Proctalgia secondary to rectal arteriovenous malformation and inferior mesenteric vein stenosis in a patient post liver transplant.

BACKGROUND: Chronic proctalgia can have a major impact upon quality of life. There are many potential aetiologies however, in some patients no cause can be identified. CASE PRESENTATION: We present a patient post liver transplant with intractable proctalgia, despite multidisciplinary management including opioids, nerve blocks and surgical intervention. An underlying rectal arteriovenous malformation (AVM) was subsequently identified and successfully treated with embolotherapy. The onset of symptoms coincided with the development of inferior mesenteric vein stenosis, likely leading to engorgement of the malformation due to impaired venous outflow. Neovascularisation secondary to the liver transplant procedure may also have contributed to growth of the lesion. CONCLUSION: This is a rare presentation of rectal AVM. These lesions can be treated with minimally invasive embolisation/sclerotherapy and should be considered in cases of unexplained proctalgia.

Declining incidence of keratinocyte carcinoma in organ transplant recipients.

BACKGROUND: All organ transplant populations are predisposed to increased rates of keratinocyte carcinoma (KC). Since this increased risk was first appreciated, immunosuppressive regimens have changed and organ transplant recipients (OTRs) have been aggressively screened for KC. There is a perception that these measures have impacted on KC incidence but there is a paucity of population-based studies on post-transplant rates of basal cell carcinoma (BCC). OBJECTIVES: To identify trends in incidence rates for KC following solid organ transplantation over the past two decades. METHODS: This nationwide, population-based study included all solid OTRs transplanted between 1994 and 2014. Patient data were matched to national cancer registry data to determine the standardized incidence ratio (SIR) of KC in solid OTRs compared with the general population. RESULTS: In total 3580 solid OTRs were included. The total follow-up time was 28 407 person-years (median follow-up 7·11 years). The overall SIRs for squamous cell carcinoma (SCC) and BCC were 19·7 and 7·0, respectively. Our study documents a progressive fall in the SIRs for SCC and BCC from peak SIRs (95% confidence intervals) in 1994-1996 of 26·4 (21·5-32·4) and 9·1 (7·4-11·3) to 6·3 (2·3-16·7) and 3·2 (1·4-7·1) in 2012-2014, respectively. The ratio of SCC to BCC has remained at 3 to 1 over the last two decades. CONCLUSIONS: Our study is the first to demonstrate a significant reduction over the past two decades in the incidences of both SCC and BCC following solid organ transplantation. The SCC-to-BCC ratio was maintained, demonstrating that both are reducing equally. This trend coincided with temporal changes in immunosuppressive protocols and the introduction of skin cancer prevention programmes. What's already known about this topic? Prior studies have shown that the risk of cutaneous squamous cell carcinoma (SCC) has declined over recent decades following solid organ transplantation. It is not known whether the risk of basal cell carcinoma (BCC) has reduced in line with this. What does this study add? Our study documents a progressive fall in the risk of SCC and BCC following solid organ transplantation over the last two decades. The SCC-to-BCC ratio was maintained, demonstrating that both are reducing equally. The trends observed in our study coincided with temporal changes in immunosuppressive protocols and the introduction of cancer prevention programmes, suggesting that these factors have positively impacted on the risk of keratinocyte carcinoma in this cohort.

Effectiveness of interferon-free therapy for the treatment of HCV-patients with compensated cirrhosis treated through the Irish early access program.

BACKGROUND: We investigated the real-world effectiveness of interferon-free regimens for the treatment of patients with compensated cirrhosis infected with hepatitis C virus (HCV). METHOD: Using the Irish national HCV treatment registry, the effectiveness and safety of interferon-free regimens for HCV-infected patients treated between April 2015 and August 2016, was determined. RESULTS: A SVR12 was achieved in 86% of subjects treated with sofosbuvir/ledipasvir ± ribavirin (SOF/LDV±RBV), 93% treated with paritaprevir, ombitasvir and ritonavir combined with dasabuvir ± ribavirin (3D±RBV) and 89% treated with sofosbuvir/daclatasvir ± ribavirin (SOF/DCV±RBV). The discontinuation rate was 5% and the on-treatment mortality rate was 1%. CONCLUSION: The availability of interferon-free regimens represents a significant breakthrough for the treatment of HCV infection. Treatments options, with high SVR12 rates, are now available for patients with compensated cirrhosis who were unsuitable for treatment with interferon-based regimens. Data obtained from studies conducted in real world practice provide robust information fundamental for input into future economic evaluations for agents used for the treatment of HCV infection.

Purified Human Dental Pulp Stem Cells Promote Osteogenic Regeneration.

Human dental pulp stem/progenitor cells (hDPSCs) are attractive candidates for regenerative therapy because they can be easily expanded to generate colony-forming unit-fibroblasts (CFU-Fs) on plastic and the large cell numbers required for transplantation. However, isolation based on adherence to plastic inevitably changes the surface marker expression and biological properties of the cells. Consequently, little is currently known about the original phenotypes of tissue precursor cells that give rise to plastic-adherent CFU-Fs. To better understand the in vivo functions and translational therapeutic potential of hDPSCs and other stem cells, selective cell markers must be identified in the progenitor cells. Here, we identified a dental pulp tissue-specific cell population based on the expression profiles of 2 cell-surface markers LNGFR (CD271) and THY-1 (CD90). Prospectively isolated, dental pulp-derived LNGFR(Low+)THY-1(High+) cells represent a highly enriched population of clonogenic cells--notably, the isolated cells exhibited long-term proliferation and multilineage differentiation potential in vitro. The cells also expressed known mesenchymal cell markers and promoted new bone formation to heal critical-size calvarial defects in vivo. These findings suggest that LNGFR(Low+)THY-1(High+) dental pulp-derived cells provide an excellent source of material for bone regenerative strategies.

Natural Killer Cells and Liver Transplantation: Orchestrators of Rejection or Tolerance?

Natural killer (NK) cells are highly heterogeneous innate lymphocytes with a diverse repertoire of phenotypes and functions. Their role in organ transplantation has been poorly defined due to conflicting clinical and experimental data. There is evidence that NK cells can contribute to graft rejection and also to tolerance induction. In most solid organ transplantation settings, the role of NK cells is only considered from the perspective of the recipient immune system. In contrast to other organs, the liver contains major resident populations of immune cells, particularly enriched with innate lymphocytes such as NK cells, NKT cells, and gamma-delta T cells. Liver transplantation therefore results in a unique meeting of donor and recipient immune systems. The unusual immune repertoire and tolerogenic environment of the liver may explain why this potentially inflammatory "meeting" often results in attenuated immune responses and reduced requirement for immunosuppression. Recent trials of immunosuppression withdrawal in liver transplant patients have identified NK cell features as possible predictors of tolerance. Here we propose that hepatic NK cells play a key role in the induction of tolerance post-liver transplant and examine potential mechanisms by which these cells influence liver transplant outcome.

Hepatitis C in the era of direct-acting antivirals: real-world costs of untreated chronic hepatitis C; a cross-sectional study.

BACKGROUND: Recent advances in Hepatitis C therapeutics offer the possibility of cure but will be expensive. The cost of treatment may be partially offset by the avoidance of advanced liver disease. We performed a micro-costing study of the ambulatory healthcare utilisation of patients with Hepatitis C supplemented with inpatient diagnosis related group costs. METHODS: The staff utilisation costs associated with a Hepatitis C ambulatory visit were measured and combined with the costs of investigations to establish a mean cost per consultation. An annualised estimate of cost was produced by multiplying this by the number of consultations accessed, stratified by degree of liver impairment. Inpatient costs were established by identifying the number of inpatient episodes and multiplying by Irish diagnosis related group costs. Non-parametric bootstrapping was performed to derive mean and 95%CI values. RESULTS: Two hundred and twenty-five patients were identified. The cost of an outpatient medical review was €136 (€3.60 SD). The cost of a Hepatitis C nursing review was €128 (€7.30 SD). The annual mean costs of care were as follows (95%CI): Mild €398 (€336, €482), Moderate €417(€335, €503), Compensated cirrhosis €1790 (€990, €3164), Decompensated cirrhosis €8302 (€3945, €14,637), Transplantation Year 1 €137,176 (€136,024, €138,306), Transplantation after Year 1 €5337 (€4942, €5799), Hepatocellular carcinoma €21,992 (€15,222, €29,467), Sustained virological response €44 (€16, €73). CONCLUSIONS: The direct medical cost associated with Hepatitis C care in Ireland is substantial and increases exponentially with progression of liver disease. The follow-up costs of patients with a sustained virological response in this cohort were low in comparison to patients with chronic infection.

Historical epidemiology of hepatitis C virus (HCV) in select countries - volume 2.

Chronic hepatitis C virus (HCV) infection is a leading cause of liver related morbidity and mortality. In many countries, there is a lack of comprehensive epidemiological data that are crucial in implementing disease control measures as new treatment options become available. Published literature, unpublished data and expert consensus were used to determine key parameters, including prevalence, viremia, genotype and the number of patients diagnosed and treated. In this study of 15 countries, viremic prevalence ranged from 0.13% in the Netherlands to 2.91% in Russia. The largest viremic populations were in India (8 666 000 cases) and Russia (4 162 000 cases). In most countries, males had a higher rate of infections, likely due to higher rates of injection drug use (IDU). Estimates characterizing the infected population are critical to focus screening and treatment efforts as new therapeutic options become available.

Strategies to manage hepatitis C virus (HCV) infection disease burden - volume 2.

The hepatitis C virus (HCV) epidemic was forecasted through 2030 for 15 countries, and the relative impact of two scenarios was considered: (i) increased treatment efficacy while holding the treated population constant and (ii) increased treatment efficacy and increased annual treated population. Increasing levels of diagnosis and treatment, in combination with improved treatment efficacy, were critical for achieving substantial reductions in disease burden. In most countries, the annual treated population had to increase several fold to achieve the largest reductions in HCV-related morbidity and mortality. This suggests that increased capacity for screening and treatment will be critical in many countries. Birth cohort screening is a helpful tool for maximizing resources. In most of the studied countries, the majority of patients were born between 1945 and 1985.

The present and future disease burden of hepatitis C virus (HCV) infections with today's treatment paradigm - volume 2.

Morbidity and mortality attributable to chronic hepatitis C virus (HCV) infection are increasing in many countries as the infected population ages. Models were developed for 15 countries to quantify and characterize the viremic population, as well as estimate the number of new infections and HCV related deaths from 2013 to 2030. Expert consensus was used to determine current treatment levels and outcomes in each country. In most countries, viremic prevalence has already peaked. In every country studied, prevalence begins to decline before 2030, when current treatment levels were held constant. In contrast, cases of advanced liver disease and liver related deaths will continue to increase through 2030 in most countries. The current treatment paradigm is inadequate if large reductions in HCV related morbidity and mortality are to be achieved.

Operator training requirements and diagnostic accuracy of Fibroscan in routine clinical practice.

BACKGROUND: Fibroscan is a quick, non-invasive technique used to measure liver stiffness (kPa), which correlates with fibrosis. To achieve a valid liver stiffness evaluation (LSE) the operator must obtain all the following three criteria: (1) ≥10 successful liver stiffness measurements; (2) IQR/median ratio <0.30 and (3) ≥60% measurement success rate. OBJECTIVES: To assess the operator training requirements and the importance of adhering to the LSE validity criteria in routine clinical practice. METHODS: We retrospectively analysed the LSE validity rates of 2311 Fibroscans performed (1 August 2008 to 31 July 2011) in our tertiary liver outpatients department at the University Hospital Birmingham, UK. The diagnostic accuracy of Fibroscan was assessed in 153 patients, by comparing LSE (valid and invalid) with the modified Ishak fibrosis stage on liver biopsy. RESULTS: Learning curve analysis highlighted that the greatest improvement in validity of LSE rates occurs in the operator's first 10 Fibroscans, reaching 64.7% validity by the 50th Fibroscan. The correlation between LSE and the fibrosis stage on liver biopsy was superior in patients with a valid LSE (n=97) compared with those with an invalid LSE (n=56) (rs 0.577 vs 0.259; p=0.022). Area under receiving operating characteristics for significant fibrosis was greater when LSE was valid (0.83 vs 0.66; p=0.048). Using an LSE cut-off of 8 kPa, the negative predictive value of valid LSE was superior to invalid LSE for the detection of significant (84% vs 71%) and advanced fibrosis (100% vs 93%). CONCLUSIONS: Fibroscan requires minimal operator training (≥10 observed on patients), and when a valid LSE is obtained, it is an accurate tool for excluding advanced liver fibrosis. To ensure the diagnostic accuracy of Fibroscan it is essential that the recommended LSE validity criteria are adhered to in routine clinical practice.

Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS): a prospective cohort study.

OBJECTIVE: To evaluate mildly abnormal liver function test (LFT) results in general practice among patients who do not have known liver disease. DESIGN: Prospective cohort study of people with abnormal LFT results identified in primary care. Participants were intensively investigated using a common protocol and followed up for 2 years. Substudies investigated the psychological sequelae of abnormal test results, clinicians' reasons for testing, decision options when LFT results were abnormal and early detection of liver fibrosis. SETTING: Eleven primary-care practices: eight in Birmingham and three in Lambeth. PARTICIPANTS: Adults with abnormal LFT results who did not have pre-existing or obvious liver disease. Eight analytes were included in the panel of LFTs. MAIN OUTCOME MEASURES: Statistical tests were used to identify the interactions between clinical features, the initial pattern of abnormal LFT results and (1) specific viral, genetic and autoimmune diseases, such as viral hepatitis, haemochromatosis and primary biliary cirrhosis; (2) a range of other serious diseases, such as metastatic cancer and hypothyroidism; (3) 'fatty liver' not associated with the above; and (4) the absence of detectable disease. RESULTS: Fewer than 5% of people with abnormal LFT results had a specific disease of the liver, and many of these were unlikely to need treatment. The diagnostic potential of the LFT panel is largely subsumed into just two analytes: alanine aminotransferase (ALT) and alkaline phosphatase (ALP). Gamma-glutamyltransferase (GGT) offers a small increase in sensitivity at the margin at the cost of a large loss of specificity. Eighty-four per cent of abnormal LFT results remain abnormal on retesting 1 month later. In many cases, carrying out a definitive or specific test will be more efficient than repeating LFTs, with a view to specific testing only if the test remains abnormal. An ultrasound diagnosis of 'fatty liver' was present in nearly 40% of patients with abnormal LFTs and a small amount of weight loss over 2 years was associated with a reduced incidence of liver fat. There was a J-shaped relationship between alcohol intake and fatty liver in men. An abnormal LFT result causes temporary anxiety, which does not appear to promote sustained behaviour change. CONCLUSIONS: Liver disease is rare among people with abnormal LFT results in primary care. Only two analytes (ALT and ALP) are helpful in identifying the majority of liver disease. GGT adds little information in return for a high false-positive rate but it is sensitive to alcohol intake. LFT results seldom revert from abnormal to normal over a 1-month period, and modelling shows that repeating an abnormal LFT panel, as recommended in the current guidelines, is inefficient. LFTs are often undertaken to meet perceived patient need for a blood test, but as they are neither specific nor indicative of any particular disease they are among the least suitable tests for this purpose. Obesity and raised ALT provide strong evidence for a presumptive diagnosis of 'fatty' liver. Abnormal LFTs and 'fatty' liver provoke only short-term anxiety and neither is associated with sustained weight loss. Even a small amount of weight loss reduces liver fat. FUTURE WORK RECOMMENDATIONS: (1) the cases of 'fatty liver' and controls should be followed up in the long term to identify features that predict development of hepatosteatosis and then cirrhosis; (2) the acceptability of replacing the traditional six- to eight-analyte LFT panel with a drop down menu including the ALT/ALP combination should be evaluated. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Systematic review: pentoxifylline for the treatment of severe alcoholic hepatitis.

BACKGROUND: Acute alcoholic hepatitis (AH) is a severe manifestation of alcoholic liver disease with a grave prognosis. Pentoxifylline, an oral antitumour necrosis factor agent, has been reported to reduce mortality and incidence of hepatorenal syndrome (HRS) in severe alcoholic hepatitis (SAH). AIM: To summarise evidence for the use of pentoxifylline in SAH. METHODS: A literature search was undertaken using MeSH terms 'hepatitis, alcoholic' and 'pentoxifylline' using the set operator AND. We included randomised controlled trials examining pentoxifylline in SAH, published as abstracts or full manuscripts. Risk ratios (RRs) were calculated for pooled data using random effects modelling. Risk of bias was assessed using Cochrane group criteria and quality of trials assessed using 'Consolidated Standards of Reporting Trials' CONSORT guidelines. RESULTS: Ten trials including 884 participants were included, from six papers and four abstracts. There was significant heterogeneity between trials regarding control groups and trial end-points. Treatment was given for 28 days in all trials except one. Pooling of data showed a reduced incidence of fatal HRS with pentoxifylline compared with placebo (RR: 0.47, 0.26-0.86, P = 0.01), but no survival benefit at 1 month (RR: 0.58, 0.31-1.07, P = 0.06). There were no significant differences between treatment groups in trials of pentoxifylline vs. corticosteroid, or vs. combination therapy. CONCLUSIONS: Pentoxifylline appears superior to placebo in prevention of fatal HRS and thus may be effective treatment of SAH when corticosteroids are contraindicated. However, multiple trials have failed to show conclusive superiority of either pentoxifylline or corticosteroids.

Psychiatric nurses' attitudes towards children visiting their parents in psychiatric inpatient units.

BACKGROUND: The provision of care for children of parents with a mental health problem is an area that is frequently neglected by health-care practitioners. OBJECTIVES: The aim of the overall study was to explore psychiatric nurses' knowledge of, attitudes and practice towards the support needs of children whose parent has a mental health problem. This paper specifically addresses the views of psychiatric nurses towards children visiting their parent in a mental health inpatient facility. METHOD: This study employed a self-completion survey design with a sample of 114 registered psychiatric nurses from one integrated mental health service in Ireland. RESULTS: The majority of participants were in favour of children visiting their parent when in hospital, but were of the view that the visiting areas should be away from the main ward location and designed to be child-friendly. Many expressed concerns about the standard of visiting facilities and worried about the potentially negative impact of a visit on the child's well-being. In relation to education on child-care issues, a significant majority of the participants reported not having received any education in the child-care issues identified and, as a likely consequence, rated their knowledge as insufficient. CONCLUSIONS: This study highlights the need for further work in the areas of practitioner education, child-friendly visiting facilities, and the development of policy and practice guidelines around children whose parents experience a mental health problem.

Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program.

BACKGROUND: Non-alcoholic fatty liver disease has reached epidemic proportions in type 2 diabetes (T2D). Glucagon-like peptide-1 analogues are licensed in T2D, yet little data exist on efficacy and safety in liver injury. AIM: To assess the safety and efficacy of 26-week liraglutide on liver parameters in comparison with active-placebo. METHODS: Individual patient data meta-analysis was performed using patient-level data combined from six 26-week, phase-III, randomised controlled T2D trials, which comprise the 'Liraglutide Effect and Action in Diabetes' (LEAD) program. The LEAD-2 sub-study was analysed to assess the effect on CT-measured hepatic steatosis. RESULTS: Of 4442 patients analysed, 2241 (50.8%) patients had an abnormal ALT at baseline [mean ALT 33.8(14.9) IU/L in females; 47.3(18.3) IU/L in males]. Liraglutide 1.8 mg reduced ALT in these patients vs. placebo (-8.20 vs. -5.01 IU/L; P = 0.003), and was dose-dependent (no significant differences vs. placebo with liraglutide 0.6 or 1.2 mg). This effect was lost after adjusting for liraglutide's reduction in weight (mean ALT difference vs. placebo -1.41 IU/L, P = 0.21) and HbA1c (+0.57 IU/L, P = 0.63). Adverse effects with 1.8 mg liraglutide were similar between patients with and without baseline abnormal ALT. In LEAD-2 sub-study, liraglutide 1.8 mg showed a trend towards improving hepatic steatosis vs. placebo (liver-to-spleen attenuation ratio +0.10 vs. 0.00; P = 0.07). This difference was reduced when correcting for changes in weight (+0.06, P = 0.25) and HbA(1c) (0.00, P = 0.93). CONCLUSIONS: Twenty-six weeks' liraglutide 1.8 mg is safe, well tolerated and improves liver enzymes in patients with type 2 diabetes. This effect appears to be mediated by its action on weight loss and glycaemic control.

Review article: liver transplantation for the pulmonary disorders of portal hypertension.

BACKGROUND: Liver transplantation is potentially a life-saving therapeutic intervention for patients with portopulmonary hypertension and hepatopulmonary syndrome. However, due to limited data, listing criteria for patients with these conditions have not been clearly established. Indeed, this has led some to speculate that transplantation may not be appropriate in cases of moderate-to-severe portopulmonary hypertension and severe hepatopulmonary syndrome. AIM: To critically discuss the utility of LT for the treatment of hepatopulmonary syndrome and portopulmonary hypertension. METHODS: A literature search was conducted in 2012 on PubMed, Ovid Embase, Ovid Medline and Scopus using the following search terms: hepatopulmonary syndrome, portopulmonary hypertension, pulmonary arterial hypertension, liver transplantation. Relevant manuscripts were included in the review. RESULTS: Liver transplantation has established itself as an effective treatment for selected patients with hepatopulmonary syndrome and portopulmonary hypertension. A multidisciplinary team approach incorporating focused strategies (both pre- and post-operatively) aimed at improving oxygenation in patients with hepatopulmonary syndrome has led to a dramatic improvement in patient outcomes. Additionally, careful patient selection and the use of targeted pulmonary vascular therapies are successfully being used to treat portopulmonary hypertension and 'bridge' patients to successful liver transplantation. CONCLUSIONS: Liver transplantation is an effective therapy for patients with hepatopulmonary syndrome and portopulmonary hypertension. However, rigorous screening and early identification of these conditions allied with aggressive pre-operative optimisation of physiology and diligent post-operative care are imperative to ensuring a good outcome.

Supporting children whose parent has a mental health problem: an assessment of the education, knowledge, confidence and practices of registered psychiatric nurses in Ireland.

Health professionals, including nurses, stand accused of ignorance or oversight of children whose parent experience a mental health problem. Psychiatric nurses are in an ideal position to respond to children's needs and support their parents in a proactive and sensitive manner. The aim of this study was to explore psychiatric nurses' education, knowledge, confidence and practice with regard to the support needs of children whose parent has a mental health problem. This study employed a self-completion anonymous survey design with a sample of registered psychiatric nurses from one integrated mental health service in Ireland. The sample reported relatively low levels of education, knowledge, confidence and supportive clinical practice when it came to children whose parent has a mental health problem. There is an urgent need for education on family-focused care, and the development of guidelines and child focused services if the needs of parents and children are to be met.