Dyslipidaemia—Hepatic and intestinal cross-talk

Cholesterol metabolism is tightly regulated with the majority of de novo cholesterol synthesis occurring in the liver and intestine. 3 Hydroxy-3-methylglutaryl coenzyme A reductase, a major enzyme involved in cholesterol synthesis, is raised in both liver and intestine in diabetic animals. Niemann PickC1-like1 protein regulates cholesterol absorption in the intestine and facilitates cholesterol transport through the liver. There is evidence to suggest that the effect of inhibition of Niemann PickC1-like1 lowers cholesterol through its effect not only in the intestine but also in the liver. ATP binding cassette proteins G5/G8 regulate cholesterol re-excretion in the intestine and in the liver, cholesterol excretion into the bile. Diabetes is associated with reduced ATP binding cassette protein G5/G8 expression in both the liver and intestine in animal models. Microsomal triglyceride transfer protein is central to the formation of the chylomicron in the intestine and VLDL in the liver. Microsomal triglyceride transfer protein mRNA is increased in diabetes in both the intestine and liver. Cross-talk between the intestine and liver is poorly documented in humans due to the difficulty in obtaining liver biopsies but animal studies are fairly consistent in showing relationships that explain in part mechanisms involved in cholesterol homeostasis.     

Iron Enhances Hepatic Fibrogenesis and Activates Transforming Growth Factor-β Signaling in Murine Hepatic Stellate Cells

Background

Although excess iron induces oxidative stress in the liver, it is unclear whether it directly activates the hepatic stellate cells (HSC).

New Developments in Therapy for Hepatic Fibrosis

Over the past 30 years, methods have been developed for isolating the principal cell types of the liver. These have made it possible to analyze quantitatively and in detail the injury response of the liver, which underlies the scarring process known as fibrosis. Attention has focused in particular on hepatic stellate cells because of their dynamic response to injury, termed activation. Metabolically quiescent in the normal liver, stellate cells in injury rapidly display properties of myofibroblasts, including expression de novo of smooth muscle proteins,     

Hepatic stem cells： existence and origin

Stem cells are not only units of biological organization,responsible for the development and the regeneration of tissue and organ systems, but also are units in evolution by natural selection. It is accepted that there is stem cell potential in the liver. Like most organs in a healthy adult,the liver maintains a perfect balance between cell gain and loss. It has three levels of cells that can respond to loss of hepatocytes: (1) Mature hepatocytes, which proliferate after normal liver tissue renewal, less severe liver damage, etc;they are numerous, unipotent, “committed“ and respond rapidly to liver injury. (2) Oval cells, which are activated to proliferate when the liver damage is extensive and chronic,or if proliferation of hepatocytes is inhibited; they lie within or immediately adjacent to the canal of Hering (Coil); they are less numerous, bipotent and respond by longer, but still limited proliferation. (3) Exogenous liver stem cells, which may derive from circulating hematopoietic stem cells (HSCs) or bone marrow stem cells; they respond to allyl alcohol injury or hepatocarcinogenesis; they are multipotent, rare,but have a very long proliferation potential. They make a more significant contribution to regeneration, and even completely restore normal function in a murine model of hereditary tyrosinaemia. How these three stem cell populations integrate to achieve a homeostatic balance remains enigmatic. This review focuses on the location,activation, markers of the three candidates of liver stem cell, and the most importantly, therapeutic potential of hepatic stem cells.     

Hepatic perfusion disorders： Etiopathogenesis and related diseases

In this article, we have reviewed the hepatic perfusion disorder (HPD), etiopathogenesis of HPD and corresponding diseases. Review of the literature was based on computer searches (PubMed, Index Medicus) and personal experiences. We considered HPD reflects perfusion differences due to redistribution of arterial blood flow among segments, subsegments and lobes of the liver. The plain CT scan findings of HPD manifests as triangular or wedge-shaped areas of low attenuation. On contrast-enhanced CT scan, HPD manifests multiple (or single) transient wedge-shaped, rotundloid or irregular appearance, homogeneous hyperattenuation (in less cases, hypoattenuation) during the hepatic arterial phase (HAP) and isoattenuated or slightly hyperattenuated areas during the portal arterial phase. Dynamic enhanced magnetic resonance (MR) features are similar to enhanced CT scan. Angiographic findings include non-opacification of portal vein on portograms or wedge-shaped segmental staining in arterial and parenchymal phases on hepatic angiograms. The causes of HPD are arterioportal shunts (APS), intrahepatic vascular compressions and portal vein occlusion, steal phenomenon by hypervascular tumors, vascular variations and any other unknown reasons. It is very important for radiologists to be familiar with the various appearances of HPD to avoid false-positive diagnosis of pseudolesions and not to overestimate the extent of the disease.     

Hepatic venous outflow obstruction： Three similar syndromes

Our goal is to provide a detailed review of venoocclusive disease （VOD）, Budd-Chiari syndrome （BCS）, and congestive hepatopathy （CH）, all of which results in hepatic venous outflow obstruction. This is the first article in which all three syndromes have been reviewed, enabling the reader to compare the characteristics of these disorders. The histological findings in VOD, BCS, and CH are almost identical： sinusoidal congestion and cell necrosis mostly in perivenular areas of hepatic acini which eventually leads to bridging fibrosis between adjacent central veins. Tender hepatomegaly with jaundice and ascites is common to all three conditions. However, the clinical presentation depends mostly on the extent and rapidity of the outflow obstruction. Although the etiology and treatment are completely different in VOD, BCS, and CH; the similarities in clinical manifestations and liver histology may suggest a common mechanism of hepatic injury and adaptation in response to increased sinusoidal pressure.     

Hepatic encephalopathy: a central neuroinflammatory disorder?

Encephalopathy and brain edema are serious central nervous system complications of liver failure. Recent studies using molecular probes and antibodies to cell-specific marker proteins have demonstrated the activation of microglial cells in the brain during liver failure and confirmed a central neuroinflammatory response. In animal models of ischemic or toxic liver injury, microglial activation and concomitantly increased expression of genes coding for proinflammatory cytokines in the brain occur early in the progression of encephalopathy and brain edema. Moreover, the prevention of these complications with mild hypothermia or N-acetylcysteine (two treatments known to manifest both peripheral and central cytoprotective properties) averts central neuroinflammation due to liver failure. Recent studies using anti-inflammatory agents such as ibuprofen and indomethacin have shown promise for the treatment of mild encephalopathy in patients with cirrhosis, whereas treatment with minocycline, a potent inhibitor of microglial activation, attenuates the encephalopathy grade and prevents brain edema in experimental acute liver failure. The precise nature of the signaling mechanisms between the failing liver and central neuroinflammation has yet to be fully elucidated; mechanisms involving blood-brain cytokine transfer and receptor-mediated cytokine signal transduction as well as a role for liver-related toxic metabolites such as ammonia have been proposed. The prevention of central proinflammatory processes will undoubtedly herald a new chapter in the development of agents for the prevention and treatment of the central nervous system complications of liver failure.     

Wedged Hepatic Venous Pressure Does Not Reflect Portal Pressure in Patients with Cirrhosis and Hepatic Veno–Venous Communications

Some cirrhotic patients have hepatic veno–venous communications (HVVC) and large porto-systemic collaterals. However, the relationship between wedged hepatic vein pressure (WHVP) and portal vein pressure (PVP) in such patients is not clear. The aim of this study was to determine the relationships between simultaneously measured WHVP and PVP, and occluded hepatic and splenic portal venography in 100 cirrhotic patients (40 alcoholic and 60 hepatitis C virus (HCV)-related cirrhosis). PVP and WHVP were closely related in both groups (alcoholic-cirrhosis: 27.8 ± 4.7 and 27.5 ± 4.8 mmHg, HCV-cirrhosis: 27.3 ± 3.7 and 26.2 ± 4.4 mmHg, respectively). Occluded hepatic venography revealed that 13 of the 100 patients had HVVC (alcoholic-cirrhosis: 4, HCV-cirrhosis: 9). In patients with HVVC, PVP (27.9 ± 3.0 mmHg) was significantly higher than WHVP (21.9 ± 3.3 mmHg, P < 0.001). Large porto-systemic collaterals did not affect the relationship. We conclude that HVVC affects the relationship between PVP and WHVP. When WHVP is measured, occluded hepatic venography should be examined to detect HVVC.     

Hepatic Venous Pressure Gradient: Worth Another Look?

Portal hypertension is one of the most important complications of chronic liver disease and accounts for significant morbidity and mortality. Measurement of the hepatic venous pressure gradient (HVPG) is a simple, invasive, and reproducible method of assessing portal venous pressure. Measurement of HVPG provides the clinician an estimate of the degree of intrahepatic portal flow resistance, guides therapy for variceal bleeding (primary and secondary prophylaxis), assesses feasibility of resection in patients with hepatocellular cancer, and predicts response to therapy of patients with chronic hepatitis C. Achieving hemodynamic targets of reducing the HVPG to <10 mmHg or a 20% reduction from baseline virtually eliminates complications related to portal hypertension from chronic liver disease. This review explores the role of HVPG measurement in the contemporary treatment of patients with cirrhosis and portal hypertension.     

Hepatic encephalopathy with status epileptics： A case report

A 62-year-old male with decompensated liver cirrhosis due to hepatitis C virus developed severe hepatic encephaiopathy with status epileptic us. The blood ammonia level on admission was more than twice the normal level. Brain computed tomography and magnetic resonance imaging were normal. In addition, electroencephalogram showed diffuse sharp waves, consistent with hepatic encephaiopathy. The status epilepticus was resolved after antiepileptic therapy (phenytoin sodium) and treatment for hepatic encephaiopathy (Branched chain amino acids). The blood ammonia level normalized with the clinical improvement and the patient did not have a recurrence of status epilepticus after the end of the antiepileptic treatment. Additionally, the electroencephalogram showed normal findings. Thus, we diagnosed the patient as hepatic encephaiopathy with status epilepticus. We consider the status epilepticus of this patient to a rare and interesting finding in hepatic encephaiopathy.     

Hepatic steatosis and hepatitis C: Still unhappy bedfellows?

Hepatic steatosis is commonly seen in patients with chronic hepatitis C virus (HCV) infection, and the prevalence is much higher prevalence than in the general population or in patients with chronic hepatitis B. Hepatic steatosis in patients with chronic hepatitis C can be due to alcohol consumption and host metabolic factors such as high body mass index (BMI), obesity, hyperlipidemia, metabolic syndrome and diabetes mellitus in which insulin resistance plays an important role. However, in genotype 3 HCV infection, hepatic steatosis can result from direct viral cytopathic effect. Demographic and clinical characteristics associated with hepatic steatosis in patients with chronic hepatitis C including older age, higher BMI, more genotype 3 infection, and higher mean serum levels of triglyceride, alanine aminotransferase and γ-glutamyl transpeptidase. The clinical relevance of hepatic steatosis in patients with chronic hepatitis C includes a close correlation with hepatic fibrosis, and a poor response to combination peginterferon and ribavirin treatment. In addition, hepatic steatosis has been reported to associate with increased frequency of hepatocellular carcinoma in patients with chronic HCV infection. Whether life style modification such as weight reduction or adding an insulin resistance reducing agent such as metformin or thiazolidinediones combined with current standard peginterferon plus ribavirin treatment will benefit to the chronic hepatitis C patients with hepatic steatosis deserves further evaluation.     

Hepatic angiomyolipoma： Dynamic computed tomography features and clinical correlation

AIM： To study the dynamic computed tomography （CT） features of hepatic angiomyolipoma （AML） in patients with or without tuberous sclerosis complex （TSC）.
METHODS： The clinical information, CT findings and histopathological results of hepatic AML were analyzed retrospectively in 10 patients.
RESULTS： Hepatic AML was prone to occur in female patients （7/10）, and most of the patients （8/10） had no specific symptoms. All tumors presented as welldefined, unenveloped nodules in the liver. Six patients with sporadic hepatic AML had a solitary hepatic nodule with a definite fat component. Non-fat components of the hepatic lesions were enhanced earlier and persistently. Prominent central vessels were noted in the portal venous phase in three patients. In four patients with hepatic AML and TSC, most of the nodules were within the peripheral liver. Seven fatdeficient nodules were found with earlier contrast enhancement and rapid contrast material washout in two patients. Lymphangioleiomyomatosis was found in one patient.
CONCLUSION： Imaging features of hepatic AML are characteristic. Correct diagnosis preoperatively can be made in combination with clinical features.     

Hepatic steatosis： A benign disease or a silent killer

Steatosis is a common feature of many liver diseases, namely non-alcoholic steatohepatitis （NASH） and hepatitis C virus （HCV） infection, but the pathogenic mechanisms differ. Insulin resistance （IR）, a key feature of metabolic syndrome, is crucial for NASH development, associated with many underlying genetically determined or acquired mitochondrial and metabolic defects and culminates to inflammation and progression to fibrosis. This may have potential implications for new drug therapy. In HCV-related disease, steatosis impacts both fibrosis progression and response to treatment. Steatosis in HCV-related disease relates to both viral factors （HCV genotype 3）, and host factors （alcohol consumption, overweight, hyperlipidemia, diabetes）. Among others, IR is a recognized factor. Hepatic steatosis is reported to be associated with disturbance in the signaling cascade of interferon and downregulation of its receptors. Thus, hepatic steatosis should not be considered a benign feature, but rather a silent killer.     

Minimal Hepatic Encephalopathy in Cirrhosis- How Long to Treat?

IntroductionMinimal hepatic encephalopathy (MHE) can reverse after short-term treatment. However, relapse rate of MHE after stopping treatment has not been studied so far. We aimed to evaluate long-term (9 months) efficacy of a short-term (3 months) treatment of MHE with lactulose/rifaximin, for maintenance of remission from MHE.Material and MethodsIn this prospective study, consecutive patients with cirrhosis and MHE were treated with lactulose/rifaximin for 3 months. After treatment, they were followed up for 6 months. Psychometric testing for diagnosis of MHE was performed at baseline, 3 months and 9 months.ResultsOf the 527 patients screened, 351 were found eligible and tested for MHE. Out of these, 112 (31.9%) patients had MHE (mean age 55.3 years; 75% males). They were randomized to receive Rifaximin (n = 57; 1,200 mg/day) or Lactulose (n = 55; 30-120 mL/day) for three months. At 3 months, 73.7% (42/57) patients in Rifaximin group experienced MHE reversal compared to 69.1% (38/55) in Lac-tulose group (p = 0.677). Six months after stopping treatment, 47.6% (20/42) in rifaximin group and 42.1% (16/38) patients in lactu-lose group experienced MHE relapse (p = 0.274). The overt hepatic encephalopathy development rate (7.1% vs. 7.9%) and mortality rate (0.23% vs. 0%) were similar in both groups. The Child-Turcotte-Pugh score and model for end stage liver disease (MELD) scores of patients who had MHE relapse were higher compared to those who didn’t. On multivariate regression analysis, MELD score was an independent predictor of MHE relapse.ConclusionOf the patients who became MHE negative after short-term (3 months) treatment with rifaximin/lactulose, almost 50% had a relapse of MHE at 6 months follow-up.     

Hepatic expression of interferon-α in chronic hepatitis B virus infection

Hepatic expression of interferon- (IFN-) was examined by immunohistochemistry in 90 Chinese patients (M/F 67:23, age: 14–69) with a spectrum of hepatitis B virus (HBV)-related chronic liver diseases. Immunoreactive IFN- was detected in sinusoidal cells in 79 patients (88%) and in mononuclear cells in 59 patients (65.6%). Patients with active liver diseases (chronic active hepatitis, active cirrhosis,N=55) had a higher level of IFN- expression compared to patients with inactive histology (N=35; sinusoidal cells,P<0.01; mononuclear cells,P<0.01). Cytoplasmic HBsAg, nuclear HBcAg, and cytoplasmic HBcAg were detected in 79 (88%), 42 (47%), and 23 (27%) patients respectively. Expression of IFN- in mononuclear cells correlated with the expression of cytoplasmic HBcAg (P<0.05) but not with nuclear HBcAg or cytoplasmic HBsAg. When the patients were divided into four different phases according to the natural history of chronic HBV infection, patients in the active liver disease phase had higher IFN- expression compared to the immunotolerant and late phase patients (P<0.01). Using double immunohistochemical staining, both IFN- and cytoplasmic HBcAg were frequently detected near inflammatory infiltrates but no correlation existed between the hepatic expression of HBsAg and IFN-. These data indicate that IFN- is expressed in the liver in HBV-related active liver diseases and that the reported suboptimal production of IFN- by PBMC in HBV-related chronic active liver diseases may be due to a redistribution of the IFN--producing mononuclear cells into the liver, the site of inflammation.     

Hepatic lipase: Friend or foe and under what circumstances?

Hepatic lipase (HL) plays a role in the metabolism of chylomicron and very low-density lipoprotein remnants, low-density lipoproteins (LDL), and high-density lipoproteins (HDL), which are all implicated in atherosclerosis. Considering the effects of HL on these lipoproteins, it appears that HL has pro- as well as antiatherogenic potential. In line with clinical observations, most effects of HL on lipoprotein metabolism during hypertriglyceridemia may be interpreted as promoting atherosclerosis (formation of small, dense LDL, lowering of HDL levels), whereas most effects during hypercholesterolemia seem to be potentially antiatherogenic (stimulation of reverse cholesterol transport, clearing of intermediate-density lipoprotein). The potential modulation of pro- or antiatherogenics effect of HL by other factors, such as LDL receptor, cholesterol ester transfer protein, lipoprotein lipase, and ATP-binding cassette A-1 activity, is discussed.