Liver Cirrhosis Treatment Diet

Liver Tracker

This new program is designed to help you live with your liver disease, and make it easier to live with liver problems. If you join Liver Tracker, you have the ability to get a supportive community that helps you cope with your liver problems in an environment that will help with your liver issues. If you non-alcoholic liver disease, liver cirrhosis, Hepatitis A and B, or alcoholic fatty liver disease, you will be a fit for this community AND we can offer you the help that you need! You will also get healthy recipes that are created by dietitians; you never again have to wonder if it is safe to eat what you are eating! You will get progress tracking to check and see if you are meeting your health goals, and the direct help of a health team. You do not have to go through this alone; let us help you!

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Liver Cirrhosis Causes and Therapy

Cirrhosis is among the top 10 causes of death in the Western World. This is largely the result of alcohol abuse, viral hepatitis and biliary diseases 75 . The causes for cirrhosis can be roughly divided into six categories 4. Autoimmune diseases such as primary biliary cirrhosis (PBC), primary sclerosing cholan-gitis (PSC) and autoimmune hepatitis, 6. Cirrhosis of unknown causes. Obviously the best treatment for cirrhosis is removal of the injurious event. In the case of viral hepatitis, viral load can at least be temporarily reduced with anti-viral agents such as lamivudine, ribavirin and or IFNa 76 . Unfortunately, complete removal of the injurious event is frequently not possible. Moreover, by the time cirrhosis is diagnosed the fibrotic process has usually progressed beyond 'the point of no return' and removal of the injurious event will have little effect. Successful pharmacological treatment to reverse the fibrotic Penicillamine, an inhibitor of collagen crosslinking, was...

Liver Cirrhosis or Fibrosis

Manufacturing Process For Aleve

Liver cirrhosis is among the top 10 causes of death in the Western world. The disease occurs after chronic damage to hepatic cells, mainly hepatocytes, which can be caused by viral hepatitis, chronic alcohol abuse or toxic injury, biliary disease, and metabolic liver disorders 64 . Liver cirrhosis is characterized by an abnormal deposition of connective tissue in the liver, which hampers the normal functions of the liver. Other features of the disease are general tissue damage, chronic inflammation, and the conversion of normal liver architecture into structurally abnormal nodules. Secondary to these anatomical changes are disturbances in the liver function and in the hemodynamics leading to portal hypertension and intrahepatic shunting 39, 64, 103 . Cirrhosis results from the inability of the liver to restore liver homeostasis 39, 64, 104 . After a single damaging event or disturbance, the liver restores the normal situation by the production of cytokines, growth factors, and...

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).

Hepatic Inflammation and Fibrosis

Virtually any insult to the liver can cause hepatocyte destruction and parenchymal inflammation. If the insult is minor and occurs only once, local restoration mechanisms will suffice to repair the damage. If, however, the insult is major or persistent, an inflammatory response will be generated. This inflammation is the result of cytokine-mediated activation of sinusoidal cells, their subsequent release of pro-inflammatory cytokines and their expression of adhesion molecules for the recruitment of circulating leucocytes. Once the damage is under control and the inciting insult has been eliminated, the inflammatory process will end and local mechanisms will proceed until the damage is repaired. Usually little scar tissue will be detectable, because of extracellular matrix remodelling. During conditions of chronic liver injury, however, the repair process does lead to scar tissue formation, which is deposited within the liver until impairment of liver function occurs. This process is...

Drug Targeting to the Liver

With no effective drugs available and the unacceptable side-effect profile of those drugs which have been studied so far, liver cirrhosis might benefit from the targeting of drugs to cells within the liver. There are several ways to intervene in the fibrotic process. One way is the targeting of drugs to SECs and KCs to modulate their release of pro-inflammatory mediators. This may arrest the inflammatory process leading to cirrhosis. Another way is the delivery of drugs to HSCs to inhibit collagen production or to enhance their extracellular matrix degrading capabilities. This chapter will focus on targeting to KCs and SECs to influence the inflammatory process that is the basis of most forms of liver cirrhosis. As mentioned before these cells have a number of specific entry mechanisms that could be used for cell-specific delivery of drugs. By either enclosing drugs in particles or by coupling drugs to macro-molecular carriers with high affinity for certain uptake mechanisms, drugs...

Bifunctional Protein Deficiency

Loss of this enzyme activity is associated with the accumulation of C27 bile acid intermediates and pristanic acid, an enlarged liver, developmental defects, hypotonia, and seizures (193-195). Early studies ascribed the biochemical defect in these patients to the absence of the L-bifunctional protein (193) however, later studies showed that mutations in the structurally related D-bifunctional protein were the cause of this genetic disease (196-198). Some, but not all, patients manifest symptoms of liver failure although all show the associated neurological deficiencies (76). This presentation makes it difficult to determine whether the accumulation of bile acid intermediates or pristanic acid is the major contributor to the observed phenotype. An effective treatment for D-bifunctional protein deficiency is not reported.

Carriers with Intrinsic Antiinflammatory Activity

AP is a membrane-anchored protein, that can be shed into the general circulation, which was shown to be able to detoxify LPS in vivo through dephosphorylation 114 .This dephos-phorylating activity could be enhanced by increasing the negative charge of the enzyme through succinylation 115 . Using AP as a carrier for anti-inflammatory drugs to KCs, the main site of LPS uptake, it could intrinsically contribute to therapeutic efficacy in cirrhosis through detoxicification of LPS. The LPS-detoxifying activity of KCs in cirrhotic livers is impaired and consequently LPS may promote the fibrotic process 116 .

Peginterferon Alfa2a 40kd In Clinical Trials

Sustained virological responses and were often seen among patients who did not achieve a sustained virological response. The efficacy and an acceptable safety profile were also seen in the difficult-to-treat patient with hepatitis C (patients with cirrhosis and hepatitis C genotype 1 virus)25, 26.

Treatment of Hepatitis CAssociated Glomerular Disease

Summary Hepatitis C virus (HCV) infection can lead to chronic active hepatitis, cirrhosis (liver scarring), and liver failure however, it is also associated with a wide range of extrahepatic features. This article reviews the treatment of glomerular disease (kidney disease) associated with HCV infection. Renal manifestations include cryoglobulinemic membranoproliferative glomerulonephritis and membranous nephropathy. The authors caution that treatment of HCV with alpha interferon is only moderately effective and suffers from a high relapse rate. More recently, combination therapy with ribavirin has led to improved suppression of HCV RNA levels. Rapidly progressive renal disease or severe cryoglobulinemic vasculitis may respond to immunosuppression with steroid, cyclophosphamide, and plasmapheresis in the acute phase. After 2 to 4 months of immunosuppression, antiviral therapy (with alpha interferon and ribavirin) should be tried. Promising new therapies on the horizon include agents...

Role Of Pina In Pineal Physiology

To determine a role for PINA in the normal pineal physiology, we have turned to the LEC rat, a strain in which PINA and ATP7B are mutated as a result of a large deletion in the C-terminal coding region (12). These rats are well-established models of Wilson's disease in which copper builds up in the liver, resulting in liver failure and death (13).

RNA Editing of HTR2C in Mental Disorders Cellular and Animal Studies

RNA editing status of HTR2C could be changed in response to stress and drugs in cellular and animal models (Iwamoto et al. 2009). The adverse effects of interferons, which are clinically used for treatment of hepatitis, cirrhosis, and cancer, include depression (Schaefer et al. 2002). Among the three ADARs, expression of ADAR1 is induced by interferon. This resulted in the generation of the ADAR1 protein with higher molecular weight (150 kDa) than that produced from a constitutive promoter (110 kDa) (Fig. 8.1) (Patterson and Samuel 1995). Using glioblastoma cell lines, Yang et al. reported that interferon induced expression of 150 kDa ADAR1 and resulted in increased RNA editing at sites A, B, and C and decrease at site D (Yang et al. 2004). They suggested the involvement of RNA editing in the pathophysiology of depression caused by interferon treatment.

Vasoactive effects of prostanoids relation to hypertension

Functional studies in the 1970s and 1980s established vasodilating prostaglandins as local mediators counteracting vasoconstrictor effects of norepinephrine or a-adrenergic neural stimuli and most prominently the vasoconstrictor effects of angiotensin II (Fig. 7-3 reviewed in Walker and Frolich 3 and Levenson et al. 4 ). In experimental or pathophysiological states associated with enhanced vasoconstrictor influences, renal hemodynamics become dependent on prostaglandin synthesis. Examples are experiments where infusion of angiotensin II decreased renal blood flow and the glomerular filtration rate and this effect was enhanced when prostaglandin synthesis was inhibited by COX inhibitors such as indomethacin 3 . Furthermore, counter-regulatory actions of prostaglandins were also suggested by clinical studies showing that indomethacin impaired renal blood flow and the glomerular filtration rate in disease states such as liver cirrhosis with ascites, congestive heart failure or nephrotic...

Other Possible Genetic Copper Toxicosis Disorders

A group of similar childhood copper-toxicosis conditions have been described and are often associated with excess intake of copper in infancy. Indian childhood cirrhosis (ICC) is a fatal disease characterized by massive hepatic copper accumulation resulting from the consumption of milk containing high concentrations of copper. Since the practice of boiling milk in brass vessels has been discouraged, the disease is disappearing (75). There is a high rate of parental consanguinity in families affected with this disease and up to 22 of siblings are affected, suggesting a genetic basis (75). Clinically, ICC can be distinguished from Wilson's disease by the characteristic liver histology, early age of onset, normal ceruloplasmin and absence of neurological involvement (75). Similar infantile copper-associated toxicity cases have been reported, and a clear autosomal recessive inheritance has been reported for the disease in Austria (76). This disease is indistinguishable clinically from ICC...

Animal Models of Wilsons Disease and ICC

Two other animal models of copper toxicosis are of interest, normal sheep and a breed of dog, the Bedlington terrier. These animals accumulate hepatic copper and this phenotype may be the result of mutations of novel copper homeostasis genes, perhaps the orthologs of the gene that is involved in Austrian childhood cirrhosis. Sheep are prone to accumulate hepatic copper, because of a reduction in biliary copper excretion and, in this respect, sheep resemble patients with WD (4). The molecular basis of this phenotype is unclear however, sheep have two forms of ATP7B, one that closely resembles the protein in other mammals and an other that has a novel N-terminal extension of 79 amino acids (86). It is possible that this novel form may play a part in the hepatic copper accumulation phenotype.

Pharmacology and pharmaceutics

Other applications NovoSeven may be effective for acute bleeding or hemosta-sis during surgery. In one study NovoSeven reversed the effects of the oral anticoagulant acenocoumarol on the prothrombin time and International Normalized Ratio (INR) in healthy volunteers, without evidence of systemic coagulation. It may also transiently correct elevated prothrombin time in patients with cirrhosis-induced coagulopathy.

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

Bioactivation screening

Liver injuries induced by drugs now constitute the major causes of acute liver failure. If liver transplant is not possible, deaths result. Liver injury is also the leading reason ( 50 )66,67 that drugs are withdrawn from the market. Alternatively, their use is restricted and special monitoring of patients is required. Bioactivation of a drug to electrophiles and free radicals and subsequent covalent binding of the drug to proteins and nucleic acids68,69 is one mechanism that produces liver injuries. However, drugs possessing functionalities susceptible to bioactivation are not always bioactivated and bioacti-vation does not always cause hepatotoxicity.67,70 Because of complexity, adverse drug reactions cannot be predicted from preclinical toxicological assessments. The pharmaceutical industry is trying to implement higher throughput methods to screen for possible formation of reactive metabolites.

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...

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)...

Nicc In The Tyrol And Germany

Between 1900 and 1974, a group of 138 infants from the Austrian province of Tyrol suffered from childhood liver cirrhosis (13,33). All of the children with symptoms died before the age of 3 yr. The clinical features of the fatal liver cirrhosis observed in the Tyrol showed striking similarities to ICC and ICT. Although the hepatic copper content was not determined in these children, the hepatic morphology was characteristic of ICC ICT. The high levels of dietary copper were attributed to the formula milk used for feeding the infants it was routinely prepared in untinned copper and brass vessels until the early 1970s. The disappearance of the disease after 1974 coincided with a change in baby feeding practices and the replacement of untinned copper and brass kitchen vessels. These observations further supported the significant role played by copper cooking utensils. However, the fact that 231 siblings remained healthy although they had been exposed to the same copper-enriched diet as...

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...

Complicating Factors In Mapping The Tyrolean Nicc Gene

The identification of an animal model with phenotypic similarities to Tyrolean NICC could prove a useful tool to studying the disease mechanism because it is usually easier to map genes in animal models because of (1) inbreeding of the strains, (2) the large size of pedigrees, and (3) the shorter generation time. There are a few current animal models in which ingestion of copper has produced cirrhosis of the liver the copper toxicosis in Bedlington terriers (57,58) and in sheep (59,60). Copper toxicosis in North Ronaldsay sheep (so-called Ronaldsay copper toxicosis or RCT) shows many

Copper Homeostasis And Metabolism

When copper entry to the body is greater than the needs, it is deposited, mainly in the liver. However, deposit by itself does not necessarily mean tissue damage. It is well known that at birth, healthy full-term neonates have copper concentrations in their liver that may be similar to those observed in individuals with copper-associated cirrhosis (20). Understanding how copper is handled by the very young child remains a most challenging question.

Chronic Toxicity In Humans

In humans, chronic toxic effects of copper associated with specific gene mutations such as Wilson's disease are well known (95-98). Rare cases of childhood cirrhosis with fatal outcome have led to postulate that genes other than Wilson's would be associated with these cases (idiopathic copper cirrhosis, idiopathic copper toxicosis). In these patients, interaction between genes and the environment that provides normal higher copper exposure determine the appearance of clinical manifestation (99-102). In all of patients, the diagnosis is made when subclinical or clinical manifestations led to the suspicion of functional liver failure or altered copper metabolism and these are demonstrated by routine laboratory measurements. In contrast to genetic conditions, the effects of chronic high copper exposure are less clear, mainly in relation to the duration of exposure and the actual copper ingestion required for triggering the effects. There are well-characterized cases of copper-associated...

Predicting Adverse Events or Side Effects

A recent example of a drug taken off the market following adverse-event occurrence that will be used to highlight the reasoning behind these requirements is troglitazone. Troglitazone is a thiazolidinedione antidiabetic agent for the management of type II diabetes mellitus. During clinical development, liver toxicity was noted in 48 of approximately 2500 patients, with 20 of the 48 patients withdrawing from treatment 49 . Elevation of liver enzymes was reversible on therapy cessation, and the FDA subsequently licensed the drug. During the first 2 years after launch, 1,000,000 patients were placed on troglitazone. Of these, 70 experienced liver failure including 60 deaths and 10 transplants, leading to troglitazone's recall 49 .

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.

Moexipril Hydrochloride

3.75 mg once daily in hepatic cirrhosis Renal impairment see notes above if eGFR less than 40mL minute 1.73m2, initial dose 3.75 mg once daily titrated to max. 15 mg once daily Pregnancy see notes above Breast-feeding see notes above Side-effects see notes above arrhythmias, angina, chest pain, syncope, cerebrovascular accident, myocardial infarction appetite and weight changes dry mouth, photosensitivity, flushing, nervousness, mood changes, anxiety, drowsiness, sleep disturbance, tin

Analytical procedures

Cholinesterase activity pose a serious problem. For example, plasma cholinesterase activity may be depressed by cirrhosis, chronic hepatitis or other liver diseases and also by drug use and abuse.34 There are no differences in cholinesterase activity associated with race in general, but plasma cholinesterase activity in North American black races has been reported to be lower than in caucasians of the same sex.24 Any results obtained using enzyme inhibition monitoring should therefore preferably be compared with values for the innate cholinesterase activity of each subject, if possible the median of three samples obtained in a pre-exposure period.35

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.

Etiology Of Liver Cancer

Independent of geography and socioeconomic factors, HCC arises typically in the context of chronic liver inflammation and liver cirrhosis. For instance, some patients suffering from hereditary hemochromatosis develop chronic liver inflammation leading to cirrhosis, and eventually to HCC in some cases (Figure

Box 161 Hepatocellular carcinoma in experimental animals

Typically, chemical carcinogens are not only mutagenic, but also elicit widespread death of hepatocytes and other liver cells. Some carcinogens destroy a large fraction of all hepatocytes, inducing fatty livers and or a state resembling cirrhosis in humans. Precursor cells of hepatocytes and biliary epithelial cells termed 'oval cells' proliferate and replace the damaged parenchyme and ducts. These cells were later also detected in human liver following the clue from rat models.

The Use of Liver Slices in Drug Targeting Research 1261 Distribution and Transport of Drug Targeting Devices

In our Institute, drug targeting devices are predominantly developed for the treatment off inflammatory diseases of the liver, such as fibrosis and cirrhosis. In order to increase the therapeutic efficacy of drugs, human serum albumin is used as a protein backbone modifying this protein by the attachment of different sugar groups or peptide molecules targets these modified proteins to specific cell types in the liver as described in more detail in Chapter 4. Anti-inflammatory agents are subsequently coupled to the protein backbone to serve as effector moieties. The temperature-dependent uptake and immunohistochemical localisation of modified proteins, Lactose27-Human Serum Albumin (Lact27-HSA), Succinylated-Human Serum Albumin (Suc-HSA) and Aconylated Human Serum Albumin (Aco-HSA), in rat and human liver slices showed that large molecules can enter the slice and are probably taken up by receptor-mediated endocytosis (Figure 12.5). These large modified proteins were found distributed...

Pharmacokinetics And Distribution

Patients with liver disease experience decreased sertraline metabolism (Hiemke and Hartter 2000). For individuals with mild liver impairment, the half-life of drug may be increased threefold ( Zoloft 2001). It is likely to be greater in patients with severe impairment, such as in those with cirrhosis. On the other hand, renal impairment does not appreciably influence the metabolism of sertraline (Hiemke and Hartter 2000).

Hepatic Stellate Cells

The hepatic stellate cell (HSC) has gained increasing interest for its participation in liver diseases, in particular liver cirrhosis 59-68 . HSC, formerly known as fat-storing cells, lipocytes, Ito cells, perisinusoidal or parasinusoidal cells, represent only 5-8 of the total number of liver cells in normal livers. These mesen-chymal cells are situated in the space of Disse between the sinusoidal endothelial cells and the basolateral membranes of hepatocytes and maintain close contact with these cells through contractile cellular branches. This intimate association between stellate cells and the other hepatic cells facilitates intercellular transport of compounds and paracrine stimulation by soluble mediators. The major function of this cell type is the storage of vitamin A as reflected by their characteristic vitamin A-lipid droplets that can be visualized by fluorescence microscopy (328 nm). The liver contains 90 of the total body content of vitamin A, of which 75 is stored in HSC....

Chronic Liver Diseases Of Interest For Drug Targeting

As mentioned before, drug targeting to the liver may be a promising therapeutic approach for hepatic diseases with a chronic character. Examples of such diseases are liver cirrhosis, viral hepatitis and other infectious liver diseases, liver carcinomas or metastases of tumors, and hepatic autoimmune diseases (hemochromatosis, Wilson's disease, and a antitrypsine deficiency). The problem with the available pharmacotherapy in these diseases is that most drugs are not liver-specific and often exhibit undesirable toxicity. In the next paragraphs, we describe the pathosis of chronic liver diseases that are the subject of experimental therapies based on the application of drug delivery systems. This knowledge is important for the development of specific carriers and for the identification of molecular regulatory pathways that may serve as targets for therapeutical interventions.

Infectious Liver Diseases

Table 3 Potential Therapeutic Intervention of Liver Cirrhosis, Which Can Be Directed to Different Stages of the Disease affinity for the liver, in particular for hepatocytes, in common. Worldwide, more than 300 million people are chronic carriers of HBV. HBV is an enveloped virus with a double-stranded circular DNA genome. The uptake of viruses into cells is thought to be receptor mediated. Although HBV is capable of infecting several tissues, its replication occurs almost exclusively within the hepatocyte. Chronic HBV infection is a major cause of mortality throughout the world, because it is often associated with cirrhosis and HCC 121 . The most effective experimental treatment currently available for HBV infection is interferon-a (IFN-a) 122, 123 . However, the clinical effects of IFN-a therapy are disappointing, because only a subset of patients respond favorably to IFN-a, and a lot of adverse effects occur. Moreover, treatment with IFN-a is quite expensive. Therefore, the search...

Pharmacokinetics And Disposition

Patients with renal and hepatic insufficiency are often subject to alterations in metabolism and clearance of drugs, compared with healthy subjects. In individuals with renal impairment, both half-life and maximum plasma levels of paroxetine have been shown to increase relative to the extent of renal disease (Doyle et al. 1989). In a single-dose study, no significant difference was observed in pharmacokinetic outcomes in patients with cirrhosis of the liver, compared with healthy volunteers (Krastev et al. 1989) however, subsequent data revealed considerable elevations in steady-state concentration and ty2 of paroxetine following 14 days of administration of paroxetine in individuals with severe liver disease (Dalhoff et al. 1991). Accordingly, patients with substantial renal or hepatic dysfunction should initially be treated with a lower dose of paroxetine than is generally recommended to avoid potential side effects associated with unusually high plasma paroxetine levels.

Mechanism Of Action

Moving from intestine to liver and concentrating in liver cells. Protein synthesis is induced in the liver by silybin, whose steroid structure stimulates both DNA and RNA synthesis. Through these activities, the regenerative capacity of the liver is activated. Silymarin is reported to alter the outer cell membrane structure of liver cells, blocking entrance of toxic substances into the cell. This blockage is so pronounced that it can reduce the death rate from Amanita phal-loides poisoning. Silymarin's effect can be explained by its antioxidant properties it scavenges free radicals. By this effect, the level of intracellular glutathione rises, becoming available for other detoxification reactions. Silybin inhibits enzymes such as lipoxygenase,66 blocking peroxidation of fatty acids and membrane lipid damage. Studies also show that silymarin protects the liver from amitriptyline, nor-triptyline, carbon tetrachloride, and cisplatin. When treated, patients with alcoholic cirrhosis showed...

Late Distal Tubule And Collecting Duct

Blood Dyscrasias Chart

Hyperplasia) and refractory edema associated with secondary aldosteronism (cardiac failure, hepatic cirrhosis, nephrotic syndrome, and severe ascites). Spironolactone is considered the diuretic of choice in patients with hepatic cirrhosis. Spironolactone, added to standard therapy, substantially reduces morbidity and mortality and ventricular arrhythmias in patients with heart failure (see Chapter 34).

Copper In Diseases And Genetic Diseases Of Copper Metabolism

In contrast to Menkes disease, Wilson disease occurs more gradually, and after birth. It results in the accumulation of excess copper in liver and some other tissues and oxidative damage (65). In this case the problem is excretion, because in the absence of the normal WND ATP7B protein, it is difficult for copper to enter the bile (see Section 1.5.). Accumulation of excess copper in tissues (although mitigated by binding to metallothionein) promotes formation of reactive oxygen species, eventually resulting in liver cirrhosis (65,181-184). The brain and some endocrine organs are also affected. Further details may be found in more recent reviews of these diseases (57,185-189).

Use Of B Antagonists In Other Cardiovascular Diseases

B Blockers may be of some value in the treatment of patients undergoing withdrawal from alcohol or those with akathisia. Propranolol and nadolol are efficacious in the primary prevention of variceal bleeding in patients with portal hypertension caused by hepatic cirrhosis.

O Factors Affecting Drug Metabolism

Chemical Kinetics Drug Metabolism

The effect of old age on drug metabolism has not been as well studied. There is some evidence in animals and humans that drug metabolism diminishes with old age.491,492 Much of the evidence, however, is based on prolonged plasma half-lives of drugs that are metabolized totally or mainly by hepatic microsomal enzymes (e.g., antipyrine, phenobarbital, acetaminophen). In evaluating the effect of age on drug metabolism, one must differentiate between normal loss of enzymatic activity with aging and the effect of a diseased liver from hepatitis, cirrhosis, etc., plus decreased renal function, because much of the water-soluble conjugation products are excreted in the liver.

Clinical Use Of Vasopressin Peptides

V2 receptor agonists (e.g., desmopressin) are also used in bleeding disorders. In most patients with type I von Willebrand's disease (vWD) and in some with type Iln vWD, desmopressin will elevate von Willebrand factor and shorten bleeding time. However, desmopressin generally is ineffective in patients with types IIa, IIb, and III vWD. Desmopressin may transiently cause a marked thrombocytopenia in individuals with type IIb vWD and is contraindicated in such patients. Desmo-pressin also increases factor VIII levels in patients with mild-to-moderate hemophilia A. Desmopressin is not indicated in patients with severe hemophilia A, those with hemophilia B, or those with factor VIII antibodies. The response of any given patient with type I vWD or hemophilia A to desmopressin should be determined with a test dose of nasal spray at the time of diagnosis or 1-2 weeks before elective surgery to assess the extent of increase in factor VIII or von Willebrand factor. In patients with renal...

Interferon Treatment of Chronic Hepatitis B

Approximately 350 million people worldwide are chronic carriers of HBV, with the majority living in Asia and Africa. In the United States approximately one million people have chronic HBV infection. Although chronically infected, individuals may remain asymptomatic for long periods. Spontaneous loss of HBeAg occurs in 7 to 20 of patients each year, but spontaneous loss of HBsAg occurs in only 1 to 2 per year 14 . Health experts estimate that 2 of patients with chronic HBV infection develop cirrhosis each year, and that 15 to 25 of patients with chronic HBV infection will die prematurely from cirrhosis or hepatocellular carcinoma (HCC). Interferon therapy should be used with great caution in patients with decompen-sated cirrhosis since treatment may flare their disease, resulting in hepatic failure, and is often associated with significant cytopenia or infection 30,31 . Other ab

Inborn Errors of Metabolism in Which the KD Is Contraindicated

There is tremendous clinical heterogeneity in fatty acid oxidation defects. Patients may be asymptomatic between attacks or severely affected from a young age. Attacks are brought on by illness, stress, and prolonged fasting. The spectrum of clinical symptoms may include hypotonia, myopathy, cardiomyopathy, recurrent rhabdomyolysis with myoglobinuria, Reye-like syndrome with liver failure, intermittent altered levels of consciousness, neuropathy, and seizures. Concurrent with the symptoms are often a nonketotic hypoglycemia, unexplained metabolic acidosis, hyperammonemia, dicar-boxylic aciduria, elevated creatinine kinase, and carnitine deficiency.

Chronic Arsenic Poisoning

The most common early signs of chronic arsenic poisoning are muscle weakness and aching, skin pigmentation (especially of the neck, eyelids, nipples, and axillae), hyperkeratosis, and edema. GI involvement is less prominent in long-term exposures. Other signs and symptoms that should arouse suspicion of arsenic poisoning include garlic odor of the breath and perspiration, excessive salivation and sweating, stomatitis, generalized itching, sore throat, coryza, lacrimation, numbness, burning or tingling of the extremities, dermatitis, vitiligo, and alopecia. Poisoning may begin insidiously with symptoms of weakness, languor, anorexia, occasional nausea and vomiting, and diarrhea or constipation. Subsequent symptoms may simulate acute coryza. Dermatitis and keratosis of the palms and soles are common features. Mee's lines are found characteristically in the fingernails (white transverse lines of deposited arsenic that usually appear 6 weeks after exposure). Desquamation and scaling of...

Drug Albumin Conjugates

Liver Cirrhosis or Fibrosis It should be realized, however, that therapeutic interference with only one cell type may not be enough to treat liver cirrhosis, because all hepatic cell types contribute to some extent to the development of the disease. Therefore, a combination of drug-targeting preparations to stellate cells, KC, endothelial cells, and or hepatocytes might improve the pharmacological therapies and compete with the liver transplantation technique. In addition to therapeutic applications, modified albumins may also be used for diagnostic purposes (an issue that will be addressed in section VI.C.4). Early assessment of the onset and progression of liver diseases is an important factor determining the disease prognosis of most patients. Conventional liver function tests measuring hepatic protein synthetic functions, excretory functions, amino transferases, and bile duct enzymes are useful but may prove insensitive in monitoring the disease progression adequately. Noninvasive...

Drugs affecting biliary composition and flow

The use of laparoscopic cholecystectomy and of endoscopic biliary techniques has limited the place of the bile acid ursodeoxycholic acid in gallstone disease. Ursodeoxycholic acid is suitable for patients with unimpaired gall bladder function, small or medium-sized radiolu-cent stones, and whose mild symptoms are not amenable to other treatment it should be used cautiously in those with liver disease (but see below). Patients should be given dietary advice (including avoidance of excessive cholesterol and calories) and they require radiological monitoring. Long-term prophylaxis may be needed after complete dissolution of the gallstones has been confirmed because they may recur in up to 25 of patients within one year of stopping treatment. Ursodeoxycholic acid is also used in primary biliary cirrhosis liver tests improve in most patients but the effect on overall survival is uncertain. Dose primary biliary cirrhosis, 10-15 mg kg daily as a single daily dose or in 1-4 divided doses...

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.

Absorption distribution metabolism and excretion

Rodent studies (see below) have demonstrated that viral damage to the liver affects the metabolism of aflatoxin. Kirby et al. (1996a) examined the expression of CYP enzymes in sections of normal human liver and in livers with hepatitis and cirrhosis. By use of immunohistochemical techniques, it was shown that in sections infected with hepatitis B virus (HBV) or hepatitis C virus (HCV), the concentration of CYP2A6 was increased in hepatocytes immediately adjacent to areas of fibrosis and inflammation. In the same tissues, CYP3A4 and CYP2B1 were somewhat increased and CYP1A2 was unaffected compared with normal liver. In HCV-infected liver, CYP2A6, CYP3A4 and CYP2B1 were increased in hepatocytes that had accumulated haemosiderin pigment.

At1 Angiotensin Ii Receptor Antagonists

ADVERSE EFFECTS AND PRECAUTIONS Adverse effects of ACE inhibitors that result from inhibiting AngII-related functions also occur with ATJ receptor antagonists, including hypotension, hyperkalemia, and reduced renal function (especially associated with renal artery stenosis). Hypotension most often occurs in patients in whom the blood pressure is highly dependent on AnglI, including those with volume depletion (e.g., with diuretics), renovascular hypertension, cardiac failure, and cirrhosis in such patients initiation of treatment with low doses and attention to volume status is essential. Hyperkalemia may occur in conjunction with other factors, such as renal insufficiency, ingestion of excess K+, and the use of drugs that promote K+ retention. Cough is much less frequent with AngII receptor antagonists, and angioedema occurs very rarely. ATj receptor antagonists also should not be administered during pregnancy and should be discontinued as soon as pregnancy is detected.

Diseases Affecting The Vasopressin System

OTHER WATER-RETAINING STATES In patients with congestive heart failure, cirrhosis, or nephrotic syndrome, effective blood volume often is reduced, and hypovolemia frequently is exacerbated by the liberal use of diuretics. Since hypovolemia stimulates vasopressin release, patients may become hyponatremic owing to vasopressin-mediated retention of water. The development of potent orally active V2 receptor antagonists and specific inhibitors of water channels in the collecting duct would provide an effective therapeutic strategy not only in patients with SIADH but also in the much more common setting of hyponatremia in patients with heart failure, cirrhosis, or nephrotic syndrome.

Isoprostanes as Oxidative Markers in Degenerative Diseases

Liver cirrhosis is associated with increased free radical production and decreased levels of antioxidants such as vitamin E, glutathione and selenium. Livers from normal and bile duct-ligated cirrhotic rats were perfused with 8-iso-PGF2a resulting in increased portal pressure in both experimental groups. There was a significantly greater change in portal pressure in response to 8-iso-PGF2a perfusion in the cirrhotic animals. This action was completely blocked, in cirrhotic rats, by the addition of SQ29548, a thromboxane receptor antagonist, to the perfusate (Marley et al., 1997).

Overview Of Diuretic

The clinical situation dictates whether a patient should receive diuretics and what therapeutic regimen should be used (i.e., type of diuretic, dose, route of administration, and speed of fluid mobilization). Acute pulmonary edema in patients with left-sided heart failure is a medical emergency requiring rapid, aggressive therapy including intravenous administration of a loop diuretic. In this setting, use of oral or less potent diuretics is inappropriate. On the other hand, mild pulmonary and venous congestion associated with chronic heart failure is best treated with an oral loop or thiazide diuretic, the dosage of which should be titrated carefully to maximize the benefit-to-risk ratio. Loop and thiazide diuretics decrease morbidity and mortality in heart failure MR antagonists also reduce morbidity and mortality in heart failure patients receiving optimal therapy with other drugs. Periodic administration of diuretics to cirrhotic patients with ascites may eliminate the necessity...

Role of Nuclear Receptors

Suppression of bile acid synthesis is mediated by FXR, which binds bile acids and activates the transcription of genes involved in bile acid and lipid metabolism (112-114). Target genes include those encoding the ileal bile acid binding protein (112), SHP (105, 106), the phospholipid transfer protein (115), several ABC transporters (116, 117), the organic anion transporting polypeptide 8(118), and apolipoprotein C-II (58). Mice deficient in FXR express high levels of cholesterol 7a-hydroxylase and sterol 12a-hydroxylase mRNAs this results in increased bile acid synthesis (119). The mutant mice accumulate bile acids in plasma due to markedly decreased levels of ABCB11, which normally transfers bile acids from the hepatocyte into the bile (92). FXR knockout mice also are hypertryglyceridemic, due in part to decreased expression of apolipoprotein C-II, which is required for the metabolism of triglycerides (58). High concentrations of dietary bile acids cause death in these mice, most...

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....

Pharmacotherapy Of Alcoholism

Naltrexone helps to maintain abstinence by reducing the urge to drink and increasing control when a slip occurs. It is not a cure for alcoholism and does not prevent relapse in all patients. Naltrexone works best when used in conjunction with some form of psychosocial therapy, such as cognitive behavioral therapy. It typically is administered after detoxification and given at a dose of 50 mg day for several months. Adherence to the regimen is important to ensure the therapeutic value of naltrexone and has proven to be a problem for some patients. The most common side effect of naltrexone is nausea, which is more common in women than in men and subsides if the patients abstain from alcohol. When given in excessive doses, naltrexone can cause liver damage. It is contraindicated in patients with liver failure or acute hepatitis and should be used only after careful consideration in patients with active liver disease.

Amiloride Hydrochloride

Indications oedema potassium conservation when used as an adjunct to thiazide or loop diuretics for hypertension, congestive heart failure, or hepatic cirrhosis with ascites Cautions monitor electrolytes diabetes mellitus With other diuretics, congestive heart failure and hypertension, initially 5-10 mg daily cirrhosis with ascites, initially 5 mg daily

Gene Mapping Based On Identity By Descent

More recently, founded populations (approx 8-15 generations ago) have become excellent resources for mapping rare diseases with a simple inheritance pattern We can search for segments that are shared by patients and then demonstrate that this sharing is IBD (Fig. 4). This haplotype sharing approach has been extremely useful in mapping a number of rare disease genes, including the gene involved in benign recurrent hepatic cholestasis (BRIC) (46), Byler's disease (47), and North American childhood cirrhosis (48). The BRIC gene, for example, was localized to chromosome 18 by performing a genomewide screen on only three patients from a religiously isolated fishing community in the Netherlands. Although the chromosomes of these three BRIC patients had undergone at least six meioses since their shared origin, the BRIC haplotype was still shared over a region of more than 20 cM (46). The situation for the Tyrolean NICC is, however, more complicated. The disease is lethal when left untreated,...

General Risk Factors

Involved in prostate carcinogenesis 41,42 . In most studies of alcohol use as a potential risk factor for prostate cancer, no evidence for an association was found (see 12, 43 ). A notable exception is a study by Hayes et al. 44 , who found a positive association in a US case-control study, but only for heavy use of alcohol. This may be related to the fact that prostate cancer risk is elevated in alcoholics with liver disease (see 13, 43 ), probably because of an impaired clearance of estrogens described in men with liver cirrhosis 45,46 .

David W Russell

I Abstract The synthesis and excretion of bile acids comprise the major pathway of cholesterol catabolism in mammals. Synthesis provides a direct means of converting cholesterol, which is both hydrophobic and insoluble, into a water-soluble and readily excreted molecule, the bile acid. The biosynthetic steps that accomplish this transformation also confer detergent properties to the bile acid, which are exploited by the body to facilitate the secretion of cholesterol from the liver. This role in the elimination of cholesterol is counterbalanced by the ability of bile acids to solubilize dietary cholesterol and essential nutrients and to promote their delivery to the liver. The synthesis of a full complement of bile acids requires 17 enzymes. The expression of selected enzymes in the pathway is tightly regulated by nuclear hormone receptors and other transcription factors, which ensure a constant supply of bile acids in an ever changing metabolic environment. Inherited mutations that...


Mice deficient in the cholesterol 7a-hydroxylase gene (Cyp7a1) have a high incidence of postnatal lethality due to liver failure, vitamin deficiencies, and lipid malabsorption (12-14). The bile acid pool size in these animals is reduced by 75 (15), and the reduction in bile acid synthesis is not compensated for by increased expression of other bile acid biosynthetic enzymes (16). Intestinal

Didanosine ddI

The most serious of ddI is pancreatitis, which has been fatal (1998j). Pancreatitis occurs in 6-7 of patients on ddI (Dolin et al., 1995 Kahn et al., 1992). As with ZDV, acute, fulminant liver failure associated with lactic acidosis has been reported (Kahn et al., 1992). ddI also causes peripheral neuropathy commonly (14-20 ) (Dolin et al., 1995 Kahn et al., 1992). Manifestations of this neuropathy include numbness and tingling sensations in hands and feet. Symptoms usually improve with drug discontinuation.


Except for the less lipid-soluble aprobarbital and phenobarbital, nearly complete metabolism and or conjugation of barbiturates in the liver precedes their renal excretion. The metabolic elimination of barbiturates is more rapid in young people than in the elderly and infants, and half-lives are increased during pregnancy partly because of the expanded volume of distribution. Chronic liver disease, especially cirrhosis, often increases the t1 2 of the biotransformable barbiturates. Repeated administration, especially of phenobarbital, shortens the t1 2 of barbiturates that are metabolized as a result of the induction of microsomal enzymes (see above).


The pathogenesis of WD is thought to result from a systemic overload of copper, which accumulates primarily in the three major targets of WD the brain, eye, and liver. The etiological significance of copper is supported by the efficacy of treatments, which are principally aimed at chelation of free copper. Clearly, although multiple lines of experimental evidence have demonstrated that copper is toxic to hepatocytes and causes oxidative damage, it is less clearly established that copper is directly harmful to the neurons of the brain under normal circumstances. Could the case for copper toxicity in neurological WD be an oversimplification Several pieces of evidence suggest that the brain disorder seen in WD is caused by more than simple copper overload. It is known, for example, that in human subjects with Wilson's disease and liver diseases, brain copper is elevated but there is sometimes no evidence of the characteristic neurological disorder. In cases of copper toxicity (Indian...


Be found in breast milk, and crosses the placenta (1998l). Nevirapine is also metabolized by the P450 system and is also an inducer of the P450 system. Consequently, nevirapine therapy increases its own metabolism. After the first 14 days of therapy, the dose must be increased from 200 mg once per day to 200 mg (one tablet) twice per day. There are no data available on dosing nevirapine in renal or liver failure. The terminal half-life of nevirapine is 25-30 h (Lamson, 1993).


(proton pump inhibitors) Hepatic impairment max. 20 mg daily in severe impairment and cirrhosis monitor liver function (discontinue if deterioration) Renal impairment max. oral dose 40 mg daily Pregnancy manufacturer advises avoid unless potential benefit outweighs risk fetotoxic in animals Breast-feeding manufacturer advises avoid unless potential benefit outweighs risk small amount present in milk in animal studies Side-effects see notes above also hyperlipidaemia,

Wilsons Disease

Wilson's disease (WD) is a genetic copper-toxicosis disorder affecting both the liver and central nervous system. In this disease, mutations of ATP7B result in reduction of biliary excretion of copper and low incorporation of copper into ceruloplasmin in the liver (Fig. 4B) (4), but for unknown reasons, not all patients have low ceruloplasmin levels. Because the uptake of copper from the small intestine is normal in WD, the reduced copper excretion results in a net positive copper balance in the body and copper gradually accumulates to high concentrations in the liver (4). The excess copper eventually causes severe liver damage, liver failure, and death. Copper also deposits in the brain, and neurological abnormalities are a major clinical feature of some patients. Disease symptoms appear at various ages, but rarely before the age of 5 yr however, there are reported cases as young as 3 yr, which can be misdiagnosed because of the young age of the patient (71). The neurological form of...


Neurological diseases discussed in the last section Are there other copper-related diseases yet to be recognized, because of mutations in the various copper chaperones or other components of the copper homeostatic system Despite these and many other questions, in contrast to even 10 yr ago, it is possible to believe that within another 10 yr the answers to these questions will be found and the molecular basis of copper transport will be substantially worked out. One can confidently expect that the discovery of gene(s) involved in the childhood copper-associated cirrhosis conditions, the Bedlington terrier, and the reason for the copper sensitivity of the sheep will be discovered and new genes will be added to the growing cast of players involved in copper homeostasis. The links between the molecules regulating cellular copper homeostasis and the physiological and pathophysiological effects of copper should be clarified. We hope that these discoveries will be accompanied by...


Indications pruritus associated with partial biliary obstruction and primary biliary cirrhosis diarrhoea associated with Crohn's disease, ileal resection, vagotomy, diabetic vagal neuropathy, and radiation hypercholesterolaemia (section 2.12) Cautions section 2.12 Contra-indications section 2.12 Pregnancy section 2.12 Breast-feeding section 2.12 Side-effects section 2.12 Dose


Indications ascites due to cirrhosis in stable patients (under close supervision), oedema due to nephrotic syndrome, hypertension (see also notes above), mild to moderate chronic heart failure diabetes insipidus (see section 6.5.2) Cautions see notes above Contra-indications see notes above Hepatic impairment see notes above Renal impairment see notes above Pregnancy see notes above Breast-feeding see notes above Side-effects see notes above also rarely jaundice and

Induced Toxicity

Storing cell (or Ito cell) is an important cell type that stores vitamin A (and other fat soluble vitamins) and can also synthesize collagen. It plays a major role in the development of cirrhosis (Ramadori, 1991). Other nonparenchy-mal cells include lymphocytes and natural killer (pit) cells, which may be important in the identification and elimination of neoplastic cells.

R3 R7 R12 R24

Primary biliary cirrhosis is a chronic, progressive, cholestatic liver disease of unknown etiology that typically affects middle-aged to elderly women. Ursodiol (administered at 13-15 mg kg day in two divided doses) reduces the concentration of primary bile acids and improves biochemical and histological features of primary biliary cirrhosis.

Looking Ahead

The fact that Tyrolean NICC has almost disappeared since untinned copper vessels have been replaced by modern household vessels raises the question of why it is still important to search for the NICC gene. First, our knowledge on copper homeostasis in humans is still limited. The identification of the NICC gene and insight into the function of its product, the protein, may broaden our understanding of the cellular processes that occur after copper has been taken up by the body. Second, childhood cirrhosis as a result of copper toxicosis is not limited to the Tyrolean population. The identification of the gene could make it possible to identify people who are either a carrier of the disease or at risk of developing copper toxicosis because they have a mutation in both alleles of the gene. The identification of high-risk people is currently only possible in families who have been exposed to high environmental copper and who have already had a child suffering from NICC.

Pharmaco Vigilance

There are well known examples of medicines which were withdrawn from the market place when previously unknown adverse reactions became apparent. It is in the best interests of any company that they should learn of any safety issues as soon as possible so they may react accordingly. For example it may be discovered that the product interacts with another medicine or that the dose needs to be carefully monitored in a certain group of patients (the elderly, those with liver failure etc.). The company will want to protect patients from any harm, will want to further investigate the problem and will want to issue any warnings that are appropriate.

Therapeutic Uses

The efficacy of conventional and pegylated IFNs is enhanced by the addition of ribavirin. In previously untreated patients, combined therapy with pegIFN alfa-2a (180 mg once weekly for 48 weeks) and ribavirin (1-1.2 g day in divided doses) gives higher sustained viral response rates than IFN-ribavirin combinations. The dose and duration of therapy depend on the specific genotype of HCV virus. Approximately 15-20 of those failing to respond to combined IFN-ribavirin will have sustained responses to combined pegIFN-ribavirin. Histological improvement may occur in patients who do not achieve sustained viral responses. In patients with compensated cirrhosis, treatment may reverse cirrhotic changes and possibly reduce the risk of hepatocellular carcinoma.


Here, we report that in the LEC rat, the noncytosolic copper was mainly detected in lysosomes. Also in Wilson's disease, the localization of hepatic copper varies with the stage of the disease In the early stage, copper is diffuse in the cytoplasm of hepatocytes, whereas later, when fibrosis and cirrhosis are the predominant histopathological features, the metal is mainly located in hepatocyte lyso-somes (22).

M Metaraminol

Priapism (section 7.4.5) unlicensed indication Cautions see under Noradrenaline Acid Tartrate longer duration of action than noradrenaline (norepi-nephrine), see below cirrhosis Hypertensive response Metaraminol has a longer duration of action than noradrenaline, and an excessive vasopressor response may cause a prolonged rise in blood pressure Contra-indications see under Noradrenaline Acid Tartrate information available Side-effects see under Noradrenaline Acid Tartrate tachycardia fatal ventricular arrhythmia reported in Laennec's cirrhosis Dose

Endothelial Cells

Endothelial cells (EC) are from mesenchymal origin and represent about 20 of the total number of liver cells. They can be divided into two types vascular endothelial cells and sinusoidal endothelial cells. In liver sections, vascular endo-thelial cells can be readily identified after HE staining in contrast to the sinusoidal endothelial cells that may be visualized with the monoclonal antibody HIS52 (anti-rat endothelial cell antigen-1) or in case of human livers with for instance anti-von Willebrand factor or anti-gp96 35, 36 . Unlike the cells of the vascular endothelium, the sinusoidal liver endothelial cells lack an underlying fibrous basement membrane. In addition, the sinusoidal endothelial cell lining contains pores, called fenestrae, that are grouped in so-called sieve plates. These features allow direct contact between the cells located in the space of Disse and the plasma, which implicates an undisturbed exchange of molecules between blood and liver cells. Loss of the...


Dermatological adverse effects include drying of the skin and mucosa, dermatitis, pruritus, swelling and fissuring of the lips, and rarely loss of body hair. Hepatic effects include hypertrophy and hyperplasia of the hepatic stellate cells, hepatomegaly, fibrosis, and cirrhosis, which can lead to portal hypertension, ascites, and jaundice. Splenomegaly is also seen. CNS effects include increased intracranial pressure (pseudotumor cerebri) leading to headache, visual disturbances (e.g., diplopia), drowsiness, vomiting, seizures, and a bulging fontanel in infants. Finally, pain in the bone and joints, with accompanying tenderness and reduced bone mineralization49 have also been reported.

Liver Cancer

Primary liver cancer, or HCC, is a rare type of cancer in Western countries, but occurs frequently in Africa and Asia. HCC is often the sequel to chronic viral hepatitis, cirrhosis, nutritional deficiencies, or specific toxins. More common types of cancer occurring in the liver are metastatic diseases, which originate mainly from primary gastrointestinal tumors. For the growth of these and other solid tumors, sprouting of the vascular system, called angiogenesis, is essential to provide an adequate blood supply to the tumor cells. Nutrients and oxygen are needed for the proliferation of tumor cells 134-136 .

Brater Algorithm

FIGURE 28-7 Brater's algorithm for diuretic therapy of chronic renal failure, nephrotic syndrome, congestive heart failure, and cirrhosis. Follow algorithm until adequate response is achieved. If adequate response is not obtained, advance to the next step. For illustrative purposes, the thiazide diuretic used in Brater's algorithm is hydrochlorothiazide (HCTZ). An alternative thiazide-type diuretic may be substituted with appropriate dosage adjustment so as to be pharmacologically equivalent to the recommended dose of HCTZ. Do not combine two K+-sparing diuretics because of the risk of hyperkalemia. CrCl indicates creatinine clearance in mL min, and ceiling dose refers to the smallest dose of diuretic that produces a near-maximal effect. Ceiling doses of loop diuretics and dosing regimens for continuous intravenous infusions of loop diuretics are disease-state-specific see Brater (1998) for recommended dosages. Doses are for adults only.

Chronic pancreatitis

Various theories have been put forward related to the precise pathophysiology of chronic pancreatitis. Experimentally, chronic pancreatitis may be induced in animals by the administration of toxins but similar links have not been conclusively identified in humans. Alterations in the protein components of pancreatic fluids have been noted which may result in the formation of sludge or intraductal plugs that become calcified into stones which produce inflammatory and fibrotic reactions.21 It has been proposed that oxidative stress underlies chronic pancreatitis with periodic bursts of free radical formation leading to chronic injury. Genetic factors have been clearly identified in hereditary pancreatitis and in association with such diseases as cystic fibrosis, but no specific marker has been identified in association with other etiologies. Intraductal hypertension is a common sequel of stone formation fibrosis and has been proposed as a source of the continuous pain that may develop in...

Proximal Tubule

Mechanism Action Furosemide

Serious toxic reactions to carbonic anhydrase inhibitors are infrequent however, these drugs are sulfonamide derivatives and, like other sulfonamides, may cause bone marrow depression, skin toxicity, sulfonamide-like renal lesions, and allergic reactions (see Chapter 43). With large doses, many patients exhibit drowsiness and paresthesias. Most adverse effects, contraindications, and drug interactions are secondary to urinary alkalinization or metabolic acidosis, including (1) diversion of ammonia of renal origin from urine into the systemic circulation, a process that may induce or worsen hepatic encephalopathy (the drugs are contraindicated in patients with hepatic cirrhosis) (2) calculus formation and ureteral colic owing to precipitation of calcium phosphate salts in an alkaline urine (3) worsened metabolic or respiratory acidosis (the drugs are contraindicated in patients with hyperchloremic acidosis or severe chronic obstructive pulmonary disease) and (4) reduced urinary...


Hepatic metabolism to the inactive glucuronide is the major route of elimination. This metabolite and chloramphenicol are excreted in the urine. Patients with impaired liver function have decreased metabolic clearance, and dose should be decreased. About 50 of chloramphenicol is bound to plasma proteins this is reduced in cirrhotic patients and in neonates. Half-life is not altered significantly by renal insufficiency or hemodialysis, and dose adjustment usually is not required. However, if the dose of chloramphenicol has been reduced because of cirrhosis, clearance by hemodialysis may be significant. Drug administration after hemodialysis minimizes this effect. Variability in the metabolism and pharmacokinetics of chloramphenicol in neonates, infants, and children necessitates monitoring of plasma drug levels.


The efficacy of HBO in the management of radiation-induced bowel injury, including proctitis, is less well reported. There is a series of case studies and very small series reporting healing of pain, tenesmus, bleeding, diarrhea, and rectal ulceration.46-51 More significantly, there are a number of retrospective studies describing complete or partial healing of rectal symptoms in patients resistant to conventional therapy for severe injuries. One of the largest retrospective studies describes 36 patients, including 9 with chronic necrotic wounds, 19 with chronic rectal bleeding, and 9 with chronic severe diarrhea.52 After 67 (12-198) HBO sessions, the authors reported 9 complete responses, 12 partial responses, and 11 non-responses (in addition, one patient died from radiation injury, two from cancer, and one from liver cirrhosis). In a study of 38 patients treated with HBO for chronic, uncontrolled rectal bleeding, treatment resulted in an improvement in 61 of cases.53 A third...


Voriconazole exhibits nonlinear kinetics, and higher doses disproportionately increase drug exposure. Genetic polymorphisms in CYP2C19 can cause up to a fourfold difference in drug exposure 20 of Asians are poor metabolizers compared to 2 of Caucasians and African Americans. Drug exposure is increased considerably in the elderly and in patients with mild or moderate hepatic insufficiency. Patients with hepatic cirrhosis should receive the same loading dose of voriconazole but half the maintenance dose.

Gsf Lichtmannegger

In Wilson's disease, a Cu toxicosis condition, and Menkes disease (including mild Menkes disease and occipital horn syndrome OHS ), a Cu deficiency disorder, Cu homeostasis is perturbed by genetic mutation. Wilson's disease is an autosomal recessive inherited disorder of Cu metabolism resulting in pathological accumulation of Cu in many tissues and organs. The Menkes disease complex of related disorders of Cu transport are responsible for abnormal neurodevelopment and connective tissue pathology that can precipitate premature death. In addition, excessive intake of Cu can result in early childhood cirrhosis (ECC, Indian Childhood Cirrhosis ICC or, when found outside India, Idiopathic Cu Toxicosis ICT ). The Wilson's disease gene encodes a Cu-transporting P-type ATPase, ATP7B. In humans, it is localized on chromosome 13. Approximately 100 mutations of the gene have been documented. They occur throughout the gene. The most common is the His1069Gln point mutation. Wilson's disease...

Cisca Wijmenga

Inherited liver cirrhosis is rarely observed in infancy or childhood in Western countries, but, recently, 138 cases of an endemic form of infantile cirrhosis were reported from several families in the Tyrol, Austria. These infants had received high amounts of dietary copper released from copper vessels used to prepare their formula milk. Extensive studies in this Tyrolean population suggested that the so-called non-Indian childhood cirrhosis (NICC) occurred only in children with a genetic defect (in homozygous form). These Tyrolean NICC families could be traced back for 10 generations and it was shown that the majority of the families were related to each other. A founder effect was therefore suggested as the most likely reason for the increased frequency of NICC in the Tyrol (i.e., the patients are all descendants of one common ancestor, who introduced the disease mutation into the population many generations ago). Thus, all of the patients in this population should carry the same...


Different mutations in the HFE alleles) develop hemochromatosis. In fact, not all do, and only a fraction of these progress towards cirrhosis and hepatocellular cancer (Figure 16.2). This demonstrates that further factors modulate the risk of inflammation and cancer. Nowadays, patients with early signs of hemochromatosis disease can be treated with iron chelators to prevent organ damage, cirrhosis, and cancer. Hemochromatosis is a comparatively rare disease, but its pathophysiology is well understood. It provides an example for other, more prevalent, but less well understood factors that cause liver cancer by a basically similar pathway through chronic inflammation and cirrhosis. The most important ones are the hepatitis viruses HBV and HCV, and alcohol abuse (Table 16.1). In a typical Central European population, 3 of all HCC cases might be associated with hemochromatosis, and 30 each with HBV, HCV, and alcohol, the remainder with other known or unknown causes. A rising incidence of...


Paracetamol has been associated with liver toxicity in association with massive overdose or chronic unintentional overdose in patients with a history of chronic alcohol abuse, malnutrition, and prolonged starvation and it is one of the most common causes of acute liver failure in the USA.109 III Patients consuming more than three units of alcohol per day should consult with their physician before taking any analgesic.95,109 III

Cancer and Nutrition

Many dietary substances are known to produce cancer. Alcohol is an excellent example of one in common usage. In people who both drink and smoke the risk is considerably magnified. The mouth, esophagus, and pharynx are the most frequent sites. These are the areas of most likely contact for both substances. The liver, of course, is also exposed to alcohol, where it is metabolized. One of seven heavy drinkers develops cirrhosis of the liver. It may be no coincidence that most primary liver cancers in the United States originate in cirrhotic livers the remainder may be virally induced. Unfortunately, the list of carcinogens occurring in many foods naturally, as additives, and as a result of storage and even cooking processes, is large and growing. Sodium nitrite, a precursor of carcinogens (nitrosamines), occurs in many foods such as vegetables naturally, and in meat products as an additive. Even where foods contain nitrate rather than nitrite, it is secreted into the saliva following...

Opioid Therapy

Opioid therapy involves the use of either weak or strong opiates, and often both are prescribed in conjunction to adequately control acute pain. Weak opiates typically come in oral preparations and are combined with varying formulations of acetaminophen, aspirin, or ibuprofen. All of these drugs have ceiling doses related to the non-opioid ingredient. For example, acetaminophen poisoning is one of the common causes of acute liver failure in the United States, and oftentimes these patients are on acetaminophen-containing opiates. Acetaminophen, also known as paracetamol or N-acetyl-p-aminophenol, causes centrilobu-lar necrosis leading to nausea, vomiting, abdominal pain, renal failure and can progress to fulminant hepatic failure (Abram 2006).