New approach could reverse liver failure

Liver Disease Survivors Guide

Renowned Health Specialist experienced in working with numerous people with liver disorders share with you and: Explains how the liver works and how liver disorders develop in Simple English without Medical Jargon. Shares the facts about cirrhosis of the liver. Explains complications and treatments in simple language. Talks about Nutrition in Liver Disease. Explains Alternative Treatments available. Talks about the latest research developments in liver disease treatment. Shares resources for Liver disease forums and help-lines. Gives you the true in-depth stories from survivors and how they coped with the challenges of liver disorder. Shares touching stories of family members who had to cope with their loved ones suffering from cirrhosis of the liver, and the strategies they used to cope with them. With Liver Disease Survivors Guide, you will discover : Credible information on Liver disease obtained from detailed interviews with specialist doctors, explained in simple language. Healthy steps in dealing with liver disorders. What to do and what not to do while learning to adapt to the liver disorder. Remarkable stories in patients own words. It gives you a real emotional experience of a person with serious liver disorder and how they view the world. Latest research on liver disorders. Best resources and direct links to forums. Direct links to get professional help and identify the best experts in your area. Alternative treatments and therapies available for liver disorders. No medical jargon or difficult language, the book is written in simple and easy to understand language.

Liver Disease Survivors Guide Summary


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Describe the changes in the cardiovascular system in patients with cirrhosis

As liver disease progresses, most patients develop a hyperdynamic circulatory state, characterized by a fall in total peripheral resistance and a compensatory rise in cardiac output. The circulating plasma volume increases in response to vasodilation, and peripheral blood flow is enhanced. Although total body volume is increased, cirrhotic patients possess decreased effective arterial blood volume. The AV oxygen gradient narrows as a result of increased peripheral shunting. Consequently the mixed venous oxygen saturation of blood is higher than normal. The response to vasopressors is decreased with cirrhosis.

What are the gastrointestinal and hematologic derangements that occur with cirrhosis

G Il complications result from portal hypertension ( 10 mm Hg). Portal hypertension leads to the development of portosystemic venous collaterals, including esophagogastric varices. Ruptured varices with hemorrhage account for one third of the mortality in patients with cirrhosis.

What is cirrhosis

Cirrhosis, the most serious sequelae of chronic hepatitis, is characterized by diffuse death of liver cells, causing fibrous tissue formation and nodular regeneration of hepatic tissue. The consequent distortion of the hepatic circulation further propagates cellular damage and results in a progressive reduction of liver cells, which eventually manifests as impairment of liver function. Hepatic synthetic failure, indicated by a prolonged prothrombin time (PT) international normalized ratio (INR), decrease in serum albumin levels, and impairment of detoxification mechanisms resulting in encephalopathy, is often termed end-stage liver disease (ESLD).

Disease Mapping Modern Developments

Oesophageal cancer three times higher than the rates in their neighbouring districts. The remarkable similarity between the maps showing male mortality from this cancer and those from cirrhosis of the liver led to the hypothesis that some form of alcohol might be causing the oesophageal cancer. The French produce a prodigious variety of alcohol wine in many parts of the country cider in the west beer in the north and east and spirits in the departments of the Nord and Paris. Analysis of the quantities of alcohol consumed by the residents of the various regions of France showed marked variations, with males in Brittany and Normandy having particularly high intakes of alcohol.27 A unique feature of this area of France is the widespread growing of apples and the production of a spirit called calvados, which is made from these apples. Traditionally, farmers were allowed to produce homemade calvados from private stills. In I960 however, a law was passed limiting the amount of calvados...

Artificial cells containing cells

Survival of acute liver failure rats (Wong and Chang 1986) lowers the high bilirubin level in congenital Gunn rats (Bruni and Chang, 1989) and prevents xenograft rejection (Wong and Chang, 1988). We developed a two-step cell encapsulation method to improve the APA method, resulting in improved survival of implanted cells (Wong and Chang, 1991a). Cell bioencapsulation for cell therapy has been extensively developed by many other groups especially using artificial cells containing endocrine tissues, hepatocytes, genetically-engineered cells and stem cells (Orive etal., 2002 Chang, 2005). This is a very broad area that will be described in much more detail in the later chapters. Below is a brief introduction to the use of this principle for stem cells and genetically-engineered cells.

Artificial Cells Containing Bioadsorbents

For the removal of other uremic wastes need to be developed. The approach has also proved to be effective in removing toxic molecules in patients with severe liver failure, resulting in the recovery of consciousness of grade4 hepatic coma patients (Chang, 1972b, 1975g Gazzard etal., 1974). Detoxification is only one of the functions of the liver, and this approach is being used as the detoxification component of hybrid liver support systems that are being developed (Liu et al., 2001).

Plasma Adiponectin Levels and Chronic Liver Diseases

In contrast to NAFLD and NASH, plasma levels of adiponectin are significantly elevated in patients with liver fibrosis and cirrhosis (97,98). This increase is thought to reflect one of the body's compensatory responses against these diseases, although it is unclear whether the mechanism by which this occurs involves enhanced adiponectin expression or decreased protein clearance.

Alcohol And The Cardiovascular System

Ethanol has long been recognized as a toxic agent affecting different organ functions both acutely and chronically 6 , A prospective study of middle-aged Swedish males registered for alcohol addiction revealed a two-fold greater increase in the incidence of clinical cardiac events than for liver cirrhosis 7 , Several factors may be responsible for the deleterious effects of alcohol on the myocardium, including (i) a direct toxic effect of ethanol or its metabolites (ii) associated nutritional deficiencies (i.e., thiamine) or (iii) direct toxicity of additives in the alcoholic beverage (i.e., lead or cobalt) 8 ,

Serological Diagnosis of CD

Caution should be exercised when patients with liver diseases are tested for antibodies against tTG. Increased levels of tTG antibodies in liver disease (especially primary biliary cirrhosis) often lead to false positive values for antibodies against tTG in ELISA. This phenomenon has been attributed to hepatic (over)expression of tTG 140 . Furthermore, the presence of high levels of immunoglobulins in these patients can additionally interfere with ELISA quantitation 141,142 . Increased small bowel permeability in cirrhotic patients 143, 144 may also contribute to alteration in immune response to endogenous tTG 141 . In these patients, the diagnosis of CD may not be confirmed by intestinal biopsy 140, 145, 146 . Interestingly, these patients are usually negative if autoantibodies are determined by immunofluorescent assay 140, 141, 145, 146 . False positive results in cirrhotic patients cannot be overcome by use of the human recombinant tTG. It should be noted that purified tTG antigen...

Surgical and Angiographic Shunts

TIPS has gained favor over the surgical shunts because it can be offered to patients with decompensated cirrhosis (Childs-Pugh Class C). Moreover, TIPS is viewed as a bridge to transplantation because it does not alter the vascular anatomy in patients who are candidates for liver transplantation. Authors at one center compared transplantation outcomes in a series of 20 patients, 7 of whom underwent TIPS prior to transplant. The other 13 had no shunt procedure. There was a trend toward better survival and lower transfusion requirement among TIPS recipients (25). In a larger series of 200 patients who received TIPS, 30-day mortality was 26 with a median follow-up of 40 months the overall rebleeding rate was 25.5 (26). However, other studies have refuted any benefit from prophylactic TIPS before liver transplantation.

In vitro and in vivo assays

To profile compound activity on CFTR-mediated Cl transport and epithelial cell function in a physiologically relevant disease model, cultured human bronchial epithelial (HBE) cells derived from CF patients carrying different mutant CFTR forms can be used. Cultured HBE exhibit several of the morphological and functional defects in airway epithelial believed to contribute to the development of CF lung disease. These include the loss of CFTR-mediated Cl and fluid secretion, excessive ENaC-mediated Na+ and fluid absorption, and decreased cilia beating secondary to decreased surface fluid 4-6,40,41 . In addition to cultured HBE, in vivo mouse models have been developed by targeted mutations in the CFTR gene. However, the use of these models in the development of CFTR modulators for the treatment of CF is limited because they lack the manifestations typically found in humans with CF, including airway and pancreatic disease 42,43 . In addition, some CFTR modulators have been shown to lack...

Complications And Other Issues

In patients with cirrhosis, ascites, and portal hypertensive bleeding, there is a high incidence of spontaneous bacterial peritonitis. It is unclear whether one is pathophysiologically linked to the other, but infection of ascitic fluid and a systemic inflammatory response may cause significant morbidity even when acute bleeding has been controlled. The postulated mechanisms include enteric bacterial translocation and reduced complement activity and opsonizing activity in ascitic fluid. It is advised that all patients with ascites receive a diagnostic paracentesis for cell count with differential and culture and sensitivity. When a diagnostic tap is not possible, empiric antibiotic therapy with a third-generation cephalosporin, such as cefotaxime, is suggested until the patient's condition allows sampling of the peritoneal fluid.

Laboratory Diagnosis

In acute infection, serum sample(s) are examined for the presence of specific IgM using an indirect or IgM capture ELISA. If an indirect ELISA is used, measures should be taken to avoid interference by rheumatoid factor (absorption of IgG). The IgM (anti- capture method is generally considered to be the most specific one. IgM antibodies can be demonstrated a few days after appearance of rash and persist for about 3 months. Also IgG (anti-E1) antibodies appear early and usually persist for life. Occasionally a positive IgM test is seen in infectious mononucleosis (if the capture assay is used, preabsorption of heterophile antibodies by sheep red cells can be attempted), in autoimmune chronic active hepatitis type 1 and in parvovirus B19 infection. A positive IgM test is also seen in some cases of reinfection. In early pregnancy it is of crucial importance to exclude causes of a positive IgM test other than a primary rubella infection. An IgG...

SSAOVAP1 and other diseases

In addition to the presence of SSAO VAP-1 on endothelial cells, it is highly expressed in adipocytes (1 of total membrane proteins) where it has been suggested to play a role in glucose transport independent of the presence of insulin. Addition of benzylamine enhanced the glucose uptake in adipocytes which could be inhibited by semicarbazide. It is hypothesized that the production of hydrogen peroxide causes the recruitment of glucose transporter 4 (GLUT-4) to the cell surface which accommodates the increased glucose uptake in these cells 49,50 . It was noted that levels of plasma SSAO VAP-1 are increased in patients suffering from diabetes 10 , a disease in which insulin secretion or insulin-dependent glucose uptake in cells is compromised. In addition, elevated levels of plasma SSAO VAP-1 have been found in patients suffering from congestive heart failure and liver cirrhosis 10 , even though the role of plasma SSAO VAP-1 in physiology and or pathophysiology remains to be resolved.

Hepatitisassociated antigen See Australia antigen

Anti-HBs does not usually appear until convalescence. HBcAg does not appear in the blood. Anti-HBc appears during the disease and, unlike anti-HBs, persists for years and is a valuable marker of previous infection. HBeAg appears during the incubation period but disappears more rapidly than HBsAg. Persistence beyond 3-4 weeks may herald a chronic infection, which carries risk of hepatic cirrhosis or hepatocellular carcinoma. Not all chronic carriers of Hepatitis B virus develop chronic liver disease. A few infections result in acute hepatic failure probably due to an antigen-antibody reaction. Immune serum globulin (ISG) and hyperimmune globulin (HIG) are effective in providing passive immunity. A plasma-derived vaccine consisting of HBsAg is effective and widely used, especially in developing countries. This has been replaced in most other countries by genetically engineered vaccines derived from HBsAg produced in yeast (Recombivax, Engerovax), which...

HCV Genotyping by Nucleotide Sequencing

There are nearly 4 million persons infected with HCV in the United States, and it is estimated that 30,000 acute new infections will occur annually. Progression to chronic disease occurs in approximately 85 of individuals. Chronic HCV infection is known to progress to cirrhosis and hepatocellular carcinoma. Interferon alfa and ribavirin are used to treat this infecion. HCV genotyping is recommended after diagnosis of HCV. HCV is classified on the basis of the similarity of nucleotide sequence into major genetic groups designated genotypes. Recent studies have shown that HCV viral genotyping may be able to help in selecting therapeutic regimen and outcome of therapy. The reference standard and most definitive method for HCV genotyping is sequencing of a specific PCR-amplified portion of the HCV genome obtained from the patient, followed by phylogenetic analysis. Although all these methods are able to identify correctly the major genotypic groups, only direct nucleotide sequencing is...

Gastroesophageal Varices

Gastroesophageal varices are the most significant acute complication of portal hypertension. In the United States, cirrhosis secondary to alcohol overuse and viral hepatitis are the leading causes of portal hypertension and varices. Approximately 50 of cirrhotic patients have varices and are at risk for hemorrhage. Depending on the patient population, bleeding from gastroesophageal varices represents the second or third most common cause of acute upper GI bleeding in most series. Variceal bleeding is often massive, and the overall mortality approaches 30 (13). In addition, variceal bleeding often recurs after an initial controlled episode up to 70 of untreated patients rebleed within 1 year. The management of patients with varices is complicated by the underlying liver dysfunction associated with cirrhosis, including coagulo-pathy that may contribute significantly to hemorrhage. Treatment of patients with bleeding gastroesophageal varices requires control of the initial hemorrhage and...

Malloryweiss Syndrome

It is a common cause of upper GI bleeding accounting for approximately 5 of cases. In more than 90 of cases, the bleeding stops spontaneously (23). As with other causes of upper GI bleeding, the initial management is resuscitation followed by upper endoscopy. At the time of endoscopy, fewer than 25 of patients are actively bleeding, and endoscopic hemostasis is successful in 90 of cases (24). In noncirrhotic patients who fail endoscopic therapy and have evidence of ongoing bleeding, surgery is indicated for bleeding control. The procedure of choice is a gastrotomy with oversewing of the bleeding tears, a procedure that is very successful at controlling bleeding. Rebleeding is rare in the absence of cirrhosis. In cirrhotic patients, the appropriate management is directed at treating their portal hypertension, and the mortality rate is significant.

Indications For Liver Resection

The most common reason tumors are removed from the liver is to attempt a cure for a patient with a malignant neoplasm. Primary hepatocellular cancer, or hepatoma, is the most common malignant solid tumor worldwide. However, it is much less common in the United States. Here, the most common malignant neoplasms of the liver are metastatic deposits from lung, breast, and gastrointestinal (GI) primary sites. Some of these patients can be cured by removing the metastases from the liver. However, they are a highly selected group who have a small number of isolated colorectal or neuroendocrine metastases in the liver. Patients with metastatic lung, pancreatic, breast or gastric cancer are not reliably salvaged by resectional or ablative strategies for the liver metastases. Similarly, a minority of patients with hepatoma can be cured by resection and or ablation because these tumors tend to present at a late stage or in a cirrhotic liver that will not tolerate a resection. Nevertheless, there...

Artificial cells containing hepatocytes

The most promising use of artificial cell encapsulated hepatocytes is for short-term bridging in acute liver failure, as a liver support to allow the patient's own liver to regenerate and carry out its function. This will be described in the next chapter under regenerative medicine. However, this approach will probably have to be combined with hemoperfusion to first remove the large amount of toxins and products released by the breakdown of the acutely damaged liver. Hemoperfusion has already been successfully used for removing these materials in fulminant hepatic failure, resulting in the recovery of consciousness of patients from hepatic coma (Chang, 1972a Gazzard et al., 1974). It is only after the removal of hepatic toxins that the implanted artificial cell encapsulated hepatocytes can carry out their

Complications Of Biliaryenteric Anatomosis

Later complications of these operations revolve around progression of the disease that precipitated the need for the original operation (e.g., pancreatic cancer), complications associated with any upper abdominal operation (e.g., wound pains, hernias, adhesive bowel obstructions), and stricture of the biliary enteric anastomosis. Stricture of these anastomoses generally leads to episodes of cholangitis, and even frank obstructive jaundice. In repetitive and neglected cases this can progress to cirrhosis and portal hypertension a development that greatly complicates subsequent therapeutic maneuvers. Although early problems with the anastomosis can presage later failure, recurrence of a benign stricture may take 10 yr to develop (6). So these patients must be followed with periodic checks of their liver function tests (particularly alkaline phosphatase) for years. Whether prolonged perioperative stenting of biliary-enteric anastomoses decreases the chance of later stricture formation is...

Artificial Cells Containing Stem Cells

Increased viability of the hepatocytes both in vitro and in vivo (Liu and Chang, 2000, 2002). This has also a significantly longer effect on lowering of the high systemic bilirubin levels in congenital Gunn rats (Liu and Chang, 2003). The exact reason for this effect has to be further investigated. However, it is known that bone marrow stems cells in the presence of hepatocytes can differentiate into hepatocytes (Alison et al., 2000). Furthermore, it has been proposed that bone marrow stem cells secrete a factor that can help maintain the viability of the coencapsulated hepatocytes (Liu and Chang, 2000,2006b). Even more recently we studied the use of artificial cells containing only bone marrow stems and no hepatocytes (Liu and Chang, 2005, 2006a, 2006c). In hepatectomized rats with 90 of their liver resected, one intraperitoneal injection of these artificial cells resulted in recovery of the animal and regeneration of the liver (Liu and Chang, 2005, 2006a, 2006c). However, in the...


As aforementioned, cirrhosis is a relative contraindication to cholecystectomy because bleeding from the diseased liver parenchyma as the gallbladder is dissected can be difficult to control. This bleeding problem is compounded by portal venous hypertension and coagulation abnormalities from reduced liver synthetic function. In the event that bleeding from the gallbladder fossa cannot be satisfactorily controlled, the only option may be to decrease portal hypertension with a portal-systemic shunt of some sort (usually a TIPS).

IFNBased Treatment of Hepatitis B Virus Infection

HBV-infected patients can be subdivided into two groups according to the presence or absence of circulating hepatitis B e (HBe) antigen (Ag). HBeAg-negative patients do not produce HBeAg because the infecting virus harbors precore and or core promoter nucleotide substitutions (Carman et al. 1989). They generally have lower, fluctuating HBV DNA levels and a more severe course of disease. Chronic HBV infection currently is not curable, because covalently closed circular DNA (cc-cDNA) persists in the hepatocyte nucleus. Antiviral treatment of chronic hepatitis B has a triple aim (1) to slow the progression of fibrosis to cirrhosis (2) to prevent hepatic failure and (3) to prevent hepatocellular carcinoma. Profound and sustained inhibition of HBV replication is necessary if these goals are to be achieved. Treatment can consist of short-term therapy, generally with IFN-a, or long-term (possibly life-long) therapy with specific nucleoside nucleotide analogue inhibitors of HBV replication....

Artificial cells and regenerative medicine

Liver failure severe enough to be not compatible with life. This can be caused by acute hepatitis, massive traumatic injury or extensive cancer resection. Liver has the ability to regenerate itself to its original size if the patients can survive for a sufficient length of time under suitable conditions. Lower. We studied the use artificial cells with 3 different contents for liver regeneration. (1) hepatocytes (2) hepatocytes plus bone marrow stem cells or (3) bone marrow stem cells alone. Fig. 9.1. Upper. Liver failure severe enough to be not compatible with life. This can be caused by acute hepatitis, massive traumatic injury or extensive cancer resection. Liver has the ability to regenerate itself to its original size if the patients can survive for a sufficient length of time under suitable conditions. Lower. We studied the use artificial cells with 3 different contents for liver regeneration. (1) hepatocytes (2) hepatocytes plus bone marrow stem cells or (3)...

Galactosamineinduced fulminant hepatic failure in rats

This is a preliminary feasibility study (Wong and Chang, 1986). Hepatocytes from 125-135 g Wistar rats were isolated and enclosed in alginate-polylysine-alginate artificial cells as described under Methods in Appendix II. Intraperitoneal injection of galactosamine (140mg 100g body weight) resulted in acute liver failure in the Wistar rats of 275-285 g. Forty-eight hours after the galactosamine injection, the rats in grade II coma were separated into pairs. One rat in each pair was randomly selected as control and the other for treatment. A total of 14 rats were used. In the control group, 4 ml of alginate artificial cells containing no hepatocytes was injected intraperitoneally. In the treated group, 4 ml of alginate artificial cells containing hepatocytes were similarly injected. Each 300 micron diameter artificial cell contained 120 20S.D. hepatocytes. The total number of artificial cells was about 62,000 in the 4 ml of artificial cells injected. Thus, each injection consists of...

Mycotoxin Production by Species in Section Flavi

Aspergillus flavus and A. parasiticus are the most important toxin-producing species in the A. flavus group. While both of these species can accumulate myc-otoxins in food products, the types of toxins they produce are somewhat different. The majority of A. flavus isolates produce aflatoxins B1 and B2 and cyclopiazonic acid (CPA), although some strains have been identified that will also produce G1 and G2 aflatoxins.2627 In contrast, A. parasiticus produces all four of the above aflatoxins, but does not make CPA. All of these mycotoxins are potentially dangerous if consumed by humans. Aflatoxins B1 and B2 have been described as carcinogenic, teratogenic, and immunosuppressive and have been linked to cirrhosis and acute liver damage. The aflatoxins G1 and G2 have similar effects, and the toxicity of aflatoxin G1 is ranked just under that of B1.28 Dairy products from animals fed aflatoxin-contaminated feed may contain the M1 and M2 forms of aflatoxin. CPA also has been detected in...

Substrate Utilization Defects

A multienzyme complex that participates in the p-oxidation of fatty acids and has 3-hydroxyacyl-CoA dehydrogenase, enoyl-CoA hydratase, and 3-ketoacyl-CoA thiolase activities provides another example of a nuclear-encoded mitochondrial disorder. This trifunctional protein (TP) has four a (HADHA) and four p (HADHB) subunits. The 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase active sites are part of the HADHA cluster, and the four HADHB subunits constitute the 3-ketoacyl-CoA thio-lase domain. The clinical features of TP deficiency are sudden infant death, coma, low blood sugar, liver failure, degeneration of skeletal muscles, and cardiomyopathy. Most mutations in the HADHA and HADHB genes, which are both located at chromosome 2p23, cause loss of the entire TP complex, whereas with some HADHA gene mutations only the 3-hydroxyacyl-CoA dehydrogenase activity is abolished. Interestingly, the phenotype is the same whether the loss of TP activity is partial or complete.

Nonalcoholic Fatty Liver Disease

Several studies have documented that obesity per se is a risk factor for liver diseases, including steatosis, steatohepatitis, fibrosis, and cirrhosis. The hepatic alterations described in obesity and morbid obesity are included in the spectrum of lesions considered in the clinicopathological entity called nonalcoholic fatty liver disease (NAFLD). NAFLD is characterized by steatosis-associated hepatic injury that affects individuals who consume little or no alcohol and in whom other causes of liver disease can be excluded. The histological patterns of NAFLD are steatosis alone, nonalcoholic steato-hepatitis (NASH) in which, in addition to steatosis, lobular necroinflammatory alterations are observed and fibrosis, which can progress to cirrhosis (72).

Cytokine Measurements in Disease

Plasma measurement of TNF has been overshadowed by the finding of massively high levels of this cytokine in both patients and animals with bacteremia and endotoxemia (see later). In experimental animals sterile inflammation induces increases in IL-1 but not in TNF (M41). Surgery causes an increase in IL-6, with TNF rising only after significant hemorrhage in mice (A19). In humans, similar studies suggest that trauma in the absence of bacterial infection is not a significant stimulus to TNF production (P21). Inflammation does, however, appear to be a stimulus. Maury (M13) showed raised plasma levels in RA, myocardial infarction, and HIV infection. The highest levels were seen in myocardial infarction, but in most cases the correlation with C-reactive protein was poor. Significant elevations of TNFa and IL-1 a but not of IL-6 have been reported in alcoholic cirrhosis and acute alcoholic hepatitis (B43, F12). Not surprisingly RA, a disease strongly associated with an acute phase...

Positive Stranded RNA Viruses

HCV infection is a major global problem, with estimates of over 100 million individuals persistently infected, and an estimated * 350,000 deaths annually due to cirrhosis and heptacellular carcinoma (Perez et al. 2006). The treatment for chronic hepatitis infection is a combination therapy of pegylated type I IFN-a and ribavirin. Among the IFN inducible genes is ADAR1 p150. The site of HCV replication is the cytoplasm, and ADAR1 p150 localizes in part to the cytoplasm. Retrospective analysis of chronic hepatitis C virus-infected patients for responsiveness to treatment with IFN and ribavirin has revealed that patient genotype, in addition to the HCV virus genotype, viral load, and cirrhosis status are important factors in determining therapy responsiveness (Hwang et al. 2006 Welzel et al. 2009). And, ADAR1 is among the genes identified that associated with the responsiveness trait when DNA polymorphisms of responders and nonresponders of Taiwanese (Hwang et al. 2006) and European...

Possible mechanisms responsible for recovery of 90 hepatectomized rat model

(2) Another possible mechanism involves the hepatic growth factors (HGFs) an important factor in liver regeneration (Rokstad et al., 2002) as well as in stimulation of the transdifferentiation of BMCs into hepatocytes (Spangrude et al., 1988). The level of HGF increases in acute or chronic liver failure (Uchida and Weissman, 1992). As discussed earlier, there are two subgroups of HGF, one being of higher molecular weight of 100,000 and the other of smaller molecular weight of 64,000 (Ito and Chang, 1992). Our earlier study showed that HGF of 100,000 m.w. secreted by hepatocytes were retained and they accumulated in the artificial cells, thus helping to increase the regeneration of hepatocytes in the artificial cells (Kashani and Chang, 1988). The smaller molecule weight HGF of

Artificial Cells Containing Stem Cells in Regeneration Medicine

It would appear from the above study that implantation of artificial cells containing bone marrow stem cells results in the regeneration of the 90 hepatectomized liver and the survival of the animal. This is as effective as the injection of free hepatocytes or artificial cells containing hepatocytes. It is likely that hepatic growth factor HGF plays an important initial role followed by transdifferentiation into hepatocytes. These observations could stimulate further investigation of the potential for an alternative to hepatocytes transplantation for the treatment of acute liver failure or extensive liver resection. The use of artificial cells containing stem cells could also be investigated in other areas of regenerative medicine.

Ancha Baranova and Zobair M Younossi

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of clinicopathological conditions characterized by significant lipid deposition in the liver parenchyma of patients who do not consume excessive amounts of alcohol (1,2). At one end of the NAFLD spectrum is steatosis alone ( simple steatosis ), and at the other end are non-alcoholic steatohepatitis (NASH), NASH-related cirrhosis, and hepatocellular carcinoma. The distinction between steatosis alone and NASH can be made only by liver biopsy. NASH is characterized by hepatic steatosis and by evidence for hepatocyte ballooning degeneration, lobular inflammation, and occasionally, Mallory hyaline or sinusoidal fibrosis (3). NASH and steatosis alone have differential risk for progression (3).

Adipokines in Hepatic Fibrosis

Recent experiments provide direct evidence of the involvement of TNF-a in fibrogenic responses. When double knockout mice lacking both TNF receptors (TNFRDKO mice) are fed methionine- and choline-deficient (MCD) diets, they develop less pronounced liver steatosis than their wild-type counterparts (127). Similar findings in TNFRp55 knockout mice indicate that even partial suppression of TNF-a signaling can alleviate hepatic fibrosis (128). It seems that TNF-a increases the recruitment of Kupffer cells that can, in turn, produce extra TNF-a and hasten fibrosis in either an autocrine or a paracrine manner. Both these processes can contribute to the development of NASH progression to cirrhosis.

First observation of recovery of consciousness in hepatic coma

A 50-year-old female was admitted with a history of alcohol abuse, onset of jaundice, fatigue, nausea, vomiting, and dark urine. There was no history of contact with hepatitis or of intravenous or intramuscular medication. On admission, she had spider nevi and ascites. The diagnosis was acute alcoholic hepatitis. Her condition deteriorated after admission and she became comatose and unresponsive. After remaining comatose for two days, her condition was considered as terminal and with the insistence of her relatives she was referred by her physician to me for possible hemoperfusion since nothing else could be done. One hour after hemoperfusion, she started to regain consciousness and began to recognize her relative and answer questions in sentences. Hemoperfusion was carried out for a total of 80 min. She remained conscious for about an hour after the end of the hemoperfusion, but lapsed into coma again. Three days later she was still comatose, and a second hemoperfusion was initiated....

Preoperative Evaluation And Preparation

The etiology of the portal hypertension should be determined because this has a direct impact on outcome. Patients with nonalcoholic cirrhosis (e.g., postnecrotic cirrhosis, primary biliary cirrhosis) and those with extrahepatic portal vein thrombosis or primary hepatic fibrosis do better, and have an improved survival after the DSRS than alcoholic cirrhotics (17,18). Because prognosis is directly related to liver functional reserve, the Child-Pugh class status should be assessed. Ideally, the nutritional status should be good, there should be no encephalopathy, the serum total bilirubin should be less than 2 mg dL, the serum albumin greater than 3 g dL, there should be no ascites and the prothrombin time should be no longer than 2 sec from the control. Ultrasound assessment of liver volume (between 1000 and 2500 mL) and a functional measurement of the liver reserve by means of the galactose elimination capacity (greater than 250 mg min) will further aid the selection of good-risk...

Acute Upper Gastrointestinal Hemorrhage

In the United States, more than 300,000 annual hospital admissions can be attributed to upper GI bleeding (9). Although bleeding will stop spontaneously in most cases, persistent or recurrent bleeding accounts for the associated 5-12 mortality rate (10,11). In patients who are older than 60 years and or have cirrhosis, the mortality rate increases dramatically (11).


Endoscopy should be performed prior to angiography, as 80-90 of massive upper GI bleeding can be controlled through endoscopic or conservative means (8). Search and destroy (total body) angiographic procedures should be avoided. Endoscopic findings, even when negative, can be used to direct angiography, limiting the amount of iodinated contrast used and increasing the sensitivity of the study (61). In patients with cirrhosis, it is important that endoscopy always precede angiogra-phy. Although secondary signs of portal hypertension can be seen on arterial portography (Fig. 2), acute variceal bleeding is rarely, if ever, demonstrated.

Alternative Procedure

Because of the lack of survival benefit and relatively high rate of associated complications, peritoneovenous shunting is not frequently used (4). A third option for the treatment of refractory ascites is the diminution of portal pressures via transjugular intrahepatic portosystemic shunting (TIPS) (3). Placed percutaneously by interventional radiologists as a shunt from the portal vein to the inferior vena cava (IVC), TIPS is replacing paracentesis and peritoneovenous shunting as the treatment of choice for refractory ascites in part because TIPS is the bridge to transplantation for most of these patients who have Child-Pugh Class C cirrhosis. TIPS has worked well because surgical portosystemic shunts are contraindicated in patients with ascites complications associated with the TIPS procedure (in addition to the local and technical ones). Associated complications include significant encephalopathy in 23-30 of patients and shunt occlusion (opposite complications related by virtue of...

Alcohol And The Immune System

Alterations of the immune system due to alcohol consumption have been a focus of multiple studies that have revealed impaired delayed-type hypersensitivity responses and ameliorated host defense against infections. Acute alcohol use has been associated with increased susceptibility to infections, posttrauma immunosuppression, and a decrease in antigen-specific T-cell proliferation response 13,16 , Malnutrition and cirrhosis are two of the conditions that develop with chronic ethanol consumption that affect the efficiency of the immune system to combat infections 11,12 , Ethanol influences the function of lymphocytes, monocytes and polymorphonuclear cells 13-15 ,

Endovascular Management Of Acute Gastrointestinal Hemorrhage

After the bleeding site has been identified, the medical team (internist, gastroenterologist, interventional radiologist, and surgeon) must decide on a treatment plan that will provide the safest and most effective solution. Depending on the suspected etiology of the bleed, the age and overall status of the patient, and the experience of the interventional radiologist, temporary or permanent transcatheter therapy may be offered. Transcatheter treatment consists of embolotherapy to occlude the arterial feeder supplying the hemorrhage or the infusion of a vaso-constrictive agent in an attempt to decrease the arterial flow and allow the patient's own coagulation process to seal the lesion. In patients with cirrhosis who are bleeding from gastroesophageal varices, the interventional radiologist can decrease elevated portal venous pressures by creating a transjugular intrahepatic portosystemic shunt (TIPS) between the portal and systemic venous systems.

Alcoholic Liver Disease Role Of Free Radicals

Other hand, compounds which inhibit cytochrome P4502E1 such as chlomethiazol or diallyl sulfide 90,91 , also inhibit lipid peroxidation, radical production and result in an improvement ofhepatic morphology. Obviously, the degree of induction of cytochrome P4502E1 is of predominant importance with respect to ALD. It is, therefore, concluded that the ROS produced by this pathway may be especially important. This induction is diet dependent and enhanced with unsaturated fatty acids such as corn oil and low carbohydrates. In addition, iron, an important compound in the production ofROS, plays a significant role. Iron supplementation increases liver disease and administration of an iron chelator decreases ALD. Although, the administration of vitamin E to rodents inhibits ALD to some extent, data in humans are not very encouraging. The approach of administering vitamin E together with selenium and zinc to patients with alcoholic cirrhosis did show an improvement in mortality, but the number...

Transdermal Absorption

Unfortunately, the skin can also be a route for absorption of poisons. These include toxic alkaloids from poison ivy and other plants metals such as mercury, arsenic, and lead and solvents such as carbon tetrachloride (dry cleaning fluid), acetone (nail polish remover), paint thinner, and pesticides. Some of these can cause brain damage, liver failure, or kidney failure, which is good reason for using protective gloves when handling such substances.

Alcohol and substance abuse

Acute alcohol use may cause esophagitis, gastritis, and pancreatitis. Chronic alcohol use leads to delayed gastric emptying and relaxation of the lower esophageal sphincter, increasing the risk of aspiration. The liver undergoes transient and reversible fatty infiltration during acute alcohol use. Although such changes resolve with abstinence and the cycle can repeat itself many times, prolonged alcohol exposure leads to chronic infiltration of fat, which overtime progresses to necrosis and fibrosis of liver tissue. The initial presentation of fatty liver is hepatomegaly. When necrosis, fibrosis, and cirrhosis become apparent, the liver regresses in size. Chronic severe consumption of alcohol leads to irreversible cirrhosis and alcohol-induced hepatitis. Hepatic synthetic function is also impaired. Production of albumin and coagulation factors II, V, VII, X, and XIII is decreased. Reduction of albumin results in lower intravascular oncotic pressure and may lead to tissue edema. A...

Alcoholic versus viral or idiopathic chronic dilated cardiomyopathy DCM

Another clue to the possibility that alcoholics may have a viral pathogenesis for their chronic DCM is a little-known experiment on viral myocarditis in mice. Morin et al. 41 administered Coxsackie B virus to 48 mice. One half received laboratory chow and alcohol and the other half received laboratory chow and sweetened water. At the end of 5 weeks, 80 of the alcohol group showed microscopic cardiac involvement. Only 30 of the non-alcohol group had cardiac lesions (p 0.02). The cardiac involvement in the mice that received the alcohol was not only more frequent but also more severe than in the non-alcohol group 4T . How the damage of a viral attack on the myocardium can be augmented by alcohol is unknown, although there are many possibilities. It has been suggested, for example, that it may be due to the loss of potassium and magnesium from the myocardium or the ability of alcohol to inhibit the active transport of cations across the cell membrane 27,42 , An analogy may be made with...

Hemoperfusion for removal of unwanted or toxic substances from blood under other conditions

Hemoperfusion has been an established routineclinical method for the treatment of patients with severe suicidal and accidental poisoning for many years. Its ability to remove unwanted or toxic substances from the blood also comes in useful in other clinical conditions. This includes its use in liver failure, kidney failure and use as an immunosorbent. In liver failure and kidney failure, hemoperfusion carries out only part of the functions of these organs, mainly in the removal of toxic or unwanted substances from the blood.

Toxic And Metabolic Parkinsonism

One condition in which MRI may suggest the correct diagnosis is manganese intoxication. This is manifested by hyperintensity in Tl-weighted images in the pallida, sometimes extending caudally to the substantia nigra. Manganese accumulates in the pallida in many conditions, including liver cirrhosis with portacaval shunt and hepatic encephalopathy (76,77), long-term parenteral nutrition (78), environmental exposure in miners or industrial workers (79), or in other less clear conditions (80). Therefore, demonstration of pallidal hyperintensities in Tl-weighted images should prompt investigations of blood manganese concentrations (Fig. 7).

Hepatitis Delta Virus

Hdv Virus Genome Map

Hepatitis delta virus (HDV) is an important human pathogen that causes potentially severe acute and chronic hepatitis. It requires simultaneous infection with hepatitis B virus (HBV). The helper function provided by HBV is the envelope protein, HBsAg, which is required for the assembly and release of HDV particles, as well as the ability of these particles to attach to and infect hepatocytes, the primary targets of infection. Compared with those infected with HBV alone, individuals infected with both HDV and HBV experience more severe liver disease, including cirrhosis, hepatocellular carcinoma and liver failure. Although HDV depends on HBV, current licensed anti-HBV pharmaceuticals are ineffective for treatment of this virus because HBsAg expression remains high enough to support continued propagation. Approximately 15 million individuals worldwide are chronically infected with HDV.

What is the significance of portal pulmonary hypertension How are these patients managed in the pretransplant period

In contrast to mosttransplant recipients, portal pulmonary hypertension (PPHTN) patients have an increased risk of death because of right ventricular failure in the peritransplantation period. Physicians are uncertain which PPHTN patients may undergo transplantation because there are no patient characteristics that clearly predict outcome. Patients with moderate to severe PPHTN should not be considered candidates until they undergo a trial of vasodilator therapy. The cause of pulmonary hypertension in liver failure patients is unknown, but the disease shares many similarities with primary pulmonary hypertension. Tissue hypoxia likely plays a role. The pulmonary circulation has increased vascular resistance that is transmitted back to the right heart and liver. The pulmonary vessels of patients with PPHTN are unable to accommodate increased blood flow during periods of aggressive blood transfusion and during the hyperdynamic postreperfusion phase, potentially resulting in acute right...

Types Of Hepatectomy Resections

Right Hepatectomy With Ehbte

Although 75 of a normal liver may be resected with a reasonable expectation that enough hepatic function will remain to support regeneration of the hepatic remnant, this percentage is significantly reduced when the liver parenchyma is diffusely diseased. A larger hepatic remnant will be necessary to support regeneration and reduce the risk of fulminant hepatic insufficiency. Typically, when more than 50 of the functional capacity of the liver is removed, the possibility of liver failure becomes a threat. For these reasons, judgments about the advisability of a major resection are based upon both estimates of the normalcy of the residual hepatic cell mass (e.g., no cirrhosis) as well as how much of the functioning tissue will remain after the resection. For example, a right trisegmentectomy may be done relatively safely for a large tumor that has replaced the right lobe and medial segment of the left lobe because most hepatic function will already have shifted to the left lateral...

Gastric Antral Vascular Ectasia

GAVE is an increasingly recognized cause of occult bleeding. This condition is most common in elderly women. Patients generally experience occult bleeding and have IDA that fails to respond to oral iron therapy. Although the cause is unknown, it is seen at higher frequency with autoimmune or connective tissue disorders and atrophic gastritis, hypergastrinemia, cirrhosis, or portal hypertension. The typical endoscopic

Longterm Complications Of Hepatic Resection

Still, the most common late problem encountered by patients who have undergone some form of hepatectomy is a recurrence of the disease that precipitated the need for the original hepatectomy. For example, approx 30 of equivalently selected patients who have undergone either hepatectomy or ablations for colorectal liver metastases will have the first recurrence of their tumor confined to the liver (21-23). Patients who have undergone a hepatectomy for hepatoma usually face not only the risk of recurrence of their tumor, but also the progression of cirrhosis and complications of portal hypertension. Nevertheless, the risk of tumor reappearance in the liver of patients with severely cirrhotic livers is very high (24). Many of these recurrences may really be new tumors arising in the damaged field, but their appearance within 5 yr of successful resection or ablation is unfortunately quite reliable and ultimately lethal.

Risk Factors For Candidemia

Because of the complications associated with candidemia, researchers have investigated potential risk factors, which could be used to develop and implement preventive measures or to identify high-risk patients who might benefit from prophylactic or empiric antifungal treatment. Classic risk factors, including host- and healthcare-related factors, for candidemia are well known (38-41). Host-related factors include malignancy with chemotherapy, solid organ transplantation, hematopoietic stem cell transplantation, human immunodeficiency virus (HIV) infection, neutropenia, end-stage renal disease (ESRD) requiring hemodialysis (HD), cirrhosis, and colonization with Candida species. Healthcare-related factors include abdominal surgery, use of central venous catheters (CVCs), exposure to broad-spectrum antibiotics, corticosteroid use, ICU stay, and use of total parenteral nutrition (TPN).

Relative contraindications

Pulmonary hypertension associated with cirrhosis occurs in approximately 8 of patients and is a cause of significant intraoperative morbidity and mortality. Many liver failure patients are hypoxemic secondary to atelectasis and hepatopulmonary syndrome. All potential transplant candidates should undergo a screening transthoracic echocardiogram to assess pulmonary arterial pressures, left ventricular function, and intrapulmonary shunting. If pulmonary arterial pressures are elevated or right ventricular function is decreased, a right heart catheterization may be indicated.

Key Points Perioperative Hepatic Dysfunction

The type and severity of liver disease should be determined. Patients with acute hepatitis or Child's type C (MELD 14) cirrhosis should have elective surgeries cancelled. A complete organ system review should be performed, specifically looking for encephalopathy, ascites, portal hypertension, and renal insufficiency. A complete laboratory evaluation should be performed, including transaminases, bilirubin, albumin, basic metabolic profile, complete blood count with platelets, and a coagulation profile. For major surgery, coagulopathy should be corrected to an INR 100 x 109, and fibrinogen to 100 mg dl. A thromboelastogram may be useful in guiding component therapy when correcting a preexisting coagulopathy. The induction agents propofol, etomidate, and ketamine possess a high hepatic extraction ratio and their pharmacokinetic profile is relatively unchanged in mild-to-moderate cirrhosis. With severe hypoalbuminemia, an exaggerated induction response can be seen with thiopental....

Disorders of the Gallbladder the Pancreas and the Liver

Cirrhosis Cirrhosis is a progressive liver disease that results from long-term damage to liver cells. The liver is continuously exposed to potential toxins, including drugs (over-the-counter, prescribed, or illegal) and alcohol all of which can damage liver cells over time. Eventually the tissue becomes scarred, which blocks the flow of blood through the liver, causing liver failure and portal hypertension (high blood pressure in the veins from the intestines and spleen to the liver). In the United States, cirrhosis is among the leading causes of death. Men are more than twice as likely as women to die of chronic liver disease and cirrhosis. Heavy alcohol consumption is the most common cause of cirrhosis. Other causes of the disease include viral hepatitis, hemochromatosis (excess iron in the body), Wilson's disease (excess copper in the body), cystic fibrosis, blocked bile ducts, and adverse drug reactions. Cirrhosis does not always cause symptoms and may be detected during a routine...

Viral infections of the liver viral hepatitis

Diseases of the liver hold a special place in many types of medicine, both because of the important physiological role of this organ and because all circulating blood and lymph pass through the liver frequently. A number of different and unrelated viruses target the liver these are collectively known as hepatitis viruses. All hepatitis viruses cause liver damage that can be devastating to the infected host. Liver failure due to hepatitis virus infections is a major reason for liver Hepatitis B virus infection can lead to acute disease with attendant liver failure or can be asymptomatic. In many cases, virus is completely cleared leading to full or partial recovery of liver function. Unfortunately, a large number of infected individuals go on to become asymptomatic chronic carriers of the virus. Indeed, chronic hepatitis B infections are a leading factor in certain human liver cancers (carcinomas) prevalent in Southeast Asia. A third form of the hepatitis B virus infection (fulminant...

Ascending Cholangitis Following Portoenterostomy

Extrahepatic biliary atresia is an obliterative cholangiopathy that involves all or part of the extrahepatic biliary tree and, in many instances, the intrahepatic bile ducts. In the U.S.A., from 400 to 600 new cases of biliary atresia are encountered annually (46). The diagnosis is usually suggested by the persistence of jaundice for six weeks or more after birth. Several factors have been considered for the pathogenesis of extrahepatic biliary atresia, including viral infection (e.g., cytomegalovirus) (47), metabolic insults, and abnormalities in bile duct morphogenesis. Although selected patients benefit from prompt diagnosis and Kasai portoenterostomy surgical intervention (48,49) within the first 60 days of life, many ultimately require liver transplantation because of portal hypertension, recurrent cholangitis, and cirrhosis (50).

Roux -en Y Bypass Surgery Indications

Another indication for biliary-enteric procedures is biliary atresia in infants. These infants may have only vestigal remnants of their biliary tree. The ideal situation for a biliary-enteric anastomosis is one in which the intrahepatic ducts are normal and only the extrahepatic ducts are atretic. When there are no obvious dilated intrahepatic ducts and the condition is recognized before liver failure and cirrhosis supervene, the infant may undergo a procedure called the Kasai portoenterostomy. This operation also involves reconstruction of the extrahepatic biliary tree with a Roux-Y limb up to the hepatic hilum where the intrahepatic ducts are supposed to be. The area where the atretic ducts are above the portal vein bifurcation is cored out with hepatic parenchyma, and the jejunum is sewn to the liver there in anticipation of bile drainage from microscopic bile ductules. Success depends upon performing this operation soon enough to avoid the complications of liver failure, and on...

Treatment of Chronic HCV Infection with IFNa

Ribavirin is administered at a dose of 0.8-1.2 g day, depending on body weight and the HCV genotype (2002). Higher doses may be necessary for heavy patients. The addition of ribavirin increased the SVR rate to 41 and 43 , respectively, compared to 16 and 19 with standard IFN-a2a and IFN-a2b monotherapy (McHutchison et al. 1998 Poynard et al. 1998). In the three main registration trials (randomized controlled studies involving patients without cirrhosis), pegylated IFN-a plus ribavirin gave global SVR rates of 54-56 , compared to 18-39 with pegylated IFN-a monotherapy (Fried et al. 2002 Hadziyannis et al. 2004 Manns et al. 2001). The SVR rates ranged from 76 to 84 in patients with HCV genotype 2 or 3 infection and from 42 to 52 in patients with HCV genotype 1 infection. Little information is available on patients with other genotypes, but the SVR rates in patients with HCV genotype 4 infection appear to be close to those in patients with genotype 1 infection. Pretreatment variables...

Clinical Course

Most virus infections are acute and self-limiting, leading to lifelong immunity. Fulminant and lethal cases are usually the result of organ damage (poliomyelitis, hepatitis, encephalitis). Some infections have a biphasic clinical course (western tick-borne encephalitis, epidemic myalgia). Some viruses cause long-term infections. The pattern may be one of latency followed by reactivation and clinical recurrence (e.g. herpesviruses). Alternatively, there may be a persistent replication of virus but it may take years before clinical disease manifests itself (e.g. retroviruses and AIDS, hepatitis viruses and cirrhosis).


A randomized, controlled clinical trial is the gold standard to reveal whether the beneficial effect of moderate alcohol intake is in fact due to this alcohol intake or results from some unknown confounding factor that no cohort study, however large, could discover. However, such a trial is unlikely to be performed to establish a direct link between alcohol consumption and health. Prospective observation of representative samples is the available method that comes closest to the ideal. A good start would be to design large cohort studies with the express aim of revealing the effects of alcohol intake on health. The studies presently available have not been designed primarily to this end. The problem of confounding, given the inter-correlation of many lifestyle practices and the imprecision with which they are measured, creates subtle and complex statistical challenges. Several guidelines for safe and sensible alcohol drinking have been suggested 60-62 , However, individual...


Excreted in urine darkening its color (choluric jaundice). Conjugated hyper-bilirubinemia is mainly due to (i) obstructive or cholestatic jaundice (e.g., stones and cancers), microobstruction of intrahepatic biliary ductules by swollen damaged hepatocytes (e.g., acute hepatitis and cirrhosis) (ii) Dubin-Johnson syndrome or chronic idiopathic jaundice (a genetic disease characterized by defective secretion of other conjugated compounds such as estrogens and sulfobromophethalein) and (iii) Rotor's syndrome (a benign, autosomal recessive disorder characterized by mild conjugated hyperbiliru-binemia with otherwise normal liver function tests) 13 .

V2 Receptor Agonists

Several V2 receptor antagonists, including tolvaptan 43, lixivaptan 44 and satavaptan 45, have entered clinical trials for the treatment of hyponatremia, liver cirrhosis, chronic heart failure and polycystic kidney disease and have been extensively reviewed elsewhere 5,33 .

Intrahepatic Causes

Chronic viral hepatitis Alcoholic liver disease Primary biliary cirrhosis Malignancy infection such as acute viral hepatitis may also raise vascular resistance sufficiently to cause portal hypertension in the absence of the systemic hemodynamic changes seen in cirrhosis. In primary biliary cirrhosis (PBC), bile duct inflammation and damage to adjacent portal venule can lead to increased vascular resistance before cirrhosis occurs (5). Refer to Table 1 for other intrahepatic causes of portal hypertension.


A patient with portal hypertensive bleeding from varices or mucosal congestion may present with hematemesis, melena, hematochezia, or any combination of the above. In the evaluation of a patient with GI bleeding, the following historical features should increase the physician's concern that portal hypertension may be present. A history of excessive alcohol intake or chronic viral hepatitis should be noted. Additionally, any history of chronic parenchymal liver disease or cholangiopathy such as autoimmune hepatitis, hemochromatosis, Wilson's disease, a1-antitrypsin deficiency, primary sclerosing cholangitis (PSC), or PBC raises concern that symptoms of bleeding may be caused by portal hypertension. A history of hypercoagulability or intraabdominal malignancy should prompt concern for vascular thrombosis or malignant infiltration with concomitant portal hypertension. Extrahepatic processes such as cardiac failure can lead through congestion to cardiac cirrhosis. Chronic pancreatitis...


Fas receptor engagement is involved in a broad spectrum of liver diseases where massive apoptosis, fibrosis, inflammation and secondary-necrosis occur that can lead to lethal fulminant hepatitis. Recently RNAi was used successfully to silence Fas and to protect mice from liver failure and fibrosis in two models of autoimmune hepatitis, one being chronic and the other fulminant (90). This data provides support for the therapeutic prospects of RNAi to prevent cytotoxic liver injury.

Hepatitis B Virus

The hepatitis B virus (HBV) is a highly infectious and often nonsymptomatic virus that is transmitted primarily through blood and blood-derived fluids and is a leading cause of liver infection worldwide. The World Health Organization (WHO) estimates that 2 billion people worldwide have been infected with HBV and 350,000,000 people are chronically infected. Chronic infection results in a high risk for liver cancer and cirrhosis of the liver, which cause about 1,000,000 deaths each year. Each year up to 200,000 people become newly infected in the United States alone. Since screening for HBV began in 1969, the rate of infection through blood transfusions has greatly decreased. However, as of 2000, HBV is still transmitted through blood transfusions in 1 out of 137,000 units of blood. One reason for this is that currently available blood screening technologies detect core antibodies or surface antigens, which appear up to 8 weeks after infection. Serologic tests for hepatitis B virus...

Hepatitis C Virus

The hepatitis C virus (HCV) is a member of the Flaviviridae family of viruses, which are associated with both human and animal diseases. Hepatitis caused by HCV is the most common chronic bloodborne infection in the United States. Over 4 million Americans are believed to be infected. HCV can also be transmitted through blood transfusion. HCV causes inflammation of the liver, and up to 80 of those exposed to the virus develop a chronic infection, which can lead to liver inflammation, cirrhosis, cancer, and death. Eventually, up to 20 of people with HCV may develop cirrhosis of the liver or other severe liver diseases. As in other forms of hepatitis, individuals may be infected with the virus but may not realize


As discussed elsewhere in this volume, quite a few epidemiological studies have examined the association between morbidity and mortality from CHD and moderate alcoholic beverage consumption, and an inverse association has been established in studies involving nearly a million subjects 29 , One example of such reports is a study of American Cancer Society volunteers, which showed that the rate of death from all cardiovascular diseases was 30-40 lower among men and women who consumed at least one alcoholic drink daily than among nondrinkers. While it should be emphasized that alcohol consumption is associated with higher death rates from injuries, violence, suicide, cirrhosis, certain cancers and hemorrhagic stroke 30 , the incidence of death from heart disease is much greater compared to these other causes, making any role of platelets potentially important.

Liver Cancer

Obesity, and especially visceral adiposity, is strongly associated with nonalcoholic fatty liver disease (NAFLD), a chronic liver disease that occurs in nondrinkers but that is histologically similar to alcohol-induced liver disease (159). NAFLD is an emerging clinical problem among obese patients and is now recognized as the most common cause of abnormal liver tests (160). Disorders of glucose regulation are significantly associated with NAFLD, indicating that insulin resistance is the link between NAFLD and metabolic diseases (160). NAFLD is characterized by a spectrum of liver tissue changes ranging from accumulation of fat in the liver to nonalcoholic steatohepatitis (NASH), cirrhosis, and HCC at the most extreme end of the spectrum. Progression to NASH appears to represent the turning point from a seemingly nonprogressive condition to fibrosis, necrosis, and inflammation, and multiple cellular adaptations to the resulting oxidative stress (159). Visceral adiposity likely...

Total Shunts

A side-to-side portacaval anastomosis that is greater than 12 mm in diameter also functions like a total shunt, and in addition, the hepatofugal flow in the portal vein allows decompression of the liver sinusoids, alleviating ascites. Large-diameter interposition grafts (12-22 mm) placed between the portal vein or superior mesenteric vein, and the inferior vena cava, left renal vein, or right atrium also behave like total shunts, as does the proximal splenorenal shunt devised by Linton (7). Whereas total shunts may be effective in controlling variceal hemorrhage and ascites, the high incidence of encephalopathy (30 -40 ) and progressive liver failure from diversion of hepatic portal flow has resulted in the loss of enthusiasm for performing these operations. Furthermore, any procedure that involves dissection of the liver hilum, such as a portacaval shunt, will complicate or even exclude the future possibility of liver transplantation, which is the definitive treatment for patients...

Partial Shunts

Realizing the importance of preservation of hepatic portal flow in order to reduce the incidence of encephalopathy, and liver failure, the concept of partial shunting was actively investigated. Partial shunts are nonselective, decompressing the portal hypertension just enough to reduce variceal hemorrhage but maintaining adequate prograde portal blood flow. Initial attempts at creating a small side-to-side portacaval anastomosis (less than 12 mm) were unsuccessful as these dilated with time, with loss of hepatopetal flow (8). It was not until Sarfeh et al. reported their results with the use of small-diameter (8-10 mm) polytetrafluoroethylene (PTFE) portacaval H-grafts that true partial shunting became established (9,10). A relationship between shunt diameter, direction of portal flow, and incidence of encephalopathy was confirmed (11). Other authors have successfully adapted the use of small-diameter PTFE grafts at the mesocaval level in

Alglucosidase Alfa

Arginine vasopressin is intimately involved in volume homeostasis, and elevated levels of arginine vasopressin are responsible for the pathogenesis and progression of diseases with an imbalance of sodium and water, particularly congestive heart failure. To restore homeostasis, antagonism of vasopressin receptors is a practical solution. As such, conivaptan has been developed and launched as a dual V1a and V2 vasopressin receptor antagonist. As a competitive, reversible inhibitor of both subtypes, conivaptan can modulate systemic vascular resistance through the V1a receptor (K 0.48 nM) distributed in vascular smooth muscle cells, cardiomyocytes, hepatocytes, and platelets and blocks the renal V2 receptor (K 3.04 nM) resulting in enhanced diuresis, thereby increasing serum sodium concentration and reducing total body volume. Currently, the drug is approved for the management of refractory hyponatremia and potentially life-threatening sodium and water imbalance, but it has shown promise...

The Ketek Scandal

The FDA undertook its own analysis of the voluntary database that tracks physicians' reports of adverse events for marketed drugs. Their own analysis of the risk of liver toxicity caused by Ketek as determined by data mining of the reporting system database suggested that the compound was associated with no more risk than other, older antibiotics or than Tylenol. Serious liver toxicity from Ketek was estimated to occur 1 in 100,000 to 1 in 200,000 courses of therapy. To put this in perspective, fatal allergic reactions from the penicillins occur with a frequency of 1 in 50,000 to 1 in 67,000 courses of therapy, and serious reactions occur as often as 1 in 7,000 courses of therapy. Amoxicillin-clavulanic acid (Augmentin) (a penicillin analog) is the biggest selling antibiotic in history with peak year sales of around 2B. Augmentin is now generic. It also causes more cases of serious liver toxicity than any antibiotic on the market including Ketek. But the penicillin drugs including...

Anorectal Varices

Anorectal varices are a result of portal hypertension and represent enlarged portal-systemic collaterals. They develop as a result of hepatofugal portal venous flow through the inferior mesenteric vein to the superior hemorrhoidal veins. An important distinction is that anorectal varices are not related to hemorrhoids, which are vascular cushions of ectatic venular-arteriolar connections of the hemorrhoidal plexus, and have no direct connection to the portal system. The prevalence of anorectal varices varies somewhat, ranging from 43 to 78 in patients with cirrhosis (103-105). Anorectal varices are usually discrete, serpentine, submucosal veins. In contrast to external hemorrhoids, varices are compressible and refill rapidly. They extend from the squamous portion of the anal canal and cross the dentate line into the rectum proper. Distinguishing hemorrhoids from varices is important because of the risk of severe, recurrent hemorrhage with varices and the different approach to therapy.


HBV (Table 51-11) is the prototype virus found in the Hepadnaviridae family hepa from hepatitis and dm from the genome type). Other mammalian and avian hepadnaviruses are known to exist. Disease in humans, transmitted via perinatal, sexual, and parenteral routes, is usually asymptomatic but may result in acute or chronic hepatitis with self-limited or fatal outcomes. Fatal disease is most likely to occur in people co-infected with hepatitis D virus (delta agent), a deficient RNA virus that replicates only in cells already infected with HBV. Chronic HBV infection is a significant worldwide cause of liver cirrhosis and hepatocellular carcinoma, despite the availability of an effective vaccine. Diagnosis is provided by the detection of a battery of antibodies and viral antigens. The best indication of active viral replication and a high state of infectivity is the presence of HBV DNA in the serum, which is detected by a number of molecular tests including PCR. Additionally,

Biological Evidences

Have been suggested to play a potential role in the antiatherogenic and cardioprotective effects of bilirubin (as schematically summarized in Table 1). Bilirubin has been considered a toxic by-product associated with the potentially fatal conditions of neonatal hyperbilirubinemias, acute hepatitis, and cirrhosis until the 1980s, when its antioxidant activity was first identified 29 . Afterward, several experimental studies, both in vitro and in vivo, confirmed that bilirubin acts as an effective antioxidant compound that efficiently scavenges peroxyl radicals and suppresses the oxidation of lipids and lipoproteins, especially low-density lipoprotein lipid (LDL-C) peroxidation, and might thereby counteract atherosclerotic plaque formation and its subsequent clinical complications. This antioxidant process involves an electron donation pathway, where bilirubin is reconverted to biliverdin, but biliverdin reductase quickly regenerates bilirubin, thereby greatly boosting its antioxidant...


GABHS is the major and S. aureus is a minor cause of the classic erysipelas. Streptococci other than group A were isolated in lower extremity cellulitis involved in post-saphenous venectomy (groups C, G, and B) (2) and in neonatal cellulitis. Cellulitis due to Streptococcus pneumoniae through bacteremic route were also described (21). Enterobacteriaceae and fungi (Cryptococcus neoformans) were recovered from cellulitis in the immunocompromised host. E. coli was recovered from children with nephrotic syndrome who developed cellulitis (22). Aeromonas hydrophila is recognized as a cause of cellulitis after laceration that occurred when swimming in fresh water and Vibrio spp. can infect wounds sustained in saltwater (23). Bacteremia and cellulitis due to Vibrio vulnificus may follow ingestion of raw oysters, especially in patients with alcoholic cirrhosis (24). P. aeruginosa is the major pathogen in bacteremia-associated cellulitis in the immunocompromised host.

Cohort Studies

Were usable for only 20 cases and 86 controls. Using logistic regression, with age and sex adjustment and a detection limit for albumin adducts of 0.01 pmol mg as the cutoff value, the OR for an association between the presence of AFB1-albumin adducts and HCC was 3.2 (13 cases 95 CI range, 1.1 to 8.9). When the statistical model also included several other covariates (HBsAg, anti-HCV, family history of liver cancer or cirrhosis), the OR for AFB1-albumin adducts rose to 5.5 (95 CI range, 1.2 to 2.5). Also, an extremely high risk was associated with positive HBsAg status (OR, 129 95 CI range, 25 to 659). The authors surmised that peanut contamination was a major source of AF in this population. A cohort study was carried out by Wang et al.47 in seven townships of Taiwan, China, including three on the Penghu Islets and four on Taiwan Island. Of the total population of 89,342 eligible subjects selected from local housing office records and mailed an invitation to a cancer screening...