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Three patients with severe Clostridium difficile infection (CDI) caused by an unusual strain of C. difficile, PCR ribotype (RT) 251, were identified in New South Wales, Australia. All cases presented with severe diarrhoea, two had multiple recurrences and one died following a colectomy. C. difficile RT251 strains were isolated by toxigenic culture. Genetic characterisation was performed using techniques including toxin gene profiling, PCR ribotyping, whole genome sequencing (WGS), in-silico multi-locus-sequence-typing (MLST) and core-genome single nucleotide variant (SNV) analyses. Antimicrobial susceptibility was determined using an agar incorporation method. In vitro toxin production was confirmed by Vero cell cytotoxicity assay and pathogenicity was assessed in a murine model of CDI. All RT251 isolates contained toxin A (tcdA), toxin B (tcdB) and binary toxin (cdtA and cdtB) genes. Core-genome analyses revealed the RT251 strains were clonal, with 0–5 SNVs between isolates. WGS and MLST clustered RT251 in the same evolutionary clade (clade 2) as RT027. Despite comparatively lower levels of in vitro toxin production, in the murine model RT251 infection resembled RT027 infection. Mice showed marked weight loss, severe disease within 48 h post-infection and death. All isolates were susceptible to metronidazole and vancomycin. Our observations suggest C. difficile RT251 causes severe disease and emphasise the importance of ongoing surveillance for new and emerging strains of C. difficile with enhanced virulence.

The prevalence of lactose malabsorption (LM) is increased in the elderly, although the mechanisms responsible are still a matter of speculation. The objective of this study was to investigate the possible roles of reduced functional small intestinal absorptive area, lactase deficiency and small intestinal bacterial overgrowth (SIBO).Twenty Caucasian (Anglo-Celtic), asymptomatic, well-nourished, elderly volunteers (median age 79 years, range 70-94 years) with no clinically apparent predisposition to SIBO underwent a 50 g lactose breath hydrogen test (LBHT) and mannitol absorption test, the latter as an index of functional small intestinal absorptive area. Those with LM additionally underwent bacteriological assessment of small intestinal secretions and mucosal biopsy, to assess the contribution of SIBO and lactase deficiency, respectively, to the pathogenesis of LM in individual cases. The prevalence of SIBO was also determined in elderly subjects without LM. Twenty asymptomatic younger subjects (median age 29 years, age range 18-35 years) served as controls. All subjects were "hydrogen producers" in response to lactulose.LM was evident in 10/20 (50%) elderly subjects and 1/20 (5%) younger subjects (p=0.003). Mannitol absorption did not differ significantly in elderly and younger subjects or in elderly subjects with and without LM. SIBO was documented in 9/10 (90%) elderly subjects with LM; eradication was associated with resolution of LM. Lactase deficiency was evident in only one elderly subject with LM. SIBO was evident in 2/10 (20%) elderly subjects without LM (p=0.005 compared to those with LM). Lactulose breath hydrogen test identified only 2/11 (18%) elderly subjects with SIBO.Increased prevalence of LM in the elderly is mostly due to clinically non-apparent SIBO, rather than mucosal factors. The lactulose breath hydrogen test cannot be relied upon to identify elderly subjects with SIBO, even in those without an anatomical predisposition.

The molecular adsorbents recirculating system (MARS) is a form of artificial extracorporeal liver support which has the potential to remove substantial quantities of albumin-bound toxins postulated to contribute to the pathogenesis of liver cell damage, hemodynamic instability and multi-organ failure in patients with acute liver failure and acute-on-chronic liver failure (AoCLF). We assessed the efficacy of MARS therapy in a cohort of patients with severe liver damage unresponsive to intensive medical therapy. MARS therapy was instituted late in the clinical course of six patients with severely impaired liver function refractory to intensive medical therapy, including four with AoCLF precipitated by sepsis and two with liver dysfunction due to sepsis in the absence of pre-existing chronic liver disease. Outcome measures included markers of hemodynamic stability, renal function, serum bilirubin and bile acid levels, arterial ammonia levels, the arterial ketone body (acetoacetate/beta-hydroxybutyrate) ratio, hepatic encephalopathy grade and the plasma disappearance rate of indocyanine green. The rates of discharge from the intensive care unit and in-hospital mortality were determined. Our findings suggest that MARS treatment might be associated with some clinical efficacy even in patients with advanced multi-organ dysfunction occurring in the setting of severe liver damage and in whom treatment is instituted late in the clinical course. However, the overall survival rate (1/6; 17%) was poor. More data obtained from larger cohorts of patients enrolled in randomized controlled studies will be required in order to identify categories of liver failure patients who might benefit most from MARS treatment and to ascertain the most appropriate timing of intervention.

The rare but potentially devastating clinical syndrome of fulminant hepatic failure has as its components severe encephalopathy and finally cerebral edema, hemodynamic instability, renal failure, coagulopathy, profound metabolic disturbances and a particular susceptibility to bacterial and fungal infection. Despite advances in medical management, fulminant hepatic failure in its most severe form carries a high mortality rate unless urgent orthotopic liver transplantation is carried out. However, availability of cadaveric donor organs is limited and, due to the rapidly progressive clinical course in many cases, a substantial proportion of patients will die or develop contraindications to transplantation before the procedure can be performed. Consequently, recent interest has centred on living donor transplantation and the possibility of providing temporary liver support, either through auxiliary partial organ transplantation, extracorporeal perfusion or transplantation of hepatocytes, to allow time for either a liver graft to become available or native liver regeneration, on which spontaneous survival ultimately depends, to occur.

In patients with cirrhosis and hepatocellular carcinoma (HCC), orthotopic liver transplantation (OLT) offers hope for cure of both the complicating HCC and the underlying chronic liver disease. Excellent 5 year survival has been reported when the restrictive Milan criteria are used to select transplant candidates. Alternative recommendations have recently been proposed by groups at University of California San Francisco, University of Pittsburgh and Mount Sinai. We review current and evolving concepts regarding selection criteria for OLT in patients with HCC, along with strategies to reduce waiting times, such as the impact of the implementation of the model for end-stage liver disease (MELD) scoring system on organ distribution and the role of living donor OLT for this indication. The possible efficacy of adjuvant anti-tumour therapies in limiting HCC growth while waiting for OLT, along with factors influencing the risk of HCC recurrence post-OLT, the major cause of death in this setting, are also discussed.

Minimal hepatic encephalopathy (MHE) is an important disorder that may seriously impair daily functioning and quality of life in patients with cirrhosis. Treatment with lactulose is of benefit. The possible role of synbiotics (probiotics and fermentable fiber) has not been assessed. We screened 97 consecutive cirrhotic patients without overt hepatic encephalopathy for MHE using the number connection test and measurement of brainstem auditory evoked potentials. MHE, defined by abnormality on at least one test modality, was present in 58 (60%) patients. Fifty-five of these patients with MHE were randomized to receive a synbiotic preparation (n = 20), fermentable fiber alone (n = 20), or placebo (n = 15) for 30 days. Cirrhotic patients with MHE were found to have substantial derangements in the gut microecology, with significant fecal overgrowth of potentially pathogenic Escherichia coli and Staphylococcal species. Synbiotic treatment significantly increased the fecal content of non-urease-producing Lactobacillus species at the expense of these other bacterial species. Such modulation of the gut flora was associated with a significant reduction in blood ammonia levels and reversal of MHE in 50% of patients. Synbiotic treatment was also associated with a significant reduction in endotoxemia. The Child-Turcotte-Pugh functional class improved in nearly 50% of cases. Treatment with fermentable fiber alone was also of benefit in a substantial proportion of patients. In conclusion, treatment with synbiotics or fermentable fiber is an alternative to lactulose for the management of MHE in patients with cirrhosis.

Compression of liver parenchyma by a malignant hepatic cyst: a previously unreported manifestation of metastatic gastric cancer

Toll-like receptors (TLRs) play a key role in the innate immune response. The aim of this study was to examine the expression of TLR2 and TLR4 in chronic hepatitis B (CHB). The TLR2 and TLR4 expression on hepatocytes and Kupffer cells from fresh liver biopsies was measured from 21 patients with untreated hepatitis B e antigen (HBeAg)-positive and HBeAg-negative CHB. Parallel studies were also undertaken on monocytes from their peripheral blood. Expression of TLR2 on hepatocytes, Kupffer cells, and peripheral monocytes was significantly reduced in patients with HBeAg-positive CHB in comparison with HBeAg-negative CHB and controls, whereas it was significantly increased in HBeAg-negative CHB compared with controls. The level of TLR4 expression did not differ significantly between the groups. These results were confirmed in vitro using hepatic cell lines transduced with recombinant HBV baculovirus expressing wild-type HBV (HBeAg-positive), precore stop codon (G1896A) mutant HBV (HBeAg-negative). The functional relevance of these findings was established by the demonstration of significantly reduced cytokine production (TNF-α) and phospho-p38 kinase expression in the presence of the HBeAg. In the absence of HBeAg, HBV replication was associated with up-regulation of the TLR2 pathway leading to increased TNF-α production. Conclusion: This study demonstrates a potentially important interaction between HBeAg, HBV, and the innate immune response. (HEPATOLOGY 2007;45:102–110.)

Background/Aims Toll-like receptors (TLR’s) are critical receptors that promote innate immune responses to pathogen-associated molecular patterns. Activation of TLR’s leads to production of pro-inflammatory cytokines such as tumour necrosis factor (TNF)-α. This study investigates whether peripheral blood monocyte expression of TLR’s is disturbed in patients with chronic hepatitis C and whether levels of expression of these molecules are significantly correlated with hepatitis C virus (HCV) genotype, viral load, hepatic necroinflammatory activity, histological stage and circulating TNF-α concentrations. Methods In 18 non-cirrhotic patients with biopsy-proven, virologically-confirmed chronic hepatitis C and 32 controls, we measured expression of TLR2 and TLR4 on peripheral blood monocytes. HCV genotype, viral load, serum alanine aminotransferase (ALT) levels, histological stage of disease and circulating TNF-α and endotoxin levels were also determined. Results Peripheral blood monocyte expression of TLR2 and TLR4 were significantly increased in patients with chronic hepatitis C compared to controls, irrespective of HCV genotype or histological stage of disease. Circulating levels of TNF-α were also significantly increased in patients with chronic hepatitis C. In both the overall study cohort and patients with chronic hepatitis C, monocyte expression of TLR2, but not of TLR4, correlated significantly with serum TNF-α levels. In patients with chronic hepatitis C, monocyte expression of TLR2, but not of TLR4, also correlated significantly with serum ALT levels. Expression of TLR’s was not significantly correlated with viral load. Conclusions Up-regulation of peripheral blood monocyte expression of TLR2 and TLR4 occurs in patients with chronic hepatitis C. Increased monocyte expression of TLR2, but not of TLR4, correlates significantly with both increased circulating TNF-α levels and hepatic necroinflammatory activity in this disorder.

Persistent infection with hepatitis B virus (HBV) likely depends on viral inhibition of host defenses. We report that chronic hepatitis B e antigen-positive HBV infection is associated with a significant reduction in peripheral blood monocyte expression of Toll-like receptor 2, a key component of innate immunity, thereby providing a mechanism by which wild-type HBV may establish persistent infection.

The molecular adsorbents recirculating system (MARS) is a form of artificial extracorporeal liver support which has the potential to remove substantial quantities of albumin-bound toxins postulated to contribute to the pathogenesis of liver cell damage, hemodynamic instability and multi-organ failure in patients with acute liver failure and acute-on-chronic liver failure (AoCLF). We assessed the efficacy of MARS therapy in a cohort of patients with severe liver damage unresponsive to intensive medical therapy. MARS therapy was instituted late in the clinical course of six patients with severely impaired liver function refractory to intensive medical therapy, including four with AoCLF precipitated by sepsis and two with liver dysfunction due to sepsis in the absence of pre-existing chronic liver disease. Outcome measures included markers of hemodynamic stability, renal function, serum bilirubin and bile acid levels, arterial ammonia levels, the arterial ketone body (acetoacetate/beta-hydroxybutyrate) ratio, hepatic encephalopathy grade and the plasma disappearance rate of indocyanine green. The rates of discharge from the intensive care unit and in-hospital mortality were determined. Our findings suggest that MARS treatment might be associated with some clinical efficacy even in patients with advanced multi-organ dysfunction occurring in the setting of severe liver damage and in whom treatment is instituted late in the clinical course. However, the overall survival rate (1/6; 17%) was poor. More data obtained from larger cohorts of patients enrolled in randomized controlled studies will be required in order to identify categories of liver failure patients who might benefit most from MARS treatment and to ascertain the most appropriate timing of intervention.

In patients with cirrhosis and complicating hepatocellular carcinoma (HCC), liver transplantation (LT) offers the only hope for cure of both the HCC and cirrhosis. Recent data indicate that patients with HCC with larger intrahepatic tumor burdens than previously thought can expect excellent long-term survival with LT. However, tumor extension into the portal vein remains an absolute contraindication to LT because of early tumor recurrence. Although portal vein thrombosis (PVT) is readily detected by dynamic computed tomography or Doppler ultrasound, these do not discriminate between tumor extension and blood thrombus, which occurs commonly in cirrhosis, as the cause. We report a 46-year-old man with hepatitis B virus-related cirrhosis complicated by HCC and PVT. Positron emission tomography using F-18 FDG showed the cause of PVT to be tumor extension rather than blood thrombus, thereby contraindicating LT. In patients with HCC with PVT, abnormal F-18 FDG uptake in the portal vein indicates tumor thrombus and plays an important role in excluding LT candidacy.

Systemic vasodilatation and arterial hypotension, refractory to adrenergic vasopressors, portend a poor prognosis in patients with decompensated cirrhosis. The production of large amounts of nitric oxide, consequent to endotoxin-induced tumour necrosis factor (TNF)-alpha-mediated upregulation of inducible nitric oxide synthase (iNOS), has been suggested to be central to this phenomenon. Terlipressin has recently been shown in an animal model of cirrhosis to suppress endotoxin-induced TNF-alpha-mediated upregulation of iNOS, thereby preventing overproduction of nitric oxide and restoring normal vascular tone. We present the first evidence that this effect of terlipressin may also occur clinically, in a patient with Child-Pugh class C cirrhosis, endotoxaemia, a raised circulating TNF-alpha concentration, and marked systemic vasodilatation with refractory arterial hypotension. Beneficial effects of terlipressin on circulating nitrate and nitrite concentrations, haemodynamic status, plasma renin levels and indocyanine green clearance were comparable to those of the molecular adsorbent recirculating system (MARS). Our findings suggest that terlipressin may be the vasopressor agent of choice in patients with decompensated cirrhosis and provide a rationale for combination terlipressin and MARS therapy when the therapeutic response to either treatment alone is suboptimal.

No abstract.

BACKGROUND: Hepatic ischemia associated with coarctation of the aorta has not previously been reported in an adult; pregnancy increases the pressure gradient across a coarctation. CASE: A young woman with known coarctation of the aorta developed severe hepatic ischemia in pregnancy. A pregnancy-induced increase in the mean pressure gradient across the coarctation, from 18 mm Hg before pregnancy to 40 mm Hg in the third trimester, predisposed to critical hepatic hypoperfusion in the setting of dehydration. CONCLUSION: This case documents an association between coarctation of the aorta and hepatic ischemia, precipitated by pregnancy and dehydration in combination. It emphasizes the need in the assessment of patients with liver disease in pregnancy to consider not only traditional pregnancy-related conditions such as acute fatty liver and the hemolysis, elevated liver enzymes, low platelets syndrome, in which delivery may be necessary as a clinical emergency, but also those in which the circulatory and metabolic demands of pregnancy may precipitate liver injury.

Immune system is a major determinant of pathophysiology of inflammatory bowel disease (IBD), and cytokines are well known mediators of immune system. Recently, informations on pro-inflammatory cytokines and their role in IBD have led to development of potential therapeutic approach to manipulate these cytokines and there by inhibiting inflammation in IBD. These therapeutic approaches include inhibitors of the tumour necrosis factor (TNF)-alpha lymphocyte trafficking, type 1 T helper (Th1) cell polarization and nuclear factor type beta; immunoregulatory cytokines and various growth factors. Studies on these therapies have documented variable results and the outcomes of many clinical trials are awaited. However, these potential therapies, if become real may revolutionise approach in patients with IBD. Analysis of the inflammed mucosa from patients with Crohn disease (CD) and ulcerative colitis (UC) have shown increased expression of certain proinflammatory cytokines such as interleukin-1 (IL-1), interleukin 6 (IL-6) and TNF-alpha. The latter is important in the recruitment of neutrophils into inflammed tissue, a process which results from three physiological steps: (i) rolling, (ii) adhesion, and (iii) transendothelial migration. Understanding of the biology of chronic inflammation has expanded the therapies available for IBD and particularly CD. At present, the biological therapies that are being used in clinical practice or investigated for the treatment of IBD are predominantly proteins, usually delivered intravenously or subcutaneously. The therapies used include: 1. TNF-alpha inhibitors: infliximab, CDP 571, etanercept, onercept, CNI- 1493 and thalidomide. 2. Inhibitors of lymphocyte trafficking: natalizumab, LPD-02 and ICAM-1. 3. Inhibitors of Th1 polarization: monoclonal antibodies for IL-12, interferon (IFN)-gamma and anti IFN-gamma. 4. Immunoregulatory cytokines: IL-10 and IL-11. 5. Inhibitors of nuclear factor kappa (beta NF-kbeta.) 6. Growth factors: epidermal growth factor (EGF) and Keratinocyte growth factor (KGF).

Background & Aims: Autoimmune hepatitis (AIH) may run an aggressive clinical course if untreated. The influence of pregnancy on AIH is variable. Both flares in disease activity and remissions, often followed by a post partum flare, are well recognized. In contrast, definite AIH first presenting in the early post partum period has not been reported. Methods: We discuss a case series of 5 patients who developed severe AIH within 4 months post partum. Results: The diagnosis of AIH was definite based on internationally accepted criteria. Liver injury responded to conventional immunosuppressive therapy in all patients. Immune reactivation in the early post partum period may contribute to this entity. Conclusions: AIH should be considered in the differential diagnosis of liver dysfunction first presenting in the early post partum period.

TO THE EDITOR: In a recent issue, Pimentel et al. (1) reported a double-blind, randomized, placebo-controlled study in which normalization of the lactulose breath hydrogen test (LBHT) following antibiotic treatment was found to correlate with symptom improvement in patients with irritable bowel syndrome (IBS). The same group earlier reported that 78% of patients with IBS had an abnormal LBHT and suggested that this indicated that small intestinal bacterial overgrowth (SIBO) was common in IBS patients (2). In a letter concerning this interpretation (3), our group discussed our published experience with the LBHT, based on the only study to date in which this test has been combined with scintigraphy in order to accurately identify the luminal location of lactulose at the time at which breath hydrogen concentrations first increase, in which sensitivity and specificity for SIBO were found to be only 16.7% and 70%, respectively (4). Based on this experience, we suggested that controlled studies using culture of small intestinal aspirate as the diagnostic modality, rather than the LBHT, should be performed to further investigate the possible role of SIBO in the pathogenesis of IBS (3).

Increasing evidence suggests that derangement of gut flora is of substantial clinical relevance to patients with cirrhosis. Intestinal bacterial overgrowth and increased bacterial translocation of gut flora from the intestinal lumen, in particular, predispose to an increased potential for bacterial infection in this group. Recent studies suggest that, in addition to their role in the pathogenesis of overt infective episodes and the clinical consequences of sepsis, gut flora contributes to the pro-inflammatory state of cirrhosis even in the absence of overt infection. Furthermore, manipulation of gut flora to augment the intestinal content of lactic acid-type bacteria at the expense of other gut flora species with more pathogenic potential may favourably influence liver function in cirrhotic patients. Here we review current concepts of the various inter-relationships between gut flora, bacterial translocation, bacterial infection, pro-inflammatory cytokine production and liver function in this group.

The molecular adsorbents recirculating system (MARS®) is a form of artificial liver support that has the potential to remove substantial quantities of albumin-bound toxins that have been postulated to contribute to the pathogenesis of liver cell damage, haemodynamic instability and multi-organ failure in patients with acute liver failure (ALF) and acute-on-chronic liver failure (AoCLF). These toxins include fatty acids, bile acids, tryptophan, bilirubin, aromatic amino acids and nitric oxide. Data from controlled clinical trials are limited so far. One of two studies performed on small numbers of patients with AoCLF suggest a survival benefit, but no controlled data are available in the ALF setting. Our preliminary experience with MARS therapy, instituted late in the clinical course of five patients with severely impaired liver function, including three with AoCLF precipitated by sepsis and two with liver dysfunction due to sepsis in the absence of pre-existing chronic liver disease, indicates some clinical efficacy. However, the overall survival rate (1 of 5; 20%) remained poor. More data obtained from larger cohorts of patients enrolled in randomised controlled studies will be required in both the AoCLF and ALF settings to identify categories of liver failure patients who might benefit most from MARS treatment, to ascertain the most appropriate timing of intervention and to determine the overall impact on outcome, including cost-effectiveness.