Pitfalls in histoacryl glue injection therapy for oesophageal, gastric and ectopic varices: A review.

Histoacryl glue is used increasingly for the treatment of gastric and ectopic varices, and there is experience in its use for oesophageal varices. It is an effective treatment, yet numerous reports of complications have accumulated. This review of the literature describes the technique, explores circulatory and vascular consideration unique to portal hypertension and categorises the complications into: "Embolisation", "local venous thrombosis", "fistulisation and extravascular injection", "ulceration, erosion and extrusion", and "nidus of infection". A case is then made for standardisation of the technique and the consent process.

Do critically ill liver patients experience negative bias? A web-based survey examining doctors opinions to critical care escalation.

OBJECTIVE: To test the hypothesis that there is negative bias towards escalating levels of care in decompensated cirrhosis, compared with other patient groups. DESIGN: An electronic survey containing eight acute clinical scenarios with equivalent physiological derangement, in which respondents were asked to score the degree to which they would advocate for intensive care unit admission on a scale of 1-10. Scenarios included respiratory, haematology, vascular, renal, gastrointestinal, postoperative and hepatological conditions. Follow-up questions examined the reasons why the patient should or should not be transferred, and enquired about ceilings of care, end-of-life decisions, degree of organ support and healthcare financial rationing. 273 doctors responded. SETTING: Secondary care hospitals in south of England. PATIENTS: None involved. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Advocacy score (1-10) and subsidiary responses. RESULTS: The hepatology patient ranked 4th of 8 with a mean advocacy score of 7.2. There were no significant differences between intensivists and physicians or between grades of seniority. Of those less likely to escalate (score 1-5, n=42), the reasons given were based on unsurvivability or excessive burden of treatment rather than aetiology. One-fifth cited 'lifestyle decision'. 25 (62.5%) respondents not favouring escalation would make the patient DNACPR, 17 (42.5%) would stipulate ward-based care only and a small minority would instigate active palliation. Of those favouring escalation (advocacy score 6-10), 70% (n=122) would consider unlimited organ support. Fifty-four (29.5% of those who answered) said they 'sometimes' or 'frequently' consider resource allocation when making decisions about escalation of care. CONCLUSIONS: When compared with a variety of acute medical scenarios, doctors did not overly appear to exhibit therapeutic nihilism for patients with decompensated liver disease; however, significant variation in interpretation of the data and management approaches was identified.

Dynamic analysis of GH receptor conformational changes by split luciferase complementation.

The transmembrane GH receptor (GHR) exists at least in part as a preformed homodimer on the cell surface. Structural and biochemical studies suggest that GH binds GHR in a 1:2 stoichiometry to effect acute GHR conformational changes that trigger the activation of the receptor-associated tyrosine kinase, Janus kinase 2 (JAK2), and downstream signaling. Despite information about GHR-GHR association derived from elegant fluorescence resonance energy transfer/bioluminescence resonance energy transfer studies, an assessment of the dynamics of GH-induced GHR conformational changes has been lacking. To this end, we used a split luciferase complementation assay that allowed detection in living cells of specific ligand-independent GHR-GHR interaction. Furthermore, GH treatment acutely augmented complementation of enzyme activity between GHRs fused, respectively, to N- and C-terminal fragments of firefly luciferase. Analysis of the temporal pattern of GH-induced complementation changes, pharmacological manipulation, genetic alteration of JAK2 levels, and truncation of the GHR intracellular domain (ICD) tail suggested that GH acutely enhances proximity of the GHR homodimer partners independent of the presence of JAK2, phosphorylation of GHR-luciferase chimeras, or an intact ICD. However, subsequent reduction of complementation requires JAK2 kinase activity and the ICD tail. This conclusion is in contrast to existing models of the GHR activation process.

Growth hormone signaling in human T47D breast cancer cells: potential role for a growth hormone receptor-prolactin receptor complex.

GH receptor (GHR) and prolactin (PRL) receptor (PRLR) are structurally similar cytokine receptor superfamily members that are highly conserved among species. GH has growth-promoting and metabolic effects in various tissues in vertebrates, including humans. PRL is essential for regulation of lactation in mammals. Recent studies indicate that breast tissue bears GHR and PRLR and that both GH and PRL may impact development or behavior of breast cancer cells. An important facet of human GH (hGH) and human PRL (hPRL) biology is that although hPRL interacts only with hPRLR, hGH binds well to both hGHR and hPRLR. Presently, we investigated potential signaling effects of both hormones in the estrogen receptor- and progesterone receptor-positive human T47D breast cancer cell line. We found that this cell type expresses ample GHR and PRLR and responds well to both hGH and hPRL, as evidenced by activation of the Janus kinase 2/signal transducer and activator of transcription 5 pathway. Immunoprecipitation studies revealed specific GHR-PRLR association in these cells that was acutely enhanced by GH treatment. Although GH caused formation of disulfide-linked and chemically cross-linked GHR dimers in T47D cells, GH preferentially induced tyrosine phosphorylation of PRLR rather than GHR. Notably, both a GHR-specific ligand antagonist (B2036) and a GHR-specific antagonist monoclonal antibody (anti-GHR(ext-mAb)) failed to inhibit GH-induced signal transducer and activator of transcription 5 activation. In contrast, although the non-GHR-specific GH antagonist (G120R) and the PRL antagonist (G129R) individually only partially inhibited GH-induced activation, combined treatment with these two antagonists conferred greater inhibition than either alone. These data indicate that endogenous GHR and PRLR associate (possibly as a GHR-PRLR heterodimer) in human breast cancer cells and that GH signaling in these cells is largely mediated by the PRLR in the context of both PRLR-PRLR homodimers and GHR-PRLR heterodimers, broadening our understanding of how these related hormones and their related receptors may function in physiology and pathophysiology.

Severity of the compensatory anti-inflammatory response determined by monocyte HLA-DR expression may assist outcome prediction in cirrhosis.

PURPOSE: To investigate variations in expression of the monocyte antigen presentation molecule HLA-DR in cirrhosis. METHODS: HLA-DR expression was measured by flow cytometry in 100 patients within 48 h of admission and repeated a week later in 21 patients admitted to ICU. IL-10, TNF-α and IFN-γ secretion in response to lipopolysaccharide and recall antigens were measured by enzyme-linked immunosorbent spot (ELISPOT) assay in 12 patients (7 with clinical immunoparesis, 5 stable). RESULTS: HLA-DR level was 71% in stable patients, 53% with single organ dysfunction and 34% with multiple organ failure (p < 0.02). Within these groups, no significant differences in admission HLA-DR were seen between survivors and non-survivors. HLA-DR expression less than 40% predicted 90-day mortality with a specificity of 80% and sensitivity of 59% [area under the receiver operator curve (AUROC) 0.76]. HLA-DR less than 40% was an independent predictor of prognosis in multivariate analysis with a relative risk of 2.35 (p = 0.04), although sequential organ failure assessment score (SOFA) score displaced HLA-DR when included. In those admitted to intensive care failure to increase HLA-DR expression was predictive of death within 30 days (risk ratio 6.9, p = 0.007). Follow-up values predicted outcome with similar accuracy to acute physiology and chronic health evaluation II (APACHE II)/SOFA scores (AUROC 0.88). Response to endotoxin and recall antigen was characterised by an anti-inflammatory cytokine secretion profile, and was associated with impairment in recall antigen presentation capacity. CONCLUSIONS: HLA-DR expression less than 40% and a failure of recovery predict poor outcome in decompensated cirrhosis, but overall prognostic power remains inferior to conventional markers. Ex vivo experiments demonstrate reduced Th1 response to antigenic stimulation and an exaggerated counter-inflammatory cytokine secretion profile.

The decision to engage in end-of-life discussions: a structured approach for doctors in training.

Engaging in end-of-life discussions is a major source of anxiety for doctors in training. The authors propose the use of a decision-making model to assist trainees and their clinical supervisors in such situations. Divided into' 'patient-centred' and 'physician-centred' components, the model ensures that the following aspects are analysed: patient and family safety, patient and family choice, physician competence and physician comfort. A real but historical end-of-life scenario is presented to a foundation year 1 doctor, and the particular risks of engaging in a discussion are subsequently clarified with reference to each of the model's components.

The importance of steatosis in chronic hepatitis C infection and its management: A review.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease with approximately 180 million people infected worldwide. Hepatic steatosis is a frequent histological finding in chronic hepatitis C (CHC) infection and is 2- to 3-fold more common than would be expected by chance alone. A high body mass index with excess visceral fat distribution is associated with steatosis in patients infected with HCV genotype 1 but not genotype 3, re-enforcing the concept that in patients with CHC, some have "metabolic steatosis", predominantly HCV genotype 1, and others "viral steatosis", mainly HCV genotype 3. Accumulating evidence suggests that steatosis may contribute to progression of fibrosis in CHC. Hepatic insulin resistance appears to play a role through the pro-fibrogenic effects of compensatory hyperinsulinemia. The aim of this review was to assess the effect host and viral factors play in steatosis development in patients with CHC infection and its possible relationship with hepatocellular carcinoma. The review examines the mechanisms by which CHC infection causes hepatic steatosis, the impact hepatic steatosis has on the natural history of the disease and finally, explores if treatments leading to a reduction in the amount of steatosis might lead to improved treatment outcomes. The basic medical science of steatosis in CHC will be discussed including proposed models of steatogenesis and the influence of viral and metabolic factors at the molecular level and how these might impact on current and future therapies.

King's Score: an accurate marker of cirrhosis in chronic hepatitis C.

OBJECTIVES: Histological assessment of patients with chronic hepatitis C infection is no longer performed routinely; consequently, a simple test is needed to identify patients with significant hepatic fibrosis. METHODS: Data were collected, retrospectively, on 923 consecutive patients undergoing percutaneous liver biopsy for chronic hepatitis C at King's College Hospital between 1 January 2000 and 30 June 2006; 602 patients were accepted to form the training set and a further 105 patients to form the validation set. RESULTS: On liver biopsy, 132 (22%) had cirrhosis (Ishak F5-6) in the training set and 19 (18%) in the validation set. Factors found by multivariate analysis to be associated with fibrosis in the training set were used to construct the King's Score: age x aspartate aminotransferase x international normalized ratio / platelets. Area under receiver operating characteristic curves for predicting cirrhosis and significant fibrosis (F3-6) were 0.91 and 0.79, respectively. A King's Score of greater than or equal to 16.7 predicted cirrhosis in 34% of patients (odds ratio 36.2, 95% confidence interval, 22.0-59.6; P<0.0001) with sensitivity 86%, specificity 80% and a high negative predictive value of 96%; a score greater than or equal to 12.3 predicted F3-6 (odds ratio 33.9, 95% confidence interval, 15.2-34.4; P<0.001). The validation set confirmed the utility of this index, area under receiver operating characteristic curves 0.94 and 0.89 for cirrhosis and F3-6, respectively. CONCLUSION: The King's Score is a simple and accurate index for predicting cirrhosis in chronic hepatitis C. Patients with a score of less than 16.7 have a low risk of cirrhosis.

The importance of immune dysfunction in determining outcome in acute liver failure.

Acute liver failure (ALF) shares striking similarities with septic shock with regard to the features of systemic inflammation, progression to multiple organ dysfunction and functional immunoparesis. While the existence of opposing systemic pro- and anti-inflammatory profiles resulting in organ failure and immune dysfunction are well recognised in septic shock, characterization of these processes in ALF has only recently been described. This review explores the evolution of the systemic inflammation in acute liver failure, its relation to disease progression, exacerbation of liver injury and development of innate immune dysfunction and extra-hepatic organ failure as sequelae. Defects in innate immunity are described in hepatic and extra-hepatic compartments. Clinical studies measuring levels of pro- and anti-inflammatory cytokines and expression of the antigen presentation molecule HLA-DR on monocytes, in combination with ex-vivo experiments, demonstrate that the persistence of a compensatory anti-inflammatory response syndrome, leading to functional monocyte deactivation, is a central event in the evolution of systemic immune dysfunction. Accurate immune profiling in ALF may permit the development of immunomodulatory strategies in order to improve outcome in this condition.

Sophistry and circumstance at the end of life.

When life-threatening illness robs a patient of the ability to express their desires, medical personnel must work through the issues of management and prognosis with relatives. Management decisions are guided by medical judgement and the relatives' account of the patient's wishes, but difficulties occur when distance grows between these two factors. In these circumstances the counselling process may turn into a doctor-led justification of the medical decision. This article presents two strands of dialogue, in which a doctor, counselling for and against continuation of supportive treatment in two patients with liver failure, demonstrates selectivity and inconsistency in constructing an argument. The specific issues of loss of consciousness (with obscuration of personal identity), statistical futility' and removal of autonomy are explored and used to bolster diametrically opposed medical decisions. By examining the doctor's ability to interpret these issues according to circumstance, the author demonstrates how it is possible to shade medical facts depending on the desired outcome.

Actin-free Gc globulin: a rapidly assessed biomarker of organ dysfunction in acute liver failure and cirrhosis.

Reductions in serum levels of Gc globulin, a hepatically synthesized component of the extracellular actin scavenger system responsible for complexing circulating actin and attenuating intravascular microthrombus formation, are associated with poor outcome in acute liver failure. Clinically applicable assays of the important actin-free fraction (Af-Gc) have not been available until now. We measured actin-free Gc globulin levels with a novel, rapid assay in 61 cases of acute liver failure (ALF) and in 91 patients with cirrhosis (40 of whom were clinically unstable with extrahepatic organ dysfunction), and studied associations with liver dysfunction, extrahepatic organ dysfunction, indices of disseminated coagulation, and outcome. Reductions in Af-Gc levels mirrored hepatic dysfunction and organ dysfunction in both groups, and discriminated patients with poor prognosis from those with good prognosis in the ALF cohort. Levels were lowest in patients with ALF (10% of control values), but levels were also markedly reduced in both unstable (28%) and stable (44%) patients with cirrhosis. Associations with markers of disseminated intravascular coagulation were seen in both groups, most notably in the cirrhosis cohort, supporting a pathophysiological role for reduced Af-Gc in the evolution of organ dysfunction. In acetaminophen-induced ALF, Af-Gc identified patients with poor prognosis as well as did the Acute Physiology and Chronic Health Evaluation (APACHE II) score (area under the receiver operating characteristic curve, 0.7), and in cirrhosis, Af-Gc was an independent predictor of mortality by multifactorial analysis. In conclusion, the importance of Af-Gc reductions in the development of multiple organ dysfunction in ALF and cirrhosis is highlighted, probably resulting from reduced hepatic production and peripheral exhaustion of this arm of the extracellular actin scavenger system.

Hepatic dysfunction in sickle cell disease: a new system of classification based on global assessment.

BACKGROUND & AIMS: Hepatic dysfunction in adults with sickle cell disease varies in character and severity from self-limited cholestasis to life-threatening acute liver failure and cirrhosis. Because previous attempts to describe patterns of liver disease have not reflected clinical experience, we aimed to characterize the presentation, clinicopathologic findings, and natural history of such patients. METHODS: We reviewed the clinical, laboratory, radiographic, and histologic features with the natural history of 38 patients (mean age, 33 years) with Hb SS, SC, or S-beta thalassemia referred to a tertiary liver center for assessment. RESULTS: Distinct disease patterns were identified that comprised massive hepatocellular necrosis (5%), acute severe sequestration and cholestasis in the context of sepsis (18%), cirrhosis (18%), chronic, fluctuating sequestration without cholestasis (21%), mechanical biliary obstruction (8%), siderosis without cirrhosis (8%), generalized cholangiopathy (8%), venous outflow obstruction (3%), and miscellaneous (11%). Of the 20 who required emergency admission, 8 did not survive their index admission, and 3 patients died during follow-up admissions (4 months-4 years later). There were 3 instances of hemorrhage related to liver biopsy. One patient underwent transplantation but died. Hematologic and biochemical markers did not discriminate well between survivors and nonsurvivors. The incidence of a second hepatic pathology (ie, viral hepatitis, autoimmune disease, transfusional siderosis) was 37% and was associated with the finding of more advanced histologic fibrosis. CONCLUSIONS: Patterns of hepatic dysfunction in sickle cell disease are diverse and demand clear characterization for each individual; however, groups with a poor prognosis can be identified after collation of clinical, laboratory, and radiologic data. Findings at biopsy (which is associated with higher risk of bleeding in this group) might be anticipated by noninvasive test results.

Sickle liver disease--an unusual presentation in a compound heterozygote for HbS and a novel beta-thalassemia mutation.

A 38-year-old Ghanaian man presented with a 6-month history of worsening pruritus, jaundice, and ascites. He was previously fit and well and rarely drank alcohol. Screening tests for chronic liver disease including viral, autoimmune, and other metabolic causes including iron overload were unremarkable. A liver biopsy performed at the referring hospital demonstrated intralobular cholestasis and cirrhosis. He was listed for liver transplantation but subsequently developed sepsis with multiple organ failure and died. The sickle solubility test was positive. Blood smear showed cells consistent with liver failure and no sickle cells. Hemoglobin electrophoresis revealed HbA2 2.8%, HbF 0.5%, and HbS greater than HbA (49.6% vs. 41.3%) in the absence of blood transfusion. Sequence analysis of the beta-globin genes showed he was a compound heterozygote for the Hbs mutation at codon 6 (CAG --> GTG) and a novel mutation at position 844 of intron 2 (betaIVS2-844 C --> A). A diagnosis of sickle hepatopathy causing decompensated cirrhosis was made. This case is unusual insomuch as this patient was asymptomatic for over 35 years and represents a novel presentation of sickle cell disease. Sickle cell disease should be considered in appropriate patients when unusual presentations of liver disease arise.