Computer-assisted image analysis of liver collagen: relationship to Ishak scoring and hepatic venous pressure gradient

Histopathological scoring of disease stage uses descriptive categories without measuring the amount of fibrosis. Collagen, the major component of fibrous tissue, can be quantified by computer-assisted digital image analysis (DIA) using histological sections. We determined relationships between DIA, Ishak stage, and hepatic venous pressure gradient (HVPG) reflecting severity of fibrosis. One hundred fifteen patients with hepatitis C virus (HCV) who had undergone transplantation had 250 consecutive transjugular liver biopsies combined with HVPG (median length, 22 mm; median total portal tracts, 12), evaluated using the Ishak system and stained with Sirus red for DIA. Liver collagen was expressed as collagen proportionate area (CPA). Median CPA was 6% (0.2-45), correlating with Ishak stage (stage 6 range, 13%-45%), and with HVPG (r = 0.62; P < 0.001). Median CPA was 4.1% when HVPG was less than 6 mm Hg and 13.8% when HVPG was 6 mm Hg or more (P < 0.0001) and 6% when HVPG was less than 10 mm Hg and 17.3% when HVPG was 10 mm Hg or higher (P < 0.0001). Only CPA, not Ishak stage/grade, was independently associated by logistic regression, with HVPG of 6 mm Hg or more [odds ratio, 1.206; 95% confidence interval (CI), 1.094-1.331; P < 0.001], or HVPG of 10 mm Hg or more (odds ratio, 1.105; 95% CI, 1.026-1.191; P = 0.009). CPA increased by 50% (3.6%) compared with 20% in HVPG (1 mm Hg) in 38 patients with repeated biopsies. Conclusion: CPA assessed by DIA correlated with Ishak stage scores and HVPG measured contemporaneously. CPA was a better histological correlate with HVPG than Ishak stage, had a greater numerical change when HVPG was low, and resulted in further quantitation of fibrosis in cirrhosis.

Survival of relatives of patients with hepatocellular carcinoma

Background:Families of patients with hepatocellular carcinoma (HCC) carry a high risk of developing HCC. We determine the number of fatalities in relatives of HCC patients during an 8-year period to understand the risk and cause of HCC in relatives of patients with HCC.
Methods:From 1992 to 1997, 15 410 relatives of HCC patients in three generations were screened prospectively for HCC by ultrasonography, α-fetoprotein, liver biochemistry and viral markers. By using national citizen identification numbers, we searched the total fatalities in relatives of HCC patients between 1992 and 1999 from the national mortality data bank. The results were compared among different viral infection groups.
Results:Of the relatives studied, 37.8% were hepatitis B s antigen (HBsAg) positive (+), 4.3% were anti-hepatitis C virus (HCV) (+) and 1.7% were both HBsAg (+) and anti-HCV (+). A total of 399 fatalities, including 139 because of HCC (34.8%), 37 because of liver diseases (9.3%), 88 because of other cancers (22.1%) and 135 because of other diseases (33.8%), were found. Relatives who were HBsAg (+) or anti-HCV (+)showed a lower cumulative survival than did relatives who were negative for both HBsAg and anti-HCV. Relatives with dual infection of hepatitis B and C virus showed the highest mortality due to HCC or terminal liver diseases.
Conclusions:Chronic viral infection rather than a hereditary factor is the main cause of a familial tendency for HCC. Dual infection of hepatitis B and C virus increases the risk of HCC or decompensated liver diseases.
Background:Families of patients with hepatocellular carcinoma (HCC) carry a high risk of developing HCC. We determine the number of fatalities in relatives of HCC patients during an 8-year period to understand the risk and cause of HCC in relatives of patients with HCC.
Methods:From 1992 to 1997, 15 410 relatives of HCC patients in three generations were screened prospectively for HCC by ultrasonography, α-fetoprotein, liver biochemistry and viral markers. By using national citizen identification numbers, we searched the total fatalities in relatives of HCC patients between 1992 and 1999 from the national mortality data bank. The results were compared among different viral infection groups.
Results:Of the relatives studied, 37.8% were hepatitis B s antigen (HBsAg) positive (+), 4.3% were anti-hepatitis C virus (HCV) (+) and 1.7% were both HBsAg (+) and anti-HCV (+). A total of 399 fatalities, including 139 because of HCC (34.8%), 37 because of liver diseases (9.3%), 88 because of other cancers (22.1%) and 135 because of other diseases (33.8%), were found. Relatives who were HBsAg (+) or anti-HCV (+)showed a lower cumulative survival than did relatives who were negative for both HBsAg and anti-HCV. Relatives with dual infection of hepatitis B and C virus showed the highest mortality due to HCC or terminal liver diseases.
Conclusions:Chronic viral infection rather than a hereditary factor is the main cause of a familial tendency for HCC. Dual infection of hepatitis B and C virus increases the risk of HCC or decompensated liver diseases.

Replication of hepatitis B in HBsAg-positive siblings

Persistent hepatitis B virus (HBV) replication is important for progression of chronic liver diseases. To understand whether there is a trend of HBV replication in siblings or not, 1850 relatives of patients with hepatocellular carcinoma (HCC) were examined prospectively for liver function test, viral markers and HBV DNA. The prevalence of HBsAg in the parents', siblings', children's and grandchildren's generations were 43.4%, 57.2%, 35.5% and 32.1%, respectively. The prevalence of hepatitis B e antigen (HBeAg) in sibling's generation (mean age 44.4 years) was 19%, which is higher than that of asymptomatic HBsAg carriers. For siblings in the children's generation, the prevalence of HBeAg in hepatitis B surface antigen (HBsAg) carriers declined from 40% in the eldest siblings to 19% in the youngest siblings. In 75 families clustered with three or more HBsAg carrier siblings, the mean age for seven families of which all siblings remained HBeAg + was younger, whereas the mean age for 35 families of which all siblings had cleared HBeAg was older. For the remaining 33 families, in only 10 families had the older siblings cleared the HBeAg earlier than the younger siblings. Twenty families showed that younger siblings cleared the HBeAg earlier than the older or middle siblings. We concluded that HBV replication in HCC relatives cannot be explained by familial tendency alone. A significant number of younger siblings appeared to have a shorter HBV replication phase than their older siblings. The possible role of this in maternal–fetal transmission is discussed.

Recent advances on the roles of NO in cancer and chronic inflammatory disorders

Nitric oxide (NO) is a short-life molecule produced by the enzyme known as the nitric oxide synthase (NOS), in a reaction that converts arginine and oxygen into citrulline and NO. There are three isoforms of the enzyme: neuronal NOS (nNOS, also called NOS1), inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3). It is now known that each of these isoforms may be expressed in a variety of tissues and cell types. This paper is a review of the current knowledge of various functions of NO in diseases. We discuss in more detail its role in Cancer, the role of NO in myocardial pathophysiology, in central nervous system (CNS) pathologies. Other diseases such as inflammation, asthma, in chronic liver diseases, inflammatory bowel disease (IBD), arthritis, are also discussed. This review also covers the role of NO in cardiovascular, central nervous, pancreas, lung, gut, kidney, myoskeletal and chronic liver diseases (CLD). The ubiquitous role that the simple gas nitric oxide plays in the body, from maintaining vascular homeostasis and fighting infections to acting as a neurotransmitter and its role in cancer, has spurred a lot of interest among researchers all over the world. Nitric oxide plays an important role in the physiologic modulation of coronary artery tone and myocardial function. Nitric oxide from iNOS appears to be a key mediator of such glial-induced neuronal death. The high sensitivity of neurons to NO is partly due to NO causing inhibition of respiration, rapid glutamate release from both astrocytes and neurons, and subsequent excitotoxic death of the neurons.

Mechanisms regulating the function of the ATP7B copper-ATPase

The copper-transporting ATP7B protein is defective in patients with Wilson disease, which causes the accumulation of toxic levels of copper in the body particularly in the liver. This thesis provides new information about how ATP7B maintains copper levels in the body within safe limits.

Identification of proteins that interact with the copper transporter ATP7B

In this study proteins were identified that interact with the key liver enzyme, ATP7B that is affected in the copper toxicity disorder Wilson disease. Detailed characterisation of the interaction with glutaredoxin and dynactin subunit p62 contributes significantly towards our understanding of the mechanisms that regulate copper balance in the body.

Theobroma cacao (cocoa) supplementation in the treatment of Non-alcoholic Steatohepatitis

Non-alcoholic Steatohepatitis (NASH) is a chronic disease that results from accumulation of fat within the liver that subsequently stimulates free radicals to damage the cells of the liver. Cocoa is a rich source of antioxidants and it was found that its consumption could slow the development of NASH.

Novel genes in the liver of diabetic Psammomys obesus

Type 2 diabetes mellitus is a metabolic disease characterised by defects in insulin secretion and insulin action and disturbances in carbohydrate, fat and protein metabolism. Hepatic insulin resistance contributes to hyperglycemia and also leads to disturbances in fat metabolism in type 2 diabetes. Psammomys obesus is a unique poly genie animal model of type 2 diabetes and obesity, ideally suited for studies examining physiological and genetic aspects of these diseases. To identify metabolic abnormalities potentially contributing to the obesity and diabetes phenotype in P. obesus, indirect calorimetry was used to characterise whole body energy expenditure and substrate utilisation. Lean-NGT, obese-IGT and obese-diabetic animals were examined in fed and fasted states and following 14 days of dietary energy restriction. Energy expenditure and fat oxidation were elevated in the obese-IGT and obese-diabetic groups in proportion to body weight. Glucose oxidation was not different between groups. Obese-diabetic P. obesus displayed elevated nocturnal blood glucose levels and fat oxidation. Following 14 days of dietary energy restriction, body weight was reduced and plasma insulin and blood glucose levels were normalised in all groups. Glucose oxidation was reduced and fat oxidation was increased. After 24 hours of fasting, plasma insulin and blood glucose levels were normalised in all groups. Energy expenditure and glucose oxidation were greatly reduced and fat oxidation was increased. Following either dietary energy restriction or fasting, energy expenditure, glucose oxidation and fat oxidation were not different between groups of P. obesus. Energy expenditure and whole body substrate utilisation in P. obesus was similar to that seen in humans. P. obesus responded normally to short term fasting and dietary energy restriction. Elevated nocturnal fat oxidation rates and plasma glucose levels in obese-diabetic P. obesus may be an important factor in the pathogenesis of obesity and type 2 diabetes in these animals. These studies have further validated P. obesus as an ideal animal model of type 2 diabetes and obesity. It was hypothesised that many genes in the liver of P. obesus involved in glucose and fat metabolism would be differentially expressed between lean-NGT and obese-diabetic animals. These genes may represent significant factors in the pathophysiology of type 2 diabetes. Two gene discovery experiments were conducted using suppression subtractive hybridisation (SSH) to enrich a cDNA library for differentially expressed genes. Experiment 1 used cDNA dot blots to screen 576 clones with cDNA derived from lean-NGT and obese-diabetic animals. 6 clones were identified as overexpressed in lean-NGT animals and 6 were overexpressed in obese-diabetic animals. These 12 clones were sequenced and SYBR-Green PCR was used to confirm differential gene expression. 4 genes were overexpressed (≥1.5 fold) in lean-NGT animals and 4 genes were overexpressed (≥1.5 fold) in obese-diabetic animals. To explore the physiological role of these genes, hepatic gene expression was examined in several physiological conditions. One gene, encoding thyroxine binding globulin (TBG), was confirmed as overexpressed in lean-NGT P. obesus with ad libitum access to food, relative to both obese-IGT and obese-diabetic animals. TBG expression decreased with fasting in all animals. Fasting TBG expression remained greater in lean-NGT animals than obese-IGT and obese-diabetic animals. TBG expression was not significantly affected by dietary energy restriction. TBG is involved in thyroid metabolism and is potentially involved in the regulation of energy expenditure. Fasting increased hepatic site 1 protease (SIP) expression in lean-NGT animals but was not significantly affected in obese-IGT and obese-diabetic animals. SIP expression was not significantly affected by dietary energy restriction. SIP is involved in the proteolytic processing of steroid response element binding proteins (SREBP). SREBPs are insulin responsive and are known to be involved in lipid metabolism. Gene expression studies found TBG and SIP were associated with obesity and diabetes. Future research will determine whether TBG and SIP are important in the pathogenesis of these diseases. Experiment 2 used SSH and cDNA microarray to screen 8064 clones. 223 clones were identified as overexpressed in lean-NGT P. obesus and 274 clones were overexpressed in obese-diabetic P. obesus (p ≤0.05). The 9 most significantly differentially expressed clones identified from the microarray screen were sequenced (p ≤0.01). 7 novel genes were identified as well as; sulfotransferase related protein and albumin. These 2 genes have not previously been associated with either type 2 diabetes or obesity. It is unclear why hepatic expression of these genes may differ between lean-NGT and obese-diabetic groups of P. obesus. Subsequent studies will explore the potential role of these novel and known genes in the pathophysiology of type 2 diabetes.

Urbanicity and lifestyle risk factors for cardiometabolic diseases in rural Uganda: a cross-sectional study

Urban living is associated with unhealthy lifestyles that can increase the risk of cardiometabolic diseases. In sub-Saharan Africa (SSA), where the majority of people live in rural areas, it is still unclear if there is a corresponding increase in unhealthy lifestyles as rural areas adopt urban characteristics. This study examines the distribution of urban characteristics across rural communities in Uganda and their associations with lifestyle risk factors for chronic diseases.