Routine screening for hepatitis C in pregnancy is cost-effective in a large urban population in Ireland: a retrospective study.

OBJECTIVE: To investigate whether risk factor-based screening in pregnancy is failing to identify women with hepatitis C virus (HCV) infection and to assess the cost-effectiveness of universal screening. DESIGN: Retrospective study and model-based economic evaluation. SETTING: Two urban tertiary referral maternity units, currently using risk factor-based screening for HCV infection. POPULATION: Pregnant women who had been tested for hepatitis B, HIV but not HCV. METHODS: Anonymised sera were tested for HCV antibody. Positive sera were tested for HCV antigen. A cost-effectiveness analysis of a change to universal screening was performed using a Markov model to simulate disease progression and Monte Carlo simulations for probabilistic sensitivity analysis. MAIN OUTCOME MEASURES: Presence of HCV antigen and cost per quality-adjusted life year (QALY). RESULTS: In all, 4655 samples were analysed. Twenty had HCV antibodies and five HCV antigen. This gives an active infection rate of 5/4655, or 0.11%, compared with a rate of 0.15% in the risk-factor group. This prevalence is 65% lower than a previous study in the same hospitals from 2001 to 2005. The calculated incremental cost-effectiveness ratio (ICER) for universal screening was €3,315 per QALY gained. CONCLUSION: This study showed that the prevalence of HCV infection in pregnant women in the Dublin region has declined by 65% over the past two decades. Risk factor-based screening misses a significant proportion of infections. A change to universal maternal screening for hepatitis C would be cost-effective in our population. TWEETABLE ABSTRACT: Universal maternal screening for hepatitis C is cost-effective in this urban Irish population.

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.

Long-term follow-up of patients with spontaneous clearance of hepatitis C: does viral clearance mean cure?

Up to 40% of patients with hepatitis C virus (HCV) antibodies are negative for HCV RNA at initial evaluation. If there is a risk of viral re-activation, long term follow-up is required with attendant financial, psychological and medical implications. We investigated the risk of re-activation in the Irish anti-D cohort. Information was obtained from the national hepatitis C database which includes data on patients infected by anti-D immunoglobulin in two large outbreaks, 1977-9 and 1991-94. As part of a screening programme, starting in 1994, 64,907 females exposed to anti-D immunoglobulin were evaluated. Three hundred and forty-seven were found to be antibody positive but HCV RNA negative at initial assessment. 93% had subsequent RNA tests. There was no evidence of HCV recurrence in patients whose infection resolved spontaneously. It appears that two initial sequential negative results for HCV RNA are sufficient to confirm spontaneous viral clearance and probable cure of hepatitis C virus infection.

Reduced fibrosis in recurrent HCV with tacrolimus, azathioprine and steroids versus tacrolimus: randomised trial long term outcomes.

OBJECTIVE: Early results of a randomised trial showed reduced fibrosis due to recurrent HCV hepatitis with tacrolimus triple therapy (TT) versus monotherapy (MT) following transplantation for HCV cirrhosis. We evaluated the clinical outcomes after a median 8 years of follow-up, including differences in fibrosis assessed by collagen proportionate area (CPA). DESIGN: 103 consecutive liver transplant recipients with HCV cirrhosis receiving cadaveric grafts were randomised to tacrolimus MT (n=54) or TT (n=49) with daily tacrolimus (0.1 mg/kg divided dose), azathioprine (1 mg/kg) and prednisolone (20 mg), the last tailing off to zero by 6 months. Both groups had serial transjugular biopsies with hepatic venous pressure gradient (HVPG) measurement. Time to reach Ishak stage 4 was the predetermined endpoint. CPA was measured in all biopsies. Factors associated with HCV recurrence were evaluated. Clinical decompensation was the first occurrence of ascites/hydrothorax, variceal bleeding or encephalopathy. RESULTS: No significant preoperative, peri-operative or postoperative differences between groups were found. During 96 months median follow-up, stage 4 fibrosis was reached in 19 MT/11 TT with slower fibrosis progression in TT (p=0.009). CPA at last biopsy was 12% in MT and 8% in TT patients (p=0.004). 14 MT/ three TT patients reached HVPG≥10 mm Hg (p=0.002); 10 MT/three TT patients, decompensated. Multivariately, allocated MT (p=0.047, OR 3.23, 95% CI 1.01 to 10.3) was independently associated with decompensation: 14 MT/ seven TT died, and five MT/ four TT were retransplanted. CONCLUSIONS: Long term immunosuppression with tacrolimus, azathioprine and short term prednisolone in HCV cirrhosis recipients resulted in slower progression to severe fibrosis assessed by Ishak stage and CPA, less portal hypertension and decompensation, compared with tacrolimus alone. ISRCTN94834276--Randomised study for immunosuppression regimen in liver transplantation.

Low incidence of Pneumocystis jirovecii pneumonia in an unprophylaxed liver transplant cohort.

BACKGROUND: Liver transplant recipients are managed with a range of immunosuppressive regimens that place them at heightened risk of life-threatening opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP). No routine PJP prophylaxis is used at out institution. We reviewed the incidence of PJP in this cohort of unprophylaxed liver transplant recipients. METHODS: We examined all liver transplants performed between January 2000 and January 2012 in Ireland's National Liver Transplant Centre, St. Vincent's University Hospital, Dublin. Cases were identified through a computerized database and through the histopathology and microbiology registration system. The diagnosis of PJP was confirmed by identification of Pneumocystis cysts in bronchoalveolar lavage (BAL) fluid or on autopsy specimens using Grocott-Gomori methenamine-silver nitrate or modified Wright-Giemsa staining methods. RESULTS: During the study period, 687 liver transplants were performed. We found 7 cases of PJP with an incidence rate of 0.84 per 1000 person transplant years. Five cases occurred within 12 months of transplant with 2 cases occurring at 56 and 60 months, respectively. Two cases were diagnosed at postmortem; 1 previously had negative cytology from BAL, while the other could not be bronchoscoped because of rapid deterioration in the clinical condition. Three of the 5 treated patients died. CONCLUSIONS: The incidence of PJP in this cohort was very low, but the case fatality rate was high. Two cases occurred well after the usual recommended period of prophylaxis. In institutions with a very low risk of infection, targeted rather than universal prophylaxis may be reasonable.

Hepatic infarction, hematoma, and rupture in HELLP syndrome: support for a vasospastic hypothesis.

Purpose: HELLP syndrome is a relatively uncommon pregnancy-related condition characterized by hemolysis, elevated liver function tests, and low platelets. It can be accompanied by life-threatening hepatic complications including hepatic infarction, hematoma formation, and hepatic rupture. HELLP syndrome occurs in approximately 0.2% of pregnancies. Major hepatic complications occur in less than 1% of HELLP patients suggesting an incidence of 1/50,000. The pathogenesis is incompletely understood and in particular, it is difficult to understand a disorder with both major thrombotic and bleeding manifestations.Methods: Literature review.Results: On the basis of reports in the published literature, and our own clinical experience, we suggest that vasospasm is one of the principal drivers with hepatic ischemia, infarction, and hemorrhage as secondary events. It is known that vasoactive substances are released by the failing placenta. We suggest these cause severe vasospasm, most likely affecting the small post-sinusoidal hepatic venules. This leads to patchy or confluent hepatic ischemia and/or necrosis with a resultant increase in circulating liver enzymes. Reperfusion is associated with a fall in platelet count and microvascular hemorrhage if the microvasculature is infarcted. Blood tracks to the subcapsular space causing hematoma formation. If the hematoma ruptures the patient presents with severe abdominal pain, intra-abdominal hemorrhage, and shock.Conclusions: We suggest that hepatic and other complications associated with HELLP syndrome including placental abruption, acute renal failure, and posterior reversible encephalopathy syndrome (PRES) may also be due to regional vasospasm.

Alcohol misuse in patients with psoriasis: identification and relationship to disease severity and psychological distress.

BACKGROUND: Moderate to severe psoriasis is associated with increased alcohol intake and excessive mortality from alcohol-related causes. Alcohol biomarkers provide an objective measure of alcohol consumption. Carbohydrate-deficient transferrin (CDT) is the single most sensitive and specific alcohol biomarker. OBJECTIVES: To assess alcohol consumption in a cohort of patients with moderate to severe psoriasis using standard alcohol screening questionnaires and biomarkers. We investigated whether there was an association between alcohol intake, anxiety, depression and disease severity. METHODS: Consecutive patients with chronic plaque psoriasis were recruited and completed a range of anonymized assessments. Psoriasis severity, anxiety and depression, and the impact of psoriasis on quality of life were assessed. Alcohol screening questionnaires were administered. Blood specimens were taken and γ-glutamyltransferase (γGT) and CDT were measured. RESULTS: A total of 135 patients completed the study. Using validated questionnaires, between 22% and 32% had difficulties with alcohol. Seven per cent had CDT > 1·6% indicating a heavy alcohol intake. The Alcohol Use Disorders Identification Test (AUDIT) questionnaire was superior to other validated questionnaires in detecting alcohol misuse. There were no significant associations between measures of excessive alcohol consumption and disease severity. Excessive alcohol intake as measured by the CAGE questionnaire was associated with increased depression (P = 0·001) but other measures of alcohol excess did not correlate with psychological distress. Men had significantly more difficulties with alcohol than women (P < 0·001). CONCLUSION: Alcohol misuse is common in patients with moderate to severe psoriasis. Screening with the AUDIT questionnaire and CDT may allow the identification of patients who are misusing alcohol and allow appropriate intervention.

Successful pregnancy after liver transplantation in progressive familial intrahepatic cholestasis, type 1.

A woman who had undergone liver transplantation for genetically documented ATP8B1 disease/progressive familial intrahepatic cholestasis, type 1, successfully conceived, carried, and was delivered of a healthy child. The pregnancy and its management are described; implications are discussed.

Management of hepatorenal syndrome.

Hepatorenal syndrome is a form of acute or sub-acute renal failure which develops in patients with chronic liver disease. In contrast to other forms of acute renal failure it may be reversible using pharmacological agents. The pathogenesis involves splanchnic vasodilatation and intense renal vasoconstriction. Increasing intravascular volume and prolonged treatment with vasoconstrictor drugs reverses renal failure in a significant proportion of patients. Agents currently used include the vasopressin analogues terlipressin and the alpha1-adrenoceptor agonist midodrine. The somatostatin analogue octreotide has been used in combination therapy but is ineffective as monotherapy. Intravenous albumin is an important adjunctive treatment both in the prevention and treatment of hepatorenal syndrome. Increasing intravascular volume using TIPS (transjugular intrahepatic stent shunt) is effective in some patients and may be useful in maintaining patients who have initially responded to pharmacological therapy. Despite improvements in survival, long term prognosis is still poor and generally depends on the degree of reversibility of the underlying liver disease or access to liver transplantation.

Methadone and HCV treatment.

Relatively few patients infected with the hepatitis C virus through intravenous drug abuse receive effective antiviral therapy. The aim of this study was to determine if supervised treatment in a drug treatment centre could improve compliance with antiviral therapy. A pilot study of supervised anti-viral treatment in a community non-residential drug treatment facility was conducted. Thirteen patients infected with hepatitis C virus genotype 2 or 3 were identified in a drug treatment clinic. Six patients agreed to treatment. Full treatment course was administered in all 6 with sustained viral response in 5/6. This study demonstrates that effective treatment penetration can be improved for this patient group by shared care with drug treatment services, without the need for significant increases in resources.

Improved survival outcomes for liver transplantation.

UNLABELLED: Liver transplantation is the treatment of choice for end stage liver disease and fulminant hepatic failure. Outcome of the procedure may be dependent on multiple factors including patient selection, donor selection, and centre experience. AIM: To determine whether the outcome for liver transplantation has improved over the time for the Irish National Liver Transplant Unit since its initial set up in 1993. METHODS: All patients who underwent liver transplantation between Jan 1993 to Oct 2004 were included. Patients were sub-divided into three sequential cohorts of 90 patients each. Survival outcomes were compared between the groups. RESULTS: 270 patients (male = 137) underwent 323 liver transplants (median age 49 yrs, range 16-68 yrs). Indications included primary biliary cirrhosis (14.1%), alcohol related liver disease (6.2%), fulminant hepatic failure (14.2%), primary sclerosing cholangitis (10.1%), chronic active hepatitis (9.5%), viral hepatitis (9.5%) and cryptogenic cirrhosis (7.1%). Most procedures (85.8%) were elective. Re-transplantation rates within the first 3 months of primary procedure were 9%, 5%, and 5% for the three chronological groups. Overall calculated 3-month, 1-year and 3 year survival rates for group 1 were 87%, 82% and 77%. For the groups 2 and 3 the figures were 86%, 81%, 77% and 89%, 89%, and 81% respectively. One- and 3-year survival rates were significantly better for group 3 compared to group 1 (p < 0.05). CONCLUSIONS: Survival outcome has improved significantly over the past 12 years and is likely attributed to increasing experience of the transplant centre.

MELD score as a prognostic model for listing acute liver failure patients for liver transplantation.

OBJECTIVES: The King's College Hospital (KCH) criteria are widely used for listing patients with acute liver failure (ALF) for liver transplantation (LT). Recent reports have suggested that the Model for End-Stage Liver Disease (MELD) score may be useful in assessing prognosis in ALF (nonparacetamol). This study compares prognostic accuracy of the two systems in patients with paracetamol (POD)-induced ALF treated in this unit. METHODS: Seventy-two patients (average age 38 years; F:M ratio 2:1) admitted from 1994 to 2005 with POD-related ALF were studied. Clinical and biochemical parameters were recorded. The effect of applying a MELD score of greater than 30 as listing criteria for LT was calculated and compared with the KCH criteria. Outcomes were defined as LT, death, or full recovery. RESULTS: Thirty-one patients (43%) recovered with medical therapy, 29 (40%) patients died, and 12 (17%) underwent LT. Sixty five percent of patients had a MELD > 30 and therefore could potentially be listed on admission; however, using KCH criteria only 24% patients were listed immediately. Sensitivity and negative predictive value of MELD was higher then KCH; however, we found KCH to have much higher specificity and positive predictive value. CONCLUSION: MELD has higher sensitivity and negative predictive value for POD-induced ALF than the KCH criteria. However, the high false-positive rate associated with MELD limits its clinical utility. The high negative predictive value of MELD score may allow it to be used in conjunction with KCH criteria to avoid unneeded LT in patients who will likely recover spontaneously.

Multiple Looser zones of osteomalacia in Byler disease with associated vitamin D deficiency, phosphaturia, and elevated FGF23.

INTRODUCTION: Byler disease (progressive familial intrahepatic cholestasis) is associated metabolic bone disease as a consequence of chronic malabsorption. CASE PRESENTATION: A 33-year-old man with decompensated liver disease secondary to Byler disease was referred to the orthopaedic department with progressive pain over this right proximal tibia. On examination, he had an antalgic gait. Tenderness was localised to the proximal tibia just distal to the tibial tubercle and bilateral foot swelling. Radiographs showed multiple stress fractures characteristic of Looser zones at various stages of healing in both tibia, metatarsals (third, fourth, and fifth on the right side, and second and fourth on the left) and left femur. Bone mineral density was extremely low. Subsequent investigations were consistent with severe osteomalacia due to a combination of vitamin D deficiency and phosphaturia with elevated fibroblast factor 23 (FGF23). A good clinical response was achieved following supplementation with calcium 1000mg and vitamin D 20µg daily. DISCUSSION: Stress fractures are often associated with delay in diagnosis. Our patient presented to the orthopaedic service with multiple Looser zones that had not been previously detected. As expected, there was biochemical evidence of vitamin D deficiency. An unexpected finding was phosphaturia that was associated with marked elevation in FGF23, which has never been reported previously. CONCLUSION: Byler disease may result in Looser zones of osteomalacia due to chronic malabsorption. Renal phosphorus wasting as a consequence of unexplained marked elevation in FGF23 is thought to have contributed to the onset of osteomalacia.

Vascular actions of octreotide in the portal hypertensive rat.

1. We have investigated the actions of the somatostatin analogue octreotide in the portal hypertensive Wistar rat in vivo and in rat small mesenteric artery and aorta in vitro. 2. In small mesenteric artery, octreotide (0.1-0.3 microM) failed to produce any direct contraction, nor did it affect contractions to noradrenaline (NA, 10 microM) or endothelium-dependent relaxations to acetylcholine. 3. In rat aorta, octreotide (0.3 microM) and somatostatin (1 microM) failed to affect contractions to NA (1 microM), or concentration-contractile response curves to NA. 4. In rat vas deferens, octreotide and somatostatin significantly reduced contractile responses to electrical stimulation with pD2 values (-log IC50) of 8.19 +/- 0.10 (n = 4) and 8.16 +/- 0.26 (n = 4), respectively. Hence, the lack of effect of these agents in aorta or mesenteric artery was not due to lack of efficacy or inappropriate choice of concentration. 5. In the anaesthetized portal hypertensive rat, intravenous injection of octreotide (1-100 microg kg[-1]) did not significantly affect systemic blood pressure, nor did it affect mesenteric vascular conductance as measured by laser doppler flow probes. However, octreotide (100 microg kg[-1]) significantly reduced vascular conductance to 74.2 +/- 7.7% of control (n = 6) in porto-systemic shunt vessels as measured by laser doppler flow probes. 6. Phenylephrine (1 microg kg[-1]) significantly raised blood pressure and significantly decreased vascular conductance in both mesenteric (66.6 +/- 3.7% of control) and porto-systemic shunt vessels (58.7 +/- 10.0% of control). 7. It was concluded that octreotide has selective effects on porto-systemic shunt vessles in vivo in the portal hypertensive rat.

A practical guide to the management of oesophageal varices.

Bleeding oesophageal varices are a frequent and sometimes fatal complication of portal hypertension. Prompt resuscitation and arrest of haemorrhage are the immediate short term priorities. Vasoactive therapy to reduce portal pressure is administered on presentation. Early endoscopy is necessary to make a definitive diagnosis and initiate appropriate therapy; usually emergency sclerotherapy or banding. After the acute bleeding episode, follow-up therapy is instituted either to obliterate the varices by sclerotherapy or banding, or to chronically lower portal pressure and hence reduce the risk of bleeding pharmacologically; a combination of both strategies may be also used. Active surveillance of those at risk of developing varices is advocated. Long term beta-blocker therapy has been demonstrated to be effective in both the primary prevention of variceal haemorrhage and the prevention of rebleeding in those who have already bled. Despite a multitude of therapeutic regimes and ongoing clinical trials, mortality from this condition remains disappointingly high.

Somatostatin and octreotide in gastroenterology.

Somatostatin and octreotide have a definitive role in the management of symptomatic gut neuroendocrine tumours, particularly VIPomas and carcinoid. They probably also have a role in variceal bleeding, but this needs further confirmatory randomized trials. At present there is a potential role in the management of short bowel syndrome, dumping syndrome and gastrointestinal fistulae, but randomized clinical studies are needed. Possibly there is a role in AIDS-related diarrhoea and 'idiopathic' secretory diarrhoea, but more evidence is required. They have no role in acute pancreatitis and peptic ulcer bleeding. Irritable bowel syndrome remains unexplored but unlikely to benefit.

Review article: the transjugular intrahepatic portosystemic shunt (TIPS) in the treatment of portal hypertension.

The transjugular intrahepatic portosystemic shunt (TIPS) is a non-surgical intrahepatic shunt connecting the hepatic and portal veins. The shunt can be inserted successfully in more than 90% of patients and it effectively decompresses the portal venous circulation. Serious complications, such as intraperitoneal bleeding, occur but they are uncommon. The role of TIPS in the treatment of portal hypertension is currently being evaluated. There are few controlled data available to compare TIPS with established treatment such as drugs, injection sclerotherapy, endoscopic banding or shunt surgery. TIPS has also been used to treat ascites, the Budd-Chiari syndrome and cirrhotic hydrothorax. Concerns over the long-term patency and the true incidence of encephalopathy following TIPS raise doubts about its long-term efficacy. Controlled trials are required to demonstrate the cost-effectiveness of TIPS for individual indications before it is widely adopted. TIPS may find its most immediate application in the emergency treatment of active variceal haemorrhage refractory to standard medical and endoscopic therapy, as there is no satisfactory treatment currently available for this high-risk group. TIPS may also have a role in patients awaiting liver transplantation who bleed from varices. Long-term patency should not be an issue in this patient group and portal decompression may reduce blood transfusion requirements during transplant surgery.

Review article: beta-adrenoceptor blockers for the treatment of portal hypertension.

beta-Adrenoceptor blockers always change splanchnic haemodynamics in cirrhotic patients. Azygous blood flow, as a measure of collateral circulation including that through varices, is always reduced, but the effects on portal pressure, whether measured directly or by the wedged hepatic venous pressure, are variable. The initial correlations between a 25% reduction of resting pulse rate and similar percentage reduction in the wedge-free hepatic venous gradient, has not been reproduced in subsequent studies. Therefore, to study the effect of changes in haemodynamic indices and the likelihood of variceal bleeding, direct measurements of such indices need to be made in clinical trials. At present there are no haemodynamic or clinical factors which can be used to select patients who will have a good therapeutic response to propranolol other than those documented in the first clinical trial of propranolol for the prevention of variceal re-bleeding from Paris. Thus the hypothesis that beta-adrenoceptor blockers may lessen the incidence of bleeding in cirrhotics, by partially reducing portal pressure or flow or both, needs testing in further clinical studies. The selection criteria of the first clinical trial of propranolol in Paris need to be confirmed. Two subsequent trials, in which patients were not selected but in which many patients had similar clinical characteristics to the Paris patients, could not confirm a therapeutic effect of propranolol. No fatal complications due to propranolol administration have been reported in cirrhotic patients. Complications are reversible. Pharmacological treatment including beta-adrenoceptor blockade appears ideal for trials of primary prevention of variceal bleeding. Some preliminary results including use in decompensated cirrhotics are encouraging. However, as for trials for prevention of re-bleeding, the design and analysis of such trials needs careful evaluation to take into account the outcome of patients who discontinue medication, whether due to simple noncompliance or due to side-effects, and also the influence of abstinence from alcohol on bleeding from varices.