Granulosa cell tumor(GCT)is the most common sex cordstromal tumor,comprising 5%of all ovarian malignancies[1].The disease course is indolent,and the majority of cases present at stage 1.However,metastases may develop ...Granulosa cell tumor(GCT)is the most common sex cordstromal tumor,comprising 5%of all ovarian malignancies[1].The disease course is indolent,and the majority of cases present at stage 1.However,metastases may develop with potential sites being peritoneum,lung,brain,liver and bone[2].Due to the rarity of the disease,published evidence for management of granulosa cell tumor liver metastases(GCTLM)is limited.Surgical resection is the optimal treatment in instances where there is a high chance of achieving complete resection[3].With regards to unresectable GCTLM there is a paucity of evidence to guide treatment strategy.展开更多
Acute liver failure (ALF) is a devastating clinical syndrome characterised by progressive encephalopathy, coagulopathy, and circulatory dysfunction, which commonly leads to multiorgan failure and death. Central to the...Acute liver failure (ALF) is a devastating clinical syndrome characterised by progressive encephalopathy, coagulopathy, and circulatory dysfunction, which commonly leads to multiorgan failure and death. Central to the pathogenesis of ALF is activation of the immune system with mobilisation of cellular effectors and massive production of cytokines. As key components of the innate immune system, monocytes and macrophages are postulated to play a central role in the initiation, progression and resolution of ALF. ALF in humans follows a rapidly progressive clinical course that poses inherent difficulties in delineating the role of these pivotal immune cells. Therefore, a number of experimental models have been used to study the pathogenesis of ALF. Here we consider the evidence from experimental and human studies of ALF on the role of monocytes and macrophages in acute hepatic injury and the ensuing extrahepatic manifestations, including functional monocyte deactivation and multiple organ failure.展开更多
Cerebral oedema is a devastating consequence of acute liver failure(ALF)and may be associated with the development of intracranial hypertension and death.In ALF,some patients may develop cerebral oedema and increased ...Cerebral oedema is a devastating consequence of acute liver failure(ALF)and may be associated with the development of intracranial hypertension and death.In ALF,some patients may develop cerebral oedema and increased intracranial pressure but progression to lifethreatening intracranial hypertension is less frequent than previously described,complicating less than one third of cases who have proceeded to coma since the advent of improved clinical care.The rapid onset of encephalopathy may be dramatic with the development of asterixis,delirium,seizures and coma.Cytotoxic and vasogenic oedema mechanisms have been implicated with a preponderance of experimental data favouring a cytotoxic mechanism.Astrocyte swelling is the most consistent neuropathological finding in humans with ALF and ammonia plays a definitive role in the development of cytotoxic brain oedema.The mechanism(s)by which ammonia induces astrocyte swelling remains unclear but glutamine accumulation within astrocytes has led to the osmolyte hypothesis.Current evidence also supports an alternate‘Trojan horse’hypothesis,with glutamine as a carrier of ammonia into mitochondria,where its accumulation results in oxidative stress,energy failure and ultimately astrocyte swelling.Although a complete breakdown of the blood-brain barrier is not evident in human ALF,increased permeation to water and other small molecules such as ammonia has been demonstrated resulting from subtle alterations in the protein composition of paracellular tight junctions.At present,there is no fully efficacious therapy for cerebral oedema other than liver transplantation and this reflects our incomplete knowledge of the precise mechanisms underlying this process which remain largely unknown.展开更多
AIM To assess the practice of caring for acute liver failure(ALF) patients in varying geographic locations and medical centers.METHODS Members of the European Acute Liver Failure Consortium completed an 88-item questi...AIM To assess the practice of caring for acute liver failure(ALF) patients in varying geographic locations and medical centers.METHODS Members of the European Acute Liver Failure Consortium completed an 88-item questionnaire detailing management of ALF. Responses from 22 transplantation centers in 11 countries were analyzed,treating between 300 and 500 ALF cases and performing over 100 liver transplants(LT) for ALF annually. The questions pertained to details of the institution and their clinical activity,standards of care,referral and admission,wardbased care versus intensive care unit(ICU) as well as questions regarding liver transplantation- including criteria,limitations,and perceived performance. Clinical data was also collected from 13 centres over a 3 mo period. RESULTS The interval between referral and admission of ALF patients to specialized units was usually less than 24 h and once admitted,treatment was provided by a multidisciplinary team. Principles of care of patients with ALF were similar among centers,particularly in relation to recognition of severity and care of the more critically ill. Centers exhibited similarities in thresholds for ICU admission and management of severe hepatic encephalopathy. Over 80% of centers administered n-acetyl-cysteine to ICU patients for non-paracetamolrelated ALF. There was significant divergence in the use of prophylactic antibiotics and anti-fungals,lactulose,nutritional support and imaging investigations in admitted patients and in the monitoring and treatment of intra-cranial pressure(ICP). ICP monitoring was employed in 12 centers,with the most common indications being papilledema and renal failure. Most patients listed for transplantation underwent surgery within an average waiting time of 1-2 d. Over a period of 3 mo clinical data from 85 ALF patients was collected. Overall patient survival at 90-d was 76%. Thirty six percent of patients underwent emergency LT,with a 90% post transplant survival to hospital discharge,42% survived with medical management alone. CONCLUSION Alongside similarities in principles of care of ALF patients,major areas of divergence were present in key areas of diagnosis,monitoring,treatment and decision to transplant.展开更多
Intrahepatic portosystemic shunts(IPSS) are rare congenital anomalies arising from disordered portal vein embryogenesis.It has been described in both children and adults and may be asymptomatic or be associated with a...Intrahepatic portosystemic shunts(IPSS) are rare congenital anomalies arising from disordered portal vein embryogenesis.It has been described in both children and adults and may be asymptomatic or be associated with a variety of neurophysiological and pulmonary complications.When recognized,early intervention to occlude the shunt will reverse the associated complications.Literature review reports of surgical and radiological occlusion of the shunt,but due to its rarity,a standard therapeutic protocol has not been established.A case of a 38-year-old woman with abdominal pain and low grade encephalopathy,diagnosed with an IPSS and treated by right hepatectomy was reported.展开更多
Background: Primary and secondary liver tumors are not always amenable to resection due to location and size. Inadequate future liver remnant(FLR) may prevent patients from having a curative resection or may result in...Background: Primary and secondary liver tumors are not always amenable to resection due to location and size. Inadequate future liver remnant(FLR) may prevent patients from having a curative resection or may result in increased postoperative morbidity and mortality from complications related to small-forsize syndrome(SFSS). Data sources: This comprehensive review analyzed the principles, mechanism and risk factors associated with SFSS and presented current available options in the evaluation of FLR when planning liver surgery. In addition, it provided a detailed description of specifc modalities that can be used before, during or after surgery, in order to optimize the conditions for a safe resection and minimize the risk of SFSS. Results: Several methods which aim to reduce tumor burden, preserve healthy liver parenchyma, induce hypertrophy of FLR or prevent postoperative complications help minimize the risk of SFSS. Conclusions: With those techniques the indications of radical treatment for patients with liver tumors have signifcantly expanded. The successful outcome depends on appropriate patient selection, the individualization and modifcation of interventions and the right timing of surgery.展开更多
Satisfactory blood flow after hepatic arterial anastomosis in liver transplantation is a critical point of the operation.Problems with this anastomosis can result in hepatic artery thrombosis with resultant graft fail...Satisfactory blood flow after hepatic arterial anastomosis in liver transplantation is a critical point of the operation.Problems with this anastomosis can result in hepatic artery thrombosis with resultant graft failure and patient morbidity and mortality.Causes of hepatic artery thrombosis include problematic technique,hepatic artery dissection,external compression(e.g.from hematoma),hypercoagulable state,splenic arterial steal and rarer causes such as median arcuate ligament compression(MALC).A careful review of preoperative radiology and imaging will reveal these rare instances and enable a proper intraoperative plan.展开更多
Liver enzymes and function tests are routinely taken in clinical practice. Deranged liver enzymes however, do not always necessarily imply an underlying liver pathology. The standard liver enzymes measured include ala...Liver enzymes and function tests are routinely taken in clinical practice. Deranged liver enzymes however, do not always necessarily imply an underlying liver pathology. The standard liver enzymes measured include alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl-transpeptidase (GGT) and alanine phosphatase (ALP). These enzymes, especially ALT and AST, can be released by other organs in the body. We report an unusual case of a 48-year-old patient with deranged enzymes related exclusively to intensive exercise that resolved on discontinuing such exercise.展开更多
End-stage liver disease(ESLD) is a leading cause of morbidity and mortality amongst human immunodeficiency virus(HIV)-positive individuals. Chronic hepatitis B and hepatitis C virus(HCV) infection,drug-induced hepatot...End-stage liver disease(ESLD) is a leading cause of morbidity and mortality amongst human immunodeficiency virus(HIV)-positive individuals. Chronic hepatitis B and hepatitis C virus(HCV) infection,drug-induced hepatotoxicity related to combined antiretro-viral therapy,alcohol related liver disease and non-alcohol related fatty liver disease appear to be the leading causes. It is therefore,anticipated that more HIV-positive patients with ESLD will present as potential transplant candidates. HIV infection is no longer a contraindication to liver transplantation. Key transplantation outcomes such as rejection and infection rates as well as medium term graft and patient survival match those seen in the non-HIV infected patients in the absence of co-existing HCV infection. HIV disease does not seem to be negatively impacted by transplantation. However,HIV-HCV coinfection transplant outcomes remain suboptimal due to recurrence. In this article,we review the key challenges faced by this patient cohort in the pre- and posttransplant period.展开更多
AIM To determine the impact of Charlson comorbidity index(CCI) on waiting list(WL) and post liver retransplantation(LRT) survival.METHODS Comparative study of all adult patients assessed for primary liver transplant(P...AIM To determine the impact of Charlson comorbidity index(CCI) on waiting list(WL) and post liver retransplantation(LRT) survival.METHODS Comparative study of all adult patients assessed for primary liver transplant(PLT)(n = 1090) and patients assessed for LRT(n = 150), 2000-2007 at our centre. Demographic, clinical and laboratory variables were recorded. RESULTS Median age for all patients was 53 years and 66% were men. Median model for end stage liver disease(MELD) score was 15. Median follow-up was 7- years. For retransplant patients, 84(56%) had ≥ 1 comorbidity. The most common comorbidity was renal impairment in 66(44.3%). WL mortality was higher in patients with ≥ 1 comorbidity(76% vs 53%, P = 0.044). CCI(OR = 2.688, 95%CI: 1.222-5.912, P = 0.014) was independently associated with WL mortality. Patients with MELD score ≥ 18 had inferior WL survival(LogRank 6.469, P = 0.011). On multivariate analysis,CCI(OR = 2.823, 95%CI: 1.563-5101, P = 0.001), MELD score ≥ 18(OR 2.506, 95%CI: 1.044-6.018, P = 0.04), and requirement for organ support prior to LRT(P < 0.05) were associated with reduced post-LRT survival. Donor/graft parameters were not associated with survival(P = NS). Post-LRT mortality progressively increased according to the number of transplanted grafts(Log-Rank 18.455, P < 0.001). Post-LRT patient survival at 1-, 3- and 5-years were significantly inferior to those of PLT at 88% vs 73%, P < 0.001, 81% vs 71%, P = 0.018 and 69% vs 55%, P = 0.006, respectively. CONCLUSION Comorbidity increases WL and post-LRT mortality. Patients with MELD ≥ 18 have increased WL mortality. Patients with comorbidity or MELD ≥ 18 may benefit from earlier LRT. LRT for ≥ 3 grafts may not represent appropriate use of donated grafts.展开更多
Extracellular vesicles(EVs)are a heterogenous group of nanosized,membranebound particles which are released by most cell types.They are known to play an essential role in cellular communication by way of their varied ...Extracellular vesicles(EVs)are a heterogenous group of nanosized,membranebound particles which are released by most cell types.They are known to play an essential role in cellular communication by way of their varied cargo which includes selectively enriched proteins,lipids,and nucleic acids.In the last two decades,wide-ranging evidence has established the involvement of EVs in the regulation of immunity,with EVs released by immune and non-immune cells shown to be capable of mediating immune stimulation or suppression and to drive inflammatory,autoimmune,and infectious disease pathology.More recently,studies have demonstrated the involvement of allograft-derived EVs in alloimmune responses following transplantation,with EVs shown to be capable of eliciting allograft rejection as well as promoting tolerance.These insights are necessitating the reassessment of standard paradigms of T cell alloimmunity.In this article,we explore the latest understanding of the impact of EVs on alloresponses following transplantation and we highlight the recent technological advances which have enabled the study of EVs in clinical transplantation.Furthermore,we discuss the rapid progress afoot in the development of EVs as novel therapeutic vehicles in clinical transplantation with particular focus on liver transplantation.展开更多
The role of plasmapheresis in liver failure and hepatic encephalopathy is undefined and its use as a strategy to salvage patients with severe allograft dysfunction after liver transplantation remains investigational. ...The role of plasmapheresis in liver failure and hepatic encephalopathy is undefined and its use as a strategy to salvage patients with severe allograft dysfunction after liver transplantation remains investigational. We present a case of early allograft dysfunction following deceased donor liver transplantation(DDLT) where plasmapheresis was effective as a bridge to recovery and possibly avoiding a retransplantation. A 16 years old boy, known to have decompensated Wilson's disease underwent DDLT at our Public Sector Hospital. He received a healthy liver from a brain-dead donor, whose liver was considered too large for the boy. The graft was reduced in situ to a left lobe graft. Surgery was uneventful and the recipient was well for the initial 96 h. On Doppler and further computed tomography scan, a partial portal vein thrombus was noted. He was reexplored and a Fogarty endothombecteomy was performed. Following the second surgery, he developed severe allograft dysfunction with a peak bilirubin of 40 mg/d L. He underwent imaging to rule out technical causes for the dysfunction, followed by a liver biopsy, which revealed acute cellular rejection. Multiple cycles of plasmapheresis were initiated. Over the next two weeks, the graft demonstrated a gradual recovery. He was discharged on the 30 th postoperative day, with a serum bilirubin of 5.5 mg/d L. He remains well on follow-up, with the liver function tests improving further. Our report demonstrates the beneficial effect of plasmapheresis, which appears to be an effective treatment option for early allograft dysfunction following liver transplantation and may obviate the need for retransplantation.展开更多
Liver-related autoantibodies are crucial for the correct diagnosis and classification of autoimmune liver diseas-es(AiLD),namely autoimmune hepatitis types 1 and 2(AIH-1 and 2),primary biliary cirrhosis(PBC),and the s...Liver-related autoantibodies are crucial for the correct diagnosis and classification of autoimmune liver diseas-es(AiLD),namely autoimmune hepatitis types 1 and 2(AIH-1 and 2),primary biliary cirrhosis(PBC),and the sclerosing cholangitis variants in adults and children.AIH-1 is specified by anti-nuclear antibody(ANA) and smooth muscle antibody(SMA).AIH-2 is specified by antibody to liver kidney microsomal antigen type-1(anti-LKM1) and anti-liver cytosol type 1(anti-LC1).SMA,ANA and anti-LKM antibodies can be present in de-novo AIH following liver transplantation.PBC is specified by antimitochondrial antibodies(AMA) react-ing with enzymes of the 2-oxo-acid dehydrogenase complexes(chiefly pyruvate dehydrogenase complex E2 subunit) and disease-specific ANA mainly react-ing with nuclear pore gp210 and nuclear body sp100.Sclerosing cholangitis presents as at least two variants,first the classical primary sclerosing cholangitis(PSC) mostly affecting adult men wherein the only(and non-specific) reactivity is an atypical perinuclear antineutro-phil cytoplasmic antibody(p-ANCA),also termed peri-nuclear anti-neutrophil nuclear antibodies(p-ANNA) and second the childhood disease called autoimmune sclerosing cholangitis(ASC) with serological features resembling those of type 1 AIH.Liver diagnostic serol-ogy is a fast-expanding area of investigation as new purified and recombinant autoantigens,and automatedtechnologies such as ELISAs and bead assays,become available to complement(or even compete with) tradi-tional immunofluorescence procedures.We survey for the first time global trends in quality assurance impact-ing as it does on(1) manufacturers/purveyors of kits and reagents,(2) diagnostic service laboratories that fulfill clinicians' requirements,and(3) the end-user,the physician providing patient care,who must properly interpret test results in the overall clinical context.展开更多
The face of hepatic encephalopathy(HE) is changing.This review explores how this neurocognitive disorder,which is associated with both acute and chronic liver injury,has grown to become a dynamic syndrome that spans a...The face of hepatic encephalopathy(HE) is changing.This review explores how this neurocognitive disorder,which is associated with both acute and chronic liver injury,has grown to become a dynamic syndrome that spans a spectrum of neuropsychological impairment,from normal performance to coma.The central role of ammonia in the pathogenesis of HE remains incontrovertible.However,over the past 10 years,the HE community has begun to characterise the key roles of inflammation,infection,and oxidative/nitrosative stress in modulating the pathophysiological effects of ammonia on the astrocyte.This review explores the current thoughts and evidence base in this area and discusses the potential role of existing and novel therapies that might abrogate the oxidative and nitrosative stresses inflicted on the brain in patients with,or at risk of developing,HE.展开更多
The histological hallmark of autoimmune hepatitis(AIH) is a dense portal mononuclear cell infiltrate that invades the surrounding parenchyma and comprises T and B lymphocytes,macrophages,and plasma cells.An unknown bu...The histological hallmark of autoimmune hepatitis(AIH) is a dense portal mononuclear cell infiltrate that invades the surrounding parenchyma and comprises T and B lymphocytes,macrophages,and plasma cells.An unknown but powerful stimulus must be promoting the formation of this massive inflammatory cellular reaction that is likely to initiate and perpetuate liver damage.An autoimmune attack can follow different pathways to inflict damage on hepatocytes.Liver damage is likely to be orchestrated by CD4+ T lymphocytes recognizing an autoantigenic liver peptide.To trigger an autoimmune response,the peptide must be embraced by an HLA class Ⅱ molecule and presented to na?ve CD4+ T helper(Th0) cells by professional antigen presenting cells,with the co-stimulation of ligand-ligand fostering interaction between the two cells.Th0 cells become activated,differentiate into functional phenotypes according to the cytokines prevailing in the microenvironment and the nature of the antigen,and initiate a cascade of immune reactions determined by the cytokines produced by the activated T cells.Th1 cells,arising in the presence of the macrophage-derived interleukin(IL) -12,secrete mainly IL-2 and interferon-gamma(IFN-g),which activate macrophages,enhance expression of HLA classⅠ(increasing liver cell vulnerability to a CD8+ T cell cytotoxic attack),and induce expression of HLA class Ⅱ molecules on hepatocytes.Th2 cells,which differentiate from Th0 if the microenvironment is rich in IL-4,produce mainly IL-4,IL-10,and IL-13 which favour autoantibody production by B lymphocytes.Physiologically,Th1 and Th2 antagonize each other.Th17 cells,a recently described population,arise in the presence of transforming growth factor beta(TGF-β) and IL-6 and appear to have an important effector role in inflammation and autoimmunity.Theprocess of autoantigen recognition is strictly controlled by regulatory mechanisms,such as those exerted by CD4+CD25+ regulatory T cells,which derive from Th0 in the presence of TGF-β,but in the absence of IL-6.If regulatory mechanisms fail,the autoimmune attack is perpetuated.Over the past three decades different aspects of the above pathogenic scenario have been investigated.In particular,a defect in immunoregulation affecting CD4+CD25+ regulatory T cells(T-regs) has been demonstrated in AIH,particularly at diagnosis or during relapse.Advances in the study of autoreactive T cells have occurred mostly in AIH type 2,since the knowledge that CYP2D6 is the main autoantigen has enabled the characterization of both CD4 and CD8 T cells targeting this cytochrome.CD4 T cells from patients with type 2 AIH positive for the predisposing HLA allele DRB10701 recognize seven regions of CYP2D6,five of which are also recognized by CD8 T cells.High numbers of IFN-g producing CD4 T cells and CD8 T cells are associated with biochemical evidence of liver damage,suggesting a combined cellular immune attack.展开更多
Autoimmune hepatitis is a rare chronic inflammatory liver disease,affecting all ages,characterised by elevated transaminase and immunoglobulin G levels,positive autoantibodies,interface hepatitis at liver histology an...Autoimmune hepatitis is a rare chronic inflammatory liver disease,affecting all ages,characterised by elevated transaminase and immunoglobulin G levels,positive autoantibodies,interface hepatitis at liver histology and good response to immunosuppressive treatment. If untreated,it has a poor prognosis. The aim of this review is to summarize the evidence for standard treatment and to provide a systematic review on alternative treatments for adults and children. Standard treatment is based on steroids and azathioprine,and leads to disease remission in 80%-90% of patients. Alternative first line treatment has been attempted with budesonide or cyclosporine,but their superiority compared to standard treatment remains to be demonstrated. Second-line treatments are needed for patients not responding or intolerant to standard treatment. No randomized controlled trials have been performed for second-line options. Mycophenolate mofetil is the most widely used second-line drug,and has good efficacy particularly for patients intolerant to azathioprine,but has the major disadvantage of being teratogenic. Only few and heterogeneous data on cyclosporine,tacrolimus,everolimus and sirolimus are available. More recently,experience with the anti-tumour necrosis factoralpha infliximab and the anti-CD20 rituximab has been published,with ambivalent results; these agents may have severe side-effects and their use should be restricted to specialized centres. Clinical trials with new therapeutic options are ongoing.展开更多
Primary biliary cirrhosis(PBC),primary sclerosing cholangitis(PSC) and autoimmune hepatitis(AIH) constitute the classic autoimmune liver diseases(AILDs).While AIH target the hepatocytes,in PBC and PSC the targets of t...Primary biliary cirrhosis(PBC),primary sclerosing cholangitis(PSC) and autoimmune hepatitis(AIH) constitute the classic autoimmune liver diseases(AILDs).While AIH target the hepatocytes,in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells.Persistent liver injury,associated with chronic AILD,leads to un-resolving inflammation,cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts.Liver cirrhosis,and the resultant loss of normal liver function,inevitably ensues.Patients with cirrhosis have higher risks or morbidity and mortality,and that in the decompensated phase,complications of portal hypertension and/or liver dysfunction lead to rapid deterioration.Accurate diagnosis and monitoring of cirrhosis is,therefore of upmost importance.Liver biopsy is currently the gold standard technique,but highly promising non-invasive methodology is under development.Liver transplantation(LT) is an effective therapeutic option for the management of endstage liver disease secondary to AIH,PBC and PSC.LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy;in addition,LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids.展开更多
Congenital extrahepatic portosystemic shunt,also known as Abernethy malformation, is a rare congenital malformation. It causes shunting of blood through a communication between the portal and systemic veins such as a ...Congenital extrahepatic portosystemic shunt,also known as Abernethy malformation, is a rare congenital malformation. It causes shunting of blood through a communication between the portal and systemic veins such as a patent ductus venous. We report 3 cases of Abernethy malformation complicated by the development of hepatocellular carcinoma. Additionally, we comprehensively reviewed all previously reported cases and highlighted common features that may help in early diagnosis and appropriate management.Patients with Abernethy malformation may have an increased propensity to develop hepatocellular carcinoma. All 5 previously reported cases, plus the three of our patients, have a type 1(complete) shunt suggesting a role for absent portal blood flow in the pathogenesis of hepatocellular carcinoma. Congenital extrahepatic portosystemic shunt should be sought for in cases with raised serum ammonia, hepatic encephalopathy or hepatocellular carcinoma in the absence of cirrhosis.展开更多
BACKGROUND:The clinicopathological features of uncinate process pancreatic cancer(UPPC) are poorly described.Furthermore the anatomy of the uncinate process and its division during surgery are central to pancreaticodu...BACKGROUND:The clinicopathological features of uncinate process pancreatic cancer(UPPC) are poorly described.Furthermore the anatomy of the uncinate process and its division during surgery are central to pancreaticoduodenectomy for UPPC.We set out to describe the embryology and anatomy of the uncinate process and the clinicopathological features of UPPC.DATA SOURCES:All published case series of UPPC were reviewed and included in this review.RESULTS:The true incidence of UPPC is difficult to quantify,with the reported incidence ranging from 2.5% to 10.7% of pancreatic cancer.There are 5 published series of UPPC including 117 patients,72 males and 45 females,aged from 45-53 years to 61-84 years.The median survival was 5 or 5.5 months in 3 of the series,12.1 months in another based only on potentially resectable lesions and 17 months in another based only on resected cases.CONCLUSIONS:The number of reported series of UPPC is limited,with vague symptoms as the predominant presenting features of the disease.The prognosis is poor with synchronous venous resection demonstrating a survival advantage.展开更多
AIM: To assess serum cartilage oligomeric matrix protein(COMP) as a marker of cirrhosis and risk of progression to hepatocellular carcinoma(HCC). METHODS: A COMP enzyme-linked immunosorbentassay was used to test 187 p...AIM: To assess serum cartilage oligomeric matrix protein(COMP) as a marker of cirrhosis and risk of progression to hepatocellular carcinoma(HCC). METHODS: A COMP enzyme-linked immunosorbentassay was used to test 187 patients with chronic liver diseases at the time point of first evaluation. The selected patients included 72 with chronic hepatitis B infection, 75 with chronic hepatitis C infection, 22 with primary biliary cirrhosis, 7 with autoimmune hepatitis type 1, and 11 with alcoholic liver disease. Demographic, biochemical, histological and clinical characteristics of the patients were recorded at the first evaluation. One hundred and forty-seven patients were followed for a median [interquartile range(IQR)] duration of 96.5(102) mo. The clinical, biochemical and histological data, as well as the development of cirrhosis, HCC according to internationally accepted criteria and in case of death, a liver-related cause during the follow-up period, were recorded at the electronic database of our clinic. COMP determination was also performed in 43 healthy individuals who served as the control study group.RESULTS: COMP positivity(> 15 U/L) was detected in 22%-36% among chronic liver disease groups. Strikingly, almost 83% of COMP-positive patients were cirrhotic at baseline, independently of cause of liver disease. Among the patients who developed HCC during follow-up, 73.7%(14/19) were COMP positive at baseline. COMP positivity was significantly associated with older age(P < 0.001), advanced fibrosis(P = 0.001) and necroinflammatory activity(P = 0.001), higher aspartate aminotransferase(P < 0.001), alanine aminotransferase(P < 0.02), γ-glutamyl transpeptidase(P = 0.003), alkaline phosphatase(P = 0.001), bilirubin(P < 0.05), international normalized ratio(P = 0.002) and alpha-fetoprotein levels(P < 0.02), and lower albumin(P < 0.001), and platelet count(P = 0.008). COMP levels [median(IQR)] were significantly higher in cirrhotics compared to non-cirrhotics [13.8(7.9) U/L vs 9.8(4.6) U/L, respectively; P < 0.001]. On multivariate logistic regression analysis, COMP-positivity was independently associated only with cirrhosis(OR = 4.40, 95%CI: 1.33-14.69, P = 0.015). Kaplan-Meier analysis showed that COMP positivity was significantly associated with HCC development(P = 0.007) and higher incidence of liver-related death(P < 0.001). CONCLUSION: Elevated COMP levels are strongly associated with cirrhosis and HCC progression. Serum COMP is a new promising non-invasive biomarker for HCC risk assessment in surveillance programs.展开更多
文摘Granulosa cell tumor(GCT)is the most common sex cordstromal tumor,comprising 5%of all ovarian malignancies[1].The disease course is indolent,and the majority of cases present at stage 1.However,metastases may develop with potential sites being peritoneum,lung,brain,liver and bone[2].Due to the rarity of the disease,published evidence for management of granulosa cell tumor liver metastases(GCTLM)is limited.Surgical resection is the optimal treatment in instances where there is a high chance of achieving complete resection[3].With regards to unresectable GCTLM there is a paucity of evidence to guide treatment strategy.
文摘Acute liver failure (ALF) is a devastating clinical syndrome characterised by progressive encephalopathy, coagulopathy, and circulatory dysfunction, which commonly leads to multiorgan failure and death. Central to the pathogenesis of ALF is activation of the immune system with mobilisation of cellular effectors and massive production of cytokines. As key components of the innate immune system, monocytes and macrophages are postulated to play a central role in the initiation, progression and resolution of ALF. ALF in humans follows a rapidly progressive clinical course that poses inherent difficulties in delineating the role of these pivotal immune cells. Therefore, a number of experimental models have been used to study the pathogenesis of ALF. Here we consider the evidence from experimental and human studies of ALF on the role of monocytes and macrophages in acute hepatic injury and the ensuing extrahepatic manifestations, including functional monocyte deactivation and multiple organ failure.
基金Supported by Medical Research Council(MRC)Centre for Transplantation,King’s College London,United Kingdom-MRC grant No.MR/J006742/1The National Institute for Health Research(NIHR)Biomedical Research Centre based at Guy’s and St Thomas’NHS Foundation Trust and King’s College London
文摘Cerebral oedema is a devastating consequence of acute liver failure(ALF)and may be associated with the development of intracranial hypertension and death.In ALF,some patients may develop cerebral oedema and increased intracranial pressure but progression to lifethreatening intracranial hypertension is less frequent than previously described,complicating less than one third of cases who have proceeded to coma since the advent of improved clinical care.The rapid onset of encephalopathy may be dramatic with the development of asterixis,delirium,seizures and coma.Cytotoxic and vasogenic oedema mechanisms have been implicated with a preponderance of experimental data favouring a cytotoxic mechanism.Astrocyte swelling is the most consistent neuropathological finding in humans with ALF and ammonia plays a definitive role in the development of cytotoxic brain oedema.The mechanism(s)by which ammonia induces astrocyte swelling remains unclear but glutamine accumulation within astrocytes has led to the osmolyte hypothesis.Current evidence also supports an alternate‘Trojan horse’hypothesis,with glutamine as a carrier of ammonia into mitochondria,where its accumulation results in oxidative stress,energy failure and ultimately astrocyte swelling.Although a complete breakdown of the blood-brain barrier is not evident in human ALF,increased permeation to water and other small molecules such as ammonia has been demonstrated resulting from subtle alterations in the protein composition of paracellular tight junctions.At present,there is no fully efficacious therapy for cerebral oedema other than liver transplantation and this reflects our incomplete knowledge of the precise mechanisms underlying this process which remain largely unknown.
文摘AIM To assess the practice of caring for acute liver failure(ALF) patients in varying geographic locations and medical centers.METHODS Members of the European Acute Liver Failure Consortium completed an 88-item questionnaire detailing management of ALF. Responses from 22 transplantation centers in 11 countries were analyzed,treating between 300 and 500 ALF cases and performing over 100 liver transplants(LT) for ALF annually. The questions pertained to details of the institution and their clinical activity,standards of care,referral and admission,wardbased care versus intensive care unit(ICU) as well as questions regarding liver transplantation- including criteria,limitations,and perceived performance. Clinical data was also collected from 13 centres over a 3 mo period. RESULTS The interval between referral and admission of ALF patients to specialized units was usually less than 24 h and once admitted,treatment was provided by a multidisciplinary team. Principles of care of patients with ALF were similar among centers,particularly in relation to recognition of severity and care of the more critically ill. Centers exhibited similarities in thresholds for ICU admission and management of severe hepatic encephalopathy. Over 80% of centers administered n-acetyl-cysteine to ICU patients for non-paracetamolrelated ALF. There was significant divergence in the use of prophylactic antibiotics and anti-fungals,lactulose,nutritional support and imaging investigations in admitted patients and in the monitoring and treatment of intra-cranial pressure(ICP). ICP monitoring was employed in 12 centers,with the most common indications being papilledema and renal failure. Most patients listed for transplantation underwent surgery within an average waiting time of 1-2 d. Over a period of 3 mo clinical data from 85 ALF patients was collected. Overall patient survival at 90-d was 76%. Thirty six percent of patients underwent emergency LT,with a 90% post transplant survival to hospital discharge,42% survived with medical management alone. CONCLUSION Alongside similarities in principles of care of ALF patients,major areas of divergence were present in key areas of diagnosis,monitoring,treatment and decision to transplant.
文摘Intrahepatic portosystemic shunts(IPSS) are rare congenital anomalies arising from disordered portal vein embryogenesis.It has been described in both children and adults and may be asymptomatic or be associated with a variety of neurophysiological and pulmonary complications.When recognized,early intervention to occlude the shunt will reverse the associated complications.Literature review reports of surgical and radiological occlusion of the shunt,but due to its rarity,a standard therapeutic protocol has not been established.A case of a 38-year-old woman with abdominal pain and low grade encephalopathy,diagnosed with an IPSS and treated by right hepatectomy was reported.
文摘Background: Primary and secondary liver tumors are not always amenable to resection due to location and size. Inadequate future liver remnant(FLR) may prevent patients from having a curative resection or may result in increased postoperative morbidity and mortality from complications related to small-forsize syndrome(SFSS). Data sources: This comprehensive review analyzed the principles, mechanism and risk factors associated with SFSS and presented current available options in the evaluation of FLR when planning liver surgery. In addition, it provided a detailed description of specifc modalities that can be used before, during or after surgery, in order to optimize the conditions for a safe resection and minimize the risk of SFSS. Results: Several methods which aim to reduce tumor burden, preserve healthy liver parenchyma, induce hypertrophy of FLR or prevent postoperative complications help minimize the risk of SFSS. Conclusions: With those techniques the indications of radical treatment for patients with liver tumors have signifcantly expanded. The successful outcome depends on appropriate patient selection, the individualization and modifcation of interventions and the right timing of surgery.
文摘Satisfactory blood flow after hepatic arterial anastomosis in liver transplantation is a critical point of the operation.Problems with this anastomosis can result in hepatic artery thrombosis with resultant graft failure and patient morbidity and mortality.Causes of hepatic artery thrombosis include problematic technique,hepatic artery dissection,external compression(e.g.from hematoma),hypercoagulable state,splenic arterial steal and rarer causes such as median arcuate ligament compression(MALC).A careful review of preoperative radiology and imaging will reveal these rare instances and enable a proper intraoperative plan.
文摘Liver enzymes and function tests are routinely taken in clinical practice. Deranged liver enzymes however, do not always necessarily imply an underlying liver pathology. The standard liver enzymes measured include alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl-transpeptidase (GGT) and alanine phosphatase (ALP). These enzymes, especially ALT and AST, can be released by other organs in the body. We report an unusual case of a 48-year-old patient with deranged enzymes related exclusively to intensive exercise that resolved on discontinuing such exercise.
文摘End-stage liver disease(ESLD) is a leading cause of morbidity and mortality amongst human immunodeficiency virus(HIV)-positive individuals. Chronic hepatitis B and hepatitis C virus(HCV) infection,drug-induced hepatotoxicity related to combined antiretro-viral therapy,alcohol related liver disease and non-alcohol related fatty liver disease appear to be the leading causes. It is therefore,anticipated that more HIV-positive patients with ESLD will present as potential transplant candidates. HIV infection is no longer a contraindication to liver transplantation. Key transplantation outcomes such as rejection and infection rates as well as medium term graft and patient survival match those seen in the non-HIV infected patients in the absence of co-existing HCV infection. HIV disease does not seem to be negatively impacted by transplantation. However,HIV-HCV coinfection transplant outcomes remain suboptimal due to recurrence. In this article,we review the key challenges faced by this patient cohort in the pre- and posttransplant period.
文摘AIM To determine the impact of Charlson comorbidity index(CCI) on waiting list(WL) and post liver retransplantation(LRT) survival.METHODS Comparative study of all adult patients assessed for primary liver transplant(PLT)(n = 1090) and patients assessed for LRT(n = 150), 2000-2007 at our centre. Demographic, clinical and laboratory variables were recorded. RESULTS Median age for all patients was 53 years and 66% were men. Median model for end stage liver disease(MELD) score was 15. Median follow-up was 7- years. For retransplant patients, 84(56%) had ≥ 1 comorbidity. The most common comorbidity was renal impairment in 66(44.3%). WL mortality was higher in patients with ≥ 1 comorbidity(76% vs 53%, P = 0.044). CCI(OR = 2.688, 95%CI: 1.222-5.912, P = 0.014) was independently associated with WL mortality. Patients with MELD score ≥ 18 had inferior WL survival(LogRank 6.469, P = 0.011). On multivariate analysis,CCI(OR = 2.823, 95%CI: 1.563-5101, P = 0.001), MELD score ≥ 18(OR 2.506, 95%CI: 1.044-6.018, P = 0.04), and requirement for organ support prior to LRT(P < 0.05) were associated with reduced post-LRT survival. Donor/graft parameters were not associated with survival(P = NS). Post-LRT mortality progressively increased according to the number of transplanted grafts(Log-Rank 18.455, P < 0.001). Post-LRT patient survival at 1-, 3- and 5-years were significantly inferior to those of PLT at 88% vs 73%, P < 0.001, 81% vs 71%, P = 0.018 and 69% vs 55%, P = 0.006, respectively. CONCLUSION Comorbidity increases WL and post-LRT mortality. Patients with MELD ≥ 18 have increased WL mortality. Patients with comorbidity or MELD ≥ 18 may benefit from earlier LRT. LRT for ≥ 3 grafts may not represent appropriate use of donated grafts.
文摘Extracellular vesicles(EVs)are a heterogenous group of nanosized,membranebound particles which are released by most cell types.They are known to play an essential role in cellular communication by way of their varied cargo which includes selectively enriched proteins,lipids,and nucleic acids.In the last two decades,wide-ranging evidence has established the involvement of EVs in the regulation of immunity,with EVs released by immune and non-immune cells shown to be capable of mediating immune stimulation or suppression and to drive inflammatory,autoimmune,and infectious disease pathology.More recently,studies have demonstrated the involvement of allograft-derived EVs in alloimmune responses following transplantation,with EVs shown to be capable of eliciting allograft rejection as well as promoting tolerance.These insights are necessitating the reassessment of standard paradigms of T cell alloimmunity.In this article,we explore the latest understanding of the impact of EVs on alloresponses following transplantation and we highlight the recent technological advances which have enabled the study of EVs in clinical transplantation.Furthermore,we discuss the rapid progress afoot in the development of EVs as novel therapeutic vehicles in clinical transplantation with particular focus on liver transplantation.
文摘The role of plasmapheresis in liver failure and hepatic encephalopathy is undefined and its use as a strategy to salvage patients with severe allograft dysfunction after liver transplantation remains investigational. We present a case of early allograft dysfunction following deceased donor liver transplantation(DDLT) where plasmapheresis was effective as a bridge to recovery and possibly avoiding a retransplantation. A 16 years old boy, known to have decompensated Wilson's disease underwent DDLT at our Public Sector Hospital. He received a healthy liver from a brain-dead donor, whose liver was considered too large for the boy. The graft was reduced in situ to a left lobe graft. Surgery was uneventful and the recipient was well for the initial 96 h. On Doppler and further computed tomography scan, a partial portal vein thrombus was noted. He was reexplored and a Fogarty endothombecteomy was performed. Following the second surgery, he developed severe allograft dysfunction with a peak bilirubin of 40 mg/d L. He underwent imaging to rule out technical causes for the dysfunction, followed by a liver biopsy, which revealed acute cellular rejection. Multiple cycles of plasmapheresis were initiated. Over the next two weeks, the graft demonstrated a gradual recovery. He was discharged on the 30 th postoperative day, with a serum bilirubin of 5.5 mg/d L. He remains well on follow-up, with the liver function tests improving further. Our report demonstrates the beneficial effect of plasmapheresis, which appears to be an effective treatment option for early allograft dysfunction following liver transplantation and may obviate the need for retransplantation.
文摘Liver-related autoantibodies are crucial for the correct diagnosis and classification of autoimmune liver diseas-es(AiLD),namely autoimmune hepatitis types 1 and 2(AIH-1 and 2),primary biliary cirrhosis(PBC),and the sclerosing cholangitis variants in adults and children.AIH-1 is specified by anti-nuclear antibody(ANA) and smooth muscle antibody(SMA).AIH-2 is specified by antibody to liver kidney microsomal antigen type-1(anti-LKM1) and anti-liver cytosol type 1(anti-LC1).SMA,ANA and anti-LKM antibodies can be present in de-novo AIH following liver transplantation.PBC is specified by antimitochondrial antibodies(AMA) react-ing with enzymes of the 2-oxo-acid dehydrogenase complexes(chiefly pyruvate dehydrogenase complex E2 subunit) and disease-specific ANA mainly react-ing with nuclear pore gp210 and nuclear body sp100.Sclerosing cholangitis presents as at least two variants,first the classical primary sclerosing cholangitis(PSC) mostly affecting adult men wherein the only(and non-specific) reactivity is an atypical perinuclear antineutro-phil cytoplasmic antibody(p-ANCA),also termed peri-nuclear anti-neutrophil nuclear antibodies(p-ANNA) and second the childhood disease called autoimmune sclerosing cholangitis(ASC) with serological features resembling those of type 1 AIH.Liver diagnostic serol-ogy is a fast-expanding area of investigation as new purified and recombinant autoantigens,and automatedtechnologies such as ELISAs and bead assays,become available to complement(or even compete with) tradi-tional immunofluorescence procedures.We survey for the first time global trends in quality assurance impact-ing as it does on(1) manufacturers/purveyors of kits and reagents,(2) diagnostic service laboratories that fulfill clinicians' requirements,and(3) the end-user,the physician providing patient care,who must properly interpret test results in the overall clinical context.
基金Supported by A5 year UK Department of Health HEFCE Clinical Senior Lectureship (to Dr.Shawcross DL)
文摘The face of hepatic encephalopathy(HE) is changing.This review explores how this neurocognitive disorder,which is associated with both acute and chronic liver injury,has grown to become a dynamic syndrome that spans a spectrum of neuropsychological impairment,from normal performance to coma.The central role of ammonia in the pathogenesis of HE remains incontrovertible.However,over the past 10 years,the HE community has begun to characterise the key roles of inflammation,infection,and oxidative/nitrosative stress in modulating the pathophysiological effects of ammonia on the astrocyte.This review explores the current thoughts and evidence base in this area and discusses the potential role of existing and novel therapies that might abrogate the oxidative and nitrosative stresses inflicted on the brain in patients with,or at risk of developing,HE.
文摘The histological hallmark of autoimmune hepatitis(AIH) is a dense portal mononuclear cell infiltrate that invades the surrounding parenchyma and comprises T and B lymphocytes,macrophages,and plasma cells.An unknown but powerful stimulus must be promoting the formation of this massive inflammatory cellular reaction that is likely to initiate and perpetuate liver damage.An autoimmune attack can follow different pathways to inflict damage on hepatocytes.Liver damage is likely to be orchestrated by CD4+ T lymphocytes recognizing an autoantigenic liver peptide.To trigger an autoimmune response,the peptide must be embraced by an HLA class Ⅱ molecule and presented to na?ve CD4+ T helper(Th0) cells by professional antigen presenting cells,with the co-stimulation of ligand-ligand fostering interaction between the two cells.Th0 cells become activated,differentiate into functional phenotypes according to the cytokines prevailing in the microenvironment and the nature of the antigen,and initiate a cascade of immune reactions determined by the cytokines produced by the activated T cells.Th1 cells,arising in the presence of the macrophage-derived interleukin(IL) -12,secrete mainly IL-2 and interferon-gamma(IFN-g),which activate macrophages,enhance expression of HLA classⅠ(increasing liver cell vulnerability to a CD8+ T cell cytotoxic attack),and induce expression of HLA class Ⅱ molecules on hepatocytes.Th2 cells,which differentiate from Th0 if the microenvironment is rich in IL-4,produce mainly IL-4,IL-10,and IL-13 which favour autoantibody production by B lymphocytes.Physiologically,Th1 and Th2 antagonize each other.Th17 cells,a recently described population,arise in the presence of transforming growth factor beta(TGF-β) and IL-6 and appear to have an important effector role in inflammation and autoimmunity.Theprocess of autoantigen recognition is strictly controlled by regulatory mechanisms,such as those exerted by CD4+CD25+ regulatory T cells,which derive from Th0 in the presence of TGF-β,but in the absence of IL-6.If regulatory mechanisms fail,the autoimmune attack is perpetuated.Over the past three decades different aspects of the above pathogenic scenario have been investigated.In particular,a defect in immunoregulation affecting CD4+CD25+ regulatory T cells(T-regs) has been demonstrated in AIH,particularly at diagnosis or during relapse.Advances in the study of autoreactive T cells have occurred mostly in AIH type 2,since the knowledge that CYP2D6 is the main autoantigen has enabled the characterization of both CD4 and CD8 T cells targeting this cytochrome.CD4 T cells from patients with type 2 AIH positive for the predisposing HLA allele DRB10701 recognize seven regions of CYP2D6,five of which are also recognized by CD8 T cells.High numbers of IFN-g producing CD4 T cells and CD8 T cells are associated with biochemical evidence of liver damage,suggesting a combined cellular immune attack.
文摘Autoimmune hepatitis is a rare chronic inflammatory liver disease,affecting all ages,characterised by elevated transaminase and immunoglobulin G levels,positive autoantibodies,interface hepatitis at liver histology and good response to immunosuppressive treatment. If untreated,it has a poor prognosis. The aim of this review is to summarize the evidence for standard treatment and to provide a systematic review on alternative treatments for adults and children. Standard treatment is based on steroids and azathioprine,and leads to disease remission in 80%-90% of patients. Alternative first line treatment has been attempted with budesonide or cyclosporine,but their superiority compared to standard treatment remains to be demonstrated. Second-line treatments are needed for patients not responding or intolerant to standard treatment. No randomized controlled trials have been performed for second-line options. Mycophenolate mofetil is the most widely used second-line drug,and has good efficacy particularly for patients intolerant to azathioprine,but has the major disadvantage of being teratogenic. Only few and heterogeneous data on cyclosporine,tacrolimus,everolimus and sirolimus are available. More recently,experience with the anti-tumour necrosis factoralpha infliximab and the anti-CD20 rituximab has been published,with ambivalent results; these agents may have severe side-effects and their use should be restricted to specialized centres. Clinical trials with new therapeutic options are ongoing.
文摘Primary biliary cirrhosis(PBC),primary sclerosing cholangitis(PSC) and autoimmune hepatitis(AIH) constitute the classic autoimmune liver diseases(AILDs).While AIH target the hepatocytes,in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells.Persistent liver injury,associated with chronic AILD,leads to un-resolving inflammation,cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts.Liver cirrhosis,and the resultant loss of normal liver function,inevitably ensues.Patients with cirrhosis have higher risks or morbidity and mortality,and that in the decompensated phase,complications of portal hypertension and/or liver dysfunction lead to rapid deterioration.Accurate diagnosis and monitoring of cirrhosis is,therefore of upmost importance.Liver biopsy is currently the gold standard technique,but highly promising non-invasive methodology is under development.Liver transplantation(LT) is an effective therapeutic option for the management of endstage liver disease secondary to AIH,PBC and PSC.LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy;in addition,LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids.
文摘Congenital extrahepatic portosystemic shunt,also known as Abernethy malformation, is a rare congenital malformation. It causes shunting of blood through a communication between the portal and systemic veins such as a patent ductus venous. We report 3 cases of Abernethy malformation complicated by the development of hepatocellular carcinoma. Additionally, we comprehensively reviewed all previously reported cases and highlighted common features that may help in early diagnosis and appropriate management.Patients with Abernethy malformation may have an increased propensity to develop hepatocellular carcinoma. All 5 previously reported cases, plus the three of our patients, have a type 1(complete) shunt suggesting a role for absent portal blood flow in the pathogenesis of hepatocellular carcinoma. Congenital extrahepatic portosystemic shunt should be sought for in cases with raised serum ammonia, hepatic encephalopathy or hepatocellular carcinoma in the absence of cirrhosis.
文摘BACKGROUND:The clinicopathological features of uncinate process pancreatic cancer(UPPC) are poorly described.Furthermore the anatomy of the uncinate process and its division during surgery are central to pancreaticoduodenectomy for UPPC.We set out to describe the embryology and anatomy of the uncinate process and the clinicopathological features of UPPC.DATA SOURCES:All published case series of UPPC were reviewed and included in this review.RESULTS:The true incidence of UPPC is difficult to quantify,with the reported incidence ranging from 2.5% to 10.7% of pancreatic cancer.There are 5 published series of UPPC including 117 patients,72 males and 45 females,aged from 45-53 years to 61-84 years.The median survival was 5 or 5.5 months in 3 of the series,12.1 months in another based only on potentially resectable lesions and 17 months in another based only on resected cases.CONCLUSIONS:The number of reported series of UPPC is limited,with vague symptoms as the predominant presenting features of the disease.The prognosis is poor with synchronous venous resection demonstrating a survival advantage.
文摘AIM: To assess serum cartilage oligomeric matrix protein(COMP) as a marker of cirrhosis and risk of progression to hepatocellular carcinoma(HCC). METHODS: A COMP enzyme-linked immunosorbentassay was used to test 187 patients with chronic liver diseases at the time point of first evaluation. The selected patients included 72 with chronic hepatitis B infection, 75 with chronic hepatitis C infection, 22 with primary biliary cirrhosis, 7 with autoimmune hepatitis type 1, and 11 with alcoholic liver disease. Demographic, biochemical, histological and clinical characteristics of the patients were recorded at the first evaluation. One hundred and forty-seven patients were followed for a median [interquartile range(IQR)] duration of 96.5(102) mo. The clinical, biochemical and histological data, as well as the development of cirrhosis, HCC according to internationally accepted criteria and in case of death, a liver-related cause during the follow-up period, were recorded at the electronic database of our clinic. COMP determination was also performed in 43 healthy individuals who served as the control study group.RESULTS: COMP positivity(> 15 U/L) was detected in 22%-36% among chronic liver disease groups. Strikingly, almost 83% of COMP-positive patients were cirrhotic at baseline, independently of cause of liver disease. Among the patients who developed HCC during follow-up, 73.7%(14/19) were COMP positive at baseline. COMP positivity was significantly associated with older age(P < 0.001), advanced fibrosis(P = 0.001) and necroinflammatory activity(P = 0.001), higher aspartate aminotransferase(P < 0.001), alanine aminotransferase(P < 0.02), γ-glutamyl transpeptidase(P = 0.003), alkaline phosphatase(P = 0.001), bilirubin(P < 0.05), international normalized ratio(P = 0.002) and alpha-fetoprotein levels(P < 0.02), and lower albumin(P < 0.001), and platelet count(P = 0.008). COMP levels [median(IQR)] were significantly higher in cirrhotics compared to non-cirrhotics [13.8(7.9) U/L vs 9.8(4.6) U/L, respectively; P < 0.001]. On multivariate logistic regression analysis, COMP-positivity was independently associated only with cirrhosis(OR = 4.40, 95%CI: 1.33-14.69, P = 0.015). Kaplan-Meier analysis showed that COMP positivity was significantly associated with HCC development(P = 0.007) and higher incidence of liver-related death(P < 0.001). CONCLUSION: Elevated COMP levels are strongly associated with cirrhosis and HCC progression. Serum COMP is a new promising non-invasive biomarker for HCC risk assessment in surveillance programs.
