome.

The objective of this study was to determine the inherited gene mutation responsible for the first reported Australian case of Turcot's syndrome. DNA was extracted from the archival tissue blocks obtained at the time of the patient's original surgery and from fresh blood samples obtained from selected family members. These were analysed for mutations of the familial adenomatous polyposis gene (APC). Analysis of DNA from the archival blocks and from each of the affected family members revealed an inherited 5 base pair deletion at codon 1061 of APC. In this case, the central nervous system tumour represents an extracolonic manifestation of familial adenomatous polyposis. The underlying inherited mutation of APC has been identified. In some cases of Turcot's syndrome, other genes appear to be involved. Recent literature examining the molecular basis of Turcot's syndrome is reviewed.

Hepatitis C virus genotypes in a cohort of Australian blood donors and haemophiliac and liver transplant patients.

The aim of the present study was to characterize hepatitis C virus (HCV) genotypes using the INNO-LiPA HCV line probe assay and direct sequencing from three different HCV-RNA-positive (serum) groups: (i) blood donors (n = 59); (ii) haemophiliacs (n = 43); and (iii) patients undergoing liver transplantation (n = 26). Of 128 HCV-RNA-positive samples, 74 (58%) were genotype 1. Of these, 41 were genotype 1a, 32 were genotype 1b and one was genotype 1 indeterminate. Of the remaining 54 samples, seven (5%) were genotype 2a, two (2%) were genotype 2b, 26 (20%) were genotype 3a, three (2%) were genotype 4a, while 16 (12.5%) were of a mixed genotype. There was no significant difference between the three groups with regard to the prevalence of any specific genotype. However, in blood donors and haemophiliac patients there was a statistically significant difference in the occurrence of genotype 3a in patients with elevated alanine aminotransferase (ALT) levels (30.3%) compared with those patients with persistently normal ALT levels (5.6%; P = 0.004; chi 2). Genotype 3a was also uncommon in liver transplant patients (one of 14) with "sporadic' HCV infection. Genotype 4a was detected only in liver transplant patients. These patients had originated from Egypt (n = 1), Italy (n = 1) and Romania (n = 1).

Exon eight APC mutations account for a disproportionate number of familial adenomatous polyposis families.

The familial adenomatous polyposis gene, APC, has recently been identified. Detection of APC mutations will facilitate genetic screening in family members at risk for this disease. The length of APC makes it impractical to examine the entire coding sequence in each new family encountered. Identification of mutation cluster regions within the gene has therefore become a priority. Initial reports suggested that exon eight might contain a disproportionate number of mutations. This study describes direct sequencing of exon eight in 21 unrelated Australians with familial adenomatous polyposis. Mutations were detected in three of the 21 subjects (14%). Two were previously described point mutations changing an arginine to a stop codon. The third was a novel two base-pair deletion producing a frameshift and downstream stop codon. All three mutations segregated with the disease gene in their respective families. Three at risk children from two of these families were studied and shown not to have inherited the disease producing mutation. These results confirm that exon eight is a frequent site of mutation in familial adenomatous polyposis and should be examined routinely in families requesting genetic screening.

Allele non-amplification: a source of confusion in linkage studies employing microsatellite polymorphisms.

Microsatellite polymorphisms provide highly informative readily detectable markers for human linkage studies. This paper reports apparent non-Mendelian inheritance of a dinucleotide repeat polymorphism due to allele non-amplification. The previously hidden allele was revealed and Mendelian inheritance restored when a new CA strand primer was used for amplification. Sequencing of the hidden allele identified a single base substitution at the 3'-most position of the binding site for the original CA strand primer. Allele non-amplification is a potential source of confusion in linkage studies employing polymorphisms detected by the polymerase chain reaction. It should be considered whenever apparent non-Mendelian inheritance or non-paternity are encountered.

Tumour suppressor genes and colorectal neoplasia.

Two distinct gene classes have been implicated in colorectal carcinogenesis. Tumour promoter genes (oncogenes, dominant oncogenes) produce an excessive positive stimulus to cell proliferation. The ras family of oncogenes are an example. Acquired mutations of the c-k-ras gene are commonly found in colonic adenomas and carcinomas. Tumour suppressor genes (anti-oncogenes, recessive oncogenes) normally constrain or regulate cell proliferation. Loss of this function through gene deletion or mutation is oncogenic. Inherited tumour suppressor gene mutations have now been identified in several of the familial cancer syndromes. Acquired tumour suppressor gene mutations are found in both sporadic and hereditary cancers. Together with the tumour promoter genes they provide the genetic basis for the cellular changes occurring during carcinogenesis. The retinoblastoma gene was the first human tumour suppressor gene to be characterized and exemplifies the class. More recently, linkage studies in the hereditary cancer syndromes and the detection of specific deletions in sporadic tumours have helped to identify several new tumour suppressor genes. At least four of these (MCC, APC, p53 and DCC) apparently contribute to sporadic colorectal carcinogenesis. Germ line APC mutations produce the inherited colorectal cancer syndrome familial adenomatous polyposis (FAP). Detection of these mutations using linked markers has already found clinical application in the screening of families with this disease. In the future, genetic diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) and the recognition of those genetically susceptible to sporadic colorectal cancer may become possible. At the same time, as our understanding of the genes involved improves, new avenues for treatment and prevention of colorectal cancer may emerge.

Normal high-resolution karyotypes in 26 unrelated individuals with hereditary colorectal neoplasia.

High-resolution karyotype analysis was performed on peripheral blood cultures from 26 patients with hereditary colorectal neoplasia. The aims of this study were: first, to determine the frequency of cytogenetically visible chromosome 5q deletions in familial adenomatous polyposis and, thus, whether routine karyotype analysis should be included in screening regimens for affected families; and, second, to search for chromosomal abnormalities in hereditary nonpolyposis colorectal cancer that might assist in localizing the gene or genes responsible. No cytogenetic abnormalities were detected among 21 unrelated patients with familial adenomatous polyposis and five with hereditary nonpolyposis colorectal cancer. We conclude that cytogenetic analysis is of no value in the management of families with typical familial adenomatous polyposis or Gardner's syndrome, and should be confined to those families with atypical features such as mental retardation or facial dysmorphism.

Risk estimation in familial adenomatous polyposis using DNA probes linked to the familial adenomatous polyposis gene.

The familial adenomatous polyposis gene has recently been assigned to the long arm of chromosome five through linkage to several 5q DNA probes. These probes can now be used to trace inheritance of the disease gene in affected families. In this study, DNA samples from 152 members of 10 Australian familial adenomatous polyposis families have been examined for restriction fragment length polymorphisms detected by DNA probes C11P11, ECB27, and YN5.48. Linkage analysis confirmed linkage between the familial adenomatous polyposis gene and each probe with a maximum combined LOD score of 2.82 for C11P11, 2.90 for ECB27 and 5.49 for YN5.48 all at a recombination fraction of zero. Risk estimates were determined for the 51 at risk individuals in these families based on their restriction fragment length polymorphism data alone or in addition by including the effect of age dependent penetrance. Thirty two of those at risk (63%) could be assigned specific high (greater than or equal to 95%) or low (less than or equal to 5%) risks of developing familial adenomatous polyposis on the basis of their probe results. When the effect of age dependent penetrance was included, 26 (51%) fell at the extremes of risk (greater than or equal to 99% or less than or equal to 1%). Such estimates provide a sound basis for planning sigmoidoscopic screening of at risk family members and will thus facilitate surveillance in familial adenomatous polyposis families.

Screening studies and markers.

Primary hepatocellular carcinoma (HCC) is an important cause of death in patients with chronic liver disease and in carriers of hepatitis B virus. Because of its relative frequency in certain geographic areas, such as Asia and sub-Saharan Africa, mass screening programs have been instituted to implement secondary prevention. It is believed that early diagnosis provides the best chance of successful surgical resection and hopefully prolonged survival. Although a number of serological and imaging tests are available, the most cost-effective modality is serum alphafetoprotein (AFP) and real-time ultrasound (USS) used together. The current recommendation is recognition of high-risk groups (cirrhosis, chronic active hepatitis, and chronic hepatitis B carriers) and provision of AFP and USS testing at 3 to 6 months intervals, with recourse to fine-needle aspiration biopsy and celiac angiography for individuals who test positive with either test.

Salmonella food poisoning.

During an outbreak of Salmonella typhimurium food poisoning in September 1983, in Sydney, 10 affected subjects were admitted to the same hospital. On admission to hospital, all patients were severely dehydrated; two patients developed acute tubular necrosis, while a third patient had myopericarditis. Bacteraemia was confirmed in two patients, in one of whom no organisms were isolated from stool cultures. Antibiotic agents were administered to all patients, because of the unusually severe nature of the infection. This outbreak illustrates that salmonella gastroenteritis, although usually fairly mild and self-limiting, can be a virulent disease resulting in serious complications. Appropriate management should include careful initial assessment of suspected cases, vigorous correction of fluid and electrolyte disturbances, and judicious use of antibiotic agents when bacteraemia or severe toxaemic features are present.

Cranial arteritis. A twenty-year review of cases.

Thirty-five cases of cranial arteritis in an Australian population have been analysed. The female to male ratio was 2.2:1 and the average age of onset was 71 years. Eighty-five percent of patients suffered headache and this was most frequently temporal or bitemporal. Polymyalgia rheumatica (40%), permanent visual loss (29%) and jaw claudication (26%) were common, six patients complained of diplopia and four gave a past history of thyroid disease. The temporal artery was clinically abnormal in only 69% of cases but biopsy was positive in 26 of 28 specimens examined. Sixty-seven percent of patients had ESR's greater than 60 mm/h. The average duration of prednisone therapy was 22 months. Side effects of steroids were observed in seven of 19 patients followed up. The importance of starting steroid therapy as soon as the condition is suspected clinically is emphasised by the case of one patient who lost vision while awaiting temporal artery biopsy.