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.

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.

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.

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.

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.

Interstitial pneumonitis is a frequent complication in liver transplant recipients treated with sirolimus.

BACKGROUND: Sirolimus is a powerful immunosuppressive drug which is being used increasingly after liver transplantation because of its renal sparing and anti-tumour effects. It has been associated with uncommon, but potentially fatal, interstitial pneumonitis. AIM: To determine the frequency and outcome of sirolimus-associated pneumonitis following liver transplantation. METHODS: Retrospective study in an adult liver transplant centre. RESULTS: We identified five patients with siromimus-associated pneumonitis, three of whom were transplanted at our centre. Between 1999 and 2008 a total of 522 liver transplants were performed, in our unit, and 45 patients were switched from calcineurin inhibitors to sirolimus. Three of these 45 patients subsequently developed pneumonitis (6.7%). The most common presenting symptoms were cough and dyspnea. The duration of use of sirolimus before diagnosis of pneumonitis varied between 4 and 16 months. Trough serum sirolimus levels were elevated in 3/5 patients with pneumonitis. Sirolimus was withdrawn in all five patients with complete resolution of symptoms and radiological findings. CONCLUSIONS: Pneumonitis is a relatively common side effect of sirolimus in liver transplant patients and can occur despite normal therapeutic blood levels. It is reversible on stopping the medication. Early recognition is important to prevent unnecessary investigations and prolonged morbidity.

Rapid, early and sustained virological responses in a cohort of Irish patients treated with pegylated interferon and ribavirin for chronic hepatitis C virus infection.

BACKGROUND: The response to the treatment with pegylated interferon (PEG IFN)-α combined with ribavirin in chronic hepatitis C virus (HCV) infection varies with some patients having a rapid or early response which is not sustained. AIMS: To investigate the rates of rapid virological response (RVR), early virological response (EVR) and sustained virological response (SVR) in an Irish cohort of HCV infected patients receiving IFN-α/ribavirin. METHODS: Rates of RVR, EVR and SVR were examined in 123 patients undergoing standard treatment for chronic HCV infection between 2001 and 2007 at a Dublin Teaching Hospital. RESULTS: The rates of RVR, EVR and SVR in genotype 1 patients were 48, 68 and 50%, while in genotype 2/3 patients they were 87, 93 and 87%, respectively. The positive predictive values (PPV) of RVR for SVR in genotype 1 and genotype 2/3 patients were 90 and 92.4%, respectively. CONCLUSION: The rates of response to PEG IFN-α/ribavirin in Irish patients are consistent with other international reports. We support the regular monitoring of rapid and early virological response as a standard of care in treating chronic hepatitis C patients.

Paracetamol overdose: the liver unit perspective.

Liver failure resulting from deliberate or accidental paracetamol overdose continues to be an important reason for referral to liver transplant centres. Severe hepatic dysfunction often appears 72-96 h after overdose. Liver injury can be prevented by timely administration of the specific antidote, N-acetylcysteine. Unfortunately, administration of N-acetylcysteine is frequently delayed due to late presentation or late administration. While N-acetylcysteine works best if given within 8 h of overdose, it is beneficial at any time period and should always be given if there is concern about significant overdose, irrespective of interval from time of ingestion. Early discussion with liver transplant unit is suggested if there is any doubt or evidence of liver failure.

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.

Current concepts in the assessment and treatment of hepatic encephalopathy.

Hepatic encephalopathy (HE) is defined as a metabolically induced, potentially reversible, functional disturbance of the brain that may occur in acute or chronic liver disease. Standardized nomenclature has been proposed but a standardized approach to the treatment, particularly of persistent, episodic and recurrent encephalopathy associated with liver cirrhosis has not been proposed. This review focuses on the pathogenesis and treatment of HE in patients with cirrhosis. The pathogenesis and treatment of hepatic encephalopathy in fulminant hepatic failure is quite different and is reviewed elsewhere.

Hepatic transplantation outcomes for carefully selected cirrhotic patients with hepatocellular carcinoma: experience at a small- to medium-volume centre.

BACKGROUND: Hepatic transplantation outcomes for cirrhotic patients with hepatocellular carcinoma (HCC) at a small- to medium-volume centre are not fully known due to relative novelty of patient selection criteria. AIM: To determine hepatic transplantation outcomes for HCC at a small- to medium-volume centre. Patients and methods Hepatocellular carcinoma patients were listed for transplantation according to the International Guideline and further categorized as those fulfilling or exceeding Milan or University of San Francisco (UCSF) criteria on explanted liver morphology. Outcomes including mortality, retransplantation, and tumour recurrence rate were analysed. RESULTS: Twenty-six patients had HCC and on explanted liver morphology, Milan and UCSF criteria met 15 and 18 patients, respectively. Patients and graft survival at 3 months, 1 and 5 years were 100, 96, 84, and 88, 84, 77%, respectively. Outcomes favoured Milan criteria but did not reach statistical significance. CONCLUSIONS: Hepatic transplantation for HCC at a small-to medium-volume transplant centre had comparable survival outcomes to high-volume centres.

Late-onset CMV disease following CMV prophylaxis.

BACKGROUND: Cytomegalovirus (CMV) is the most common opportunistic infection after solid-organ transplantation, increasing morbidity and mortality. Three months of oral valganciclovir have been shown to provide effective prophylaxis. Late-onset CMV disease, occurring after the discontinuation of prophylaxis, is now increasingly recognised. AIMS: To investigate the incidence and the time of detection of CMV infections in liver transplant recipients who received CMV prophylaxis. METHODS: Retrospective review of 64 high- and moderate-risk patients with 1 year of follow-up. RESULTS: The incidence of CMV infection was 12.5%, with 4.7% disease. All cases of symptomatic CMV disease were of late-onset. CONCLUSIONS: The incidence of CMV infections in this study was low compared with literature reports; however, the late-onset disease is an emerging problem. Detection of late-onset disease may be delayed because of less frequent clinic follow-up visits. Increased regular laboratory monitoring may allow earlier detection at the asymptomatic infection stage.