Paediatric estimated average glucose in children with Type 1 diabetes.

AIM: Estimated average glucose has been used to transform HbA1c into a glucose measure that might better inform patients of their glycaemic control. The data set used to obtain the estimated average glucose equation was derived in adults with Type 1 and Type 2 diabetes, along with normal healthy control subjects, and requires testing in children. METHODS: This was a cross-sectional study of 234 children and young people (106 male) with Type 1 diabetes aged 4.0-23.5 years who underwent continuous glucose monitoring over a 5-day period along with a measure of HbA1c . Regression analysis was used to determine estimated average glucose and agreement was assessed with the average glucose estimated from the Nathan equation: Nathan average glucose equation = 1.59 (HbA1c% ) - 2.59. RESULTS: Mean HbA1c was 76 mmol/mol (25.1) [9.1 (2.3)%] and mean continuous glucose monitoring tissue glucose was 10.4 (2.6) mmol/l. The relationship between continuous glucose monitoring tissue glucose and HbA1c was described by the paediatric equation: paediatric estimated average glucose = 0.49 (HbA1c %) + 5.95 (r = 0.45; P < 0.001). The mean paediatric estimated average glucose was 10.4 (1.1) mmol/l compared with that from the Nathan average glucose equation of 11.9 (3.7) mmol/l (P < 0.001). Overall, the paediatric estimated average glucose was 2.7 mmol/l lower than the Nathan estimated average glucose, with a 95% limit of agreement of ± 0.5 mmol/l. The agreement was very close with HbA1c values below 80 mmol/mol (9.5%). CONCLUSION: These data suggest that the Nathan estimated average glucose could be used in children and young people with Type 1 diabetes. Caution should still be exercised in the estimates derived for average glucose as the data set is skewed in both Nathan and paediatric average glucose estimates in opposite directions because of the differences in average HbA1c .

Hepatocyte transplantation: a review of laboratory techniques and clinical experiences.

Orthotopic liver transplantation (OLT) is standard clinical practice for patients with severe and end-stage chronic liver disease. However, the chronic shortage of donor livers and parallel growth of the transplant waiting list mean that a substantial proportion of patients die while waiting for a donor liver. Attempts to reduce the waiting list by use of split-liver and living-related live donor techniques have had some impact, but additional approaches to management are vital if the death rate is to be significantly reduced. Extensive laboratory research work and limited clinical trials have shown that hepatocyte transplantation may be useful in bridging some patients to OLT. A major limiting factor has been the shortage of mature functioning human hepatocytes, which are currently mostly obtained from livers rejected for OLT. This review examines potential hepatocyte sources, hepatocyte isolation methods and preservation protocols that have been successfully established, along with an overview of clinical results.

Toll-like receptor expression in chronic hepatitis C: correlation with pro-inflammatory cytokine levels and liver injury.

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)-alpha. 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-alpha 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-alpha 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-alpha 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-alpha 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-alpha levels and hepatic necroinflammatory activity in this disorder.

Review article: portal vein thrombosis -- new insights into aetiology and management.

Portal vein thrombosis may occur in the presence or absence of underlying liver disease, and a combination of local and systemic factors are increasingly recognized to be important in its development. Acute and chronic portal vein thrombosis have traditionally been considered separately, although a clear clinical distinction may be difficult. Gastrooesophageal varices are an important complication of portal vein thrombosis, but they follow a different natural history to those with portal hypertension related to cirrhosis. Consensus on optimal treatment continues to be hampered by a lack of randomized trials, but recent studies demonstrate the efficacy of thrombolytic therapy in acute thrombosis, and the apparent safety and benefit of anticoagulation in patients with chronic portal vein thrombosis.

Paracetamol-induced hepatotoxicity at recommended dosage.

In patients who develop liver damage following moderate paracetamol overdose in the order of 5-10 g daily, recent fasting and nutritional impairment have been identified as key precipitants. Hepatotoxicity caused by paracetamol at recommended dosage, in the absence of exposure to enzyme-inducing drugs, has recently been described as an idiosyncratic phenomenon. The possible importance of fasting and malnutrition in this setting is uncertain. We report a severely malnourished 53-year-old woman who developed severe hepatotoxicity whilst receiving paracetamol at recommended dosage (4 g daily) following a period of fasting, in the absence of enzyme-inducing agents. Subsequent paracetamol exposure up to 2.6 g daily thrice weekly, in the setting of ongoing malnutrition and fasting as before, did not lead to recurrent liver damage. These findings indicate that paracetamol-related liver damage occurring within recommended dosage guidelines can be a dose-dependent rather than necessarily idiosyncratic phenomenon, at least in the setting of recent fasting and severe malnutrition.

Small intestinal mucosal immunity and morphometry in luminal overgrowth of indigenous gut flora.

OBJECTIVE: The aim of this study was to investigate the separate effects of indigenous oropharyngeal- and colonic-type flora on small intestinal mucosal immunity and morphometry in small intestinal bacterial overgrowth (SIBO). METHODS: A duodenal aspirate and random biopsies of underlying mucosa were obtained from 52 adult subjects (age range, 18-90 yr; median, 60 yr) without disorders that may otherwise disturb small intestinal histology or mucosal immunity. Villus height, crypt depth, villus/crypt ratios, counts of intraepithelial lymphocytes (IELs) and lamina propria total mononuclear cells, IgA, IgM, and IgG plasma cells, mast cells, and B and T lymphocytes were determined in relation to the presence or absence of SIBO and the nature of the overgrowth flora in all subjects. CD4+ve and CD8+ve T-cell counts were determined in 24 subjects. RESULTS: SIBO was present in 26 of 52 (50%) subjects. Overgrowth flora included colonic-type bacteria in 20 subjects and oropharyngeal-type flora alone in 6 subjects. Lamina propria IgA plasma cell counts were significantly increased in subjects with SIBO, irrespective of whether the overgrowth flora comprised oropharyngeal-type flora alone or included colonic-type bacteria. Neither villus height, crypt depth, villus/crypt ratios, nor total or other mononuclear cell counts in lamina propria differed significantly between subjects with and without SIBO, irrespective of the nature of the overgrowth flora. IEL counts were significantly higher than in culture-negative subjects only when the overgrowth flora included colonic-type bacteria. Even then, IEL counts were within a range currently considered normal. A significant, inverse correlation between advancing age and IEL counts became apparent after adjusting for the effect of SIBO of colonic-type flora. CONCLUSIONS: SIBO of oropharyngeal- and colonic-type flora are associated with differing disturbances of local duodenal mucosa. Nonetheless, these would not be readily apparent during routine histological assessment. Old age independently influences duodenal IEL counts.

Acute liver failure: established and putative hepatitis viruses and therapeutic implications.

Any virus that can cause an acute hepatitis will, on occasion, give rise to acute liver failure. Such infections can be separated into those due to the primary hepatitis viral infections A to E and those where hepatitis occurs as part of a systemic viral infection, as with infection with, for instance, Epstein-Barr virus, cytomegalovirus, Varicella zoster virus, adenovirus and Herpes simplex virus. In general, the frequency with which the different hepatitis viruses are responsible for acute liver failure is related to their underlying prevalence in particular countries. An apparent exception is the striking geographical variation in the reported prevalence of acute liver failure due to hepatitis C virus infection, with a much higher proportion of cases generally attributed to this agent in Japan and Taiwan than in Western countries. Recent work has focused on the possible importance of mutant hepatitis B viral strains, co- and super-infection with known hepatitis viruses and certain newly described agents that may account for otherwise unexplained cases of acute liver failure. Despite an improved understanding of the pathogenesis of complicating cerebral oedema and advances in general supportive care, it is likely that the most severely affected patients with acute liver failure due to viral causes will survive only with liver transplantation, at least until approaches for promoting adequate liver regeneration are successfully developed and implemented.

Evaluation of the rice breath hydrogen test for small intestinal bacterial overgrowth.

OBJECTIVES: The aims of this study were 1) to document the sensitivity, specificity, and predictive values of the rice breath hydrogen test for small intestinal bacterial overgrowth; 2) to determine the possible influence of concurrent gastric bacterial overgrowth and gastroduodenal pH on the efficacy of this test; and 3) to investigate whether reliability is limited by an inability of small intestinal luminal flora to ferment rice or its product of hydrolysis, maltose. METHODS: Twenty adult subjects were investigated with microbiological culture of proximal small intestinal aspirate and a 3-g/kg rice breath hydrogen test. Gastroduodenal pH, the presence or absence of gastric bacterial overgrowth, and the in vitro capability of small intestinal luminal flora to ferment rice and maltose, its product of hydrolysis, were determined. RESULTS: Sensitivity of the rice breath hydrogen test for small intestinal bacterial overgrowth was 33% and remained low even when subjects with small intestinal overgrowth with oropharyngeal-type (38%) and colonic-type flora (20%) and those with concurrent small intestinal and gastric bacterial overgrowth (40%) were considered separately. Sensitivity remained suboptimal despite favorable gastroduodenal luminal pH and documented ability of bacterial isolates to ferment rice and maltose in vitro. Specificity of the rice breath hydrogen test for small intestinal bacterial overgrowth was 91%. Positive predictive value, negative predictive value, and predictive accuracy were 75%, 63%, and 65%, respectively. CONCLUSIONS: Clinical value of the rice breath hydrogen test for detecting small intestinal bacterial overgrowth is limited. The rice breath hydrogen test is not a suitable alternative to small intestinal intubation and culture of secretions for the detection of small intestinal bacterial overgrowth.

The beta-subunit of the hepatocyte growth factor/scatter factor (HGF/SF) receptor phosphorylates and associates with CrkII: expression of CrkII enhances HGF/SF-induced mitogenesis.

CrkII, a 40 kDa adaptor possessing a Src homology (SH)2 domain followed by two SH3 domains, although not endowed with catalytic activity, participates in intracellular signalling, presumably by activating the Ras pathway. CrkII was found to be phosphorylated in response to hepatocyte growth factor/scatter factor (HGF/SF) and to associate with the beta-subunit of the HGF receptor (MET). CrkII associated with p(145betaMET) via its SH2 domain. Growth-factor-receptor-bound protein 2 (Grb2) co-immunoprecipitated with CrkII species. By transient transfection of A431 human epidermoid carcinoma cells with wild-type and dominant-negative Grb2 expression constructs lacking either the SH2 or SH3 domains, we have concluded that Grb2 does not contribute to the 'presentation' of CrkII to p(145betaMET). Overexpression of wild-type CrkII in A431 cells enhanced HGF/SF-induced proliferation, while a CrkII dominant-negative mutant lacking the SH2 domain prevented a similar proliferating response to HGF/SF. The effect of CrkII on HGF/SF-induced proliferation was also abolished in cells co-expressing CrkII and Son-of-sevenless lacking the guanine exchange domain, suggesting that CrkII is likely to induce cell proliferation partly via the Ras/mitogen-activated protein kinase route.

Acute liver failure: targeted artificial and hepatocyte-based support of liver regeneration and reversal of multiorgan failure.

Acute liver failure (ALF) still represents a major therapeutic challenge for hepatologists due to its high mortality rate as a result of multiorgan failure. Although emergency orthotopic liver transplantation represents a major advance in the management of selected patients, it is not applicable to all candidates due to limited organ availability. Therefore, new therapeutic options should be developed to bridge selected patients to transplantation or to treat patients not candidates for liver transplantation. Although new techniques for cell culture and perfusion have resulted in a number of promising devices for the provision of temporary liver support in acute liver failure, their clinical efficacy is as yet uncertain. Controlled trials on a multi-centre basis in well-defined patient groups and with standardised outcome measures, including the extent to which treatment influences cell damage and regeneration and prevents or reverses multiorgan failure, will be essential to properly evaluate the clinical value of current and evolving artificial and bioartificial devices. The same considerations must also apply to the assessment of therapeutic efficacy of hepatocyte transplantation. A better understanding of mechanisms responsible for the development of liver cell death, along with cellular and molecular mechanisms allowing surviving cells to proliferate in a hostile environment, will be required if a more targeted therapeutic approach to decreasing hepatocellular injury and enhancing liver regeneration is to be achieved. Whether extracorporeal devices or the transplantation of primary hepatocytes, stem cells or cells genetically engineered to over-express key metabolic functions, a proliferative phenotype and/or cytoprotective pathways will be best suited to meeting these demanding challenges remains to be determined.

Hepatocyte growth factor/scatter factor-induced intracellular signalling.

Hepatocyte growth factor (HGF) identical to scatter factor (SF) is a glycoprotein involved in the development of a number of cellular phenotypes, including proliferation, mitogenesis, formation of branching tubules and, in the case of tumour cells, invasion and metastasis. This fascinating cytokine transduces its activities via its receptor encoded by the c-met oncogene, coupled to a number of transducers integrating the HGF/SF signal to the cytosol and the nucleus. The downstream transducers coupled to HGF/MET, most of which participate in overlapping pathways, determine the development of the cell's phenotype, which in most cell types is dual.

Fulminant hepatic failure.

In recent years, considerable progress has been made in developing specific and supportive medical measures that have improved prognosis in FHF. Although new techniques for cell culture and perfusion have also resulted in a number of promising devices for the provision of temporary liver support, their clinical efficacy is as yet uncertain. Controlled multicenter trials in well-defined patient groups and with standardized outcome measures will be essential to evaluate the clinical value of these devices properly. The same considerations must also apply in assessing the efficacy of hepatocyte transplantation in FHF. A better understanding of mechanisms responsible for liver cell death and multiorgan failure, and the development of strategies to enhance liver regeneration may, in the future, allow a more targeted approach to therapy.

Medical management of hepatocellular carcinoma.

The possibility of effective treatment of hepatocellular carcinoma (HCC), one of the most common cancers worldwide, largely depends on its detection at an early stage before symptoms develop. Screening patients with known cirrhosis, in whom the overall annual incidence of HCC development is of the order of 1-6% (1,2), has the potential to improve the detection rate of such asymptomatic tumors. Such an approach is limited, however, by the fact that cirrhosis is unrecognized prior to presentation with HCC in up to two-thirds of patients in areas with a high incidence of this tumor, such as Asia, and in nearly half of those from low-incidence areas, such as the United Kingdom (3,4). Furthermore, the sensitivity of commonly employed screening tools, such as the serum α-fetoprotein (AFP) level and hepatic ultrasonography, is suboptimal for detecting small tumors (5). In addition, HCC may arise in noncirrhotic patients with chronic hepatitis or carriage of hepatitis B virus in the absence of histological abnormality (6,7). The fibrolamellar variant, which does not produce AFP, also arises in an otherwise normal liver and would not, therefore, be detected by conventional screening programs. Consequently, most patients continue to present with large HCCs that are not amenable to either of the potentially curative surgical options of resection or orthotopic liver transplantation (OLT). Resection is also precluded when lesions, even if small, are sited in an anatomically unsuitable central position or if hepatic functiona.