Cirrhotic Liver of the Digestive System

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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Causes Of Liver Failure Unique To Children

The most common indication for liver transplantation in children is Biliary Atresia.1 Biliary Atresia is a progressive fibro-inflammatory destruction of the extrahepatic biliary tree, which develops in approximately 1 in 15,000 newborns. The etiology of the disorder remains unknown, but as many as 10 of affected children will have associated developmental abnormalities such as polysplenia, malrotation, and intra-abdominal vascular anomalies. Some infants will benefit from the Kasai procedure but the majority will have progressive biliary cirrhosis despite surgical intervention. Metabolic liver diseases that result in cirrhosis, such as alpha-1-antitrypsin deficiency and Wilson's disease are also common indications for liver transplantation in children. Approximately 5 of the children receiving liver transplants have fulminant hepatic failure. Inborn errors of metabolism without cirrhosis such as Crigler-Najjar syndrome or Ornithine transcarbamylase deficiency are uncommon but...

Shortcomings of SPIO in Cirrhotic Liver

There are some shortcomings of SPIO-enhanced MR imaging in the diagnosis of HCC. First, SPIO-enhanced MR imaging is basically unable to assess lesion vascularity. Perfusion MR imaging using SPIO is still a work-in-progress (Figure 4.10). Second, the decrease in signal intensity of cirrhotic liver with SPIO is limited compared to that in normal liver (Elizondo et al., 1990 Kuwatsuru et al., 1997). The percentage of signal-intensity loss and liver-lesion contrast-to-noise ratio on SPIO-enhanced images was significantly higher in patients with mild liver cirrhosis (Child's class A) than in patients with severe liver cirrhosis (Child's class C) (Tang et al., 1999). Lesion-liver contrast enhancement is weaker for HCCs arising in cirrhotic liver than for hepatic metastases occurring in normal liver. Prolongation of the imaging window after SPIO administration might improve lesion-liver contrast, but structural and functional inhomo-geneity in cirrhosis could cause false-positive lesions...

Chronic liver failure

Patients admitted to intensive care with chronic liver failure may develop specific associated problems Alcohol the most frequent cause of cirrhosis in the western world acute withdrawal may lead to delirium tremens with severe agitation, hallucinations, seizures and cardiovascular disturbances.

Enlargement of Islets of Langerhans in Patients with Cirrhosis of the Liver

The Area Pancreatic Islets

In patients with cirrhosis of the liver (LC), it is known that glucose intolerance 29, 30 and pancreatic change related to portal hypertension 31 occur clinically. Pathologically, there are pancreatic fibrosis 32 and enlargements of islets 33, 34 (fig. 3). However, the relationship between glucose intolerance and the enlarged islets is not known. In 17 LC patients including any types causes, an area of the islets was statistically enlarged in 14, compared with that of controls as shown in table 4. Such findings were previously Fig. 3. The islet of Langerhans in a patient with cirrhosis of the liver. The islet was swollen and the number of B cells were decreased (a), compared to those in the control (b). Anti-insulin immunostain. X200. Fig. 3. The islet of Langerhans in a patient with cirrhosis of the liver. The islet was swollen and the number of B cells were decreased (a), compared to those in the control (b). Anti-insulin immunostain. X200. Table 4. Areas of islets, B cells and...

Extrapolations from Cirrhosis to Other Liver Diseases

However, extrapolating to patients with other liver diseases may be difficult. Different kinds of liver diseases may affect the pharmacokinetics of a drug differently. For example cholestatic and noncholestatic cirrhosis appear to affect the enzyme expression and or availability of specific enzymes in different ways 34, 35 . The amount of CYP1A2 appears to be decreased in both hepatocellular and cholestatic cirrhosis while the levels of CYP3A were only observed to decrease in patients with hepatocellular cirrhosis. The levels of CYP2E1 were reduced in patients with cholestatic cirrhosis while the decrease was seen at mRNA-but not protein-level in livers of patients with hepatocellular cirrhosis 34 . In contrast, markedly (5-10-fold) increases in CYP2E1 levels have been observed in alcoholics 36, 37 . Due to the discrepancies in effects of the different diseases, it is important to give information in the labeling regarding which population has been studied. If...

Fatty Liver Hepatitis And Cirrhosis

Chronic alcohol consumption can cause the deposition of excess triglycerol in the liver leading to a condition known as 'fatty liver'. This damage can lead to hepatitis and, if severe enough, to cirrhosis. The damage is thought to be due to the high concentrations of ethanal within the cell and if severe enough will result in cell death. Cell damage and death trigger an inflammatory response, i.e. infiltration of lymphocytes and activation of an immune response. If this is not treated it will lead to the formation of fibrous tissue and a severe reduction in the functioning of the liver.

Acute liver failure

Critically ill patients may present with acute liver failure or may develop it as part of multiple-organ failure. In both cases patients are generally catabolic, malnourished, and intolerant of water, sodium, and protein. The aim of treatment is to reduce catabolism, thus decreasing the plasma level of poorly tolerated aromatic and sulfated amino acids, and to support protein synthesis.

Hemodynamic effects of changes in lung volume

Descent will also compress the liver, increasing hepatic outflow resistance and decreasing flow from the splanchnic venous reservoirs to the right heart. Complicating this further, inspiration will shift venous flow from high-resistance splanchnic circuits, which must drain through the liver, to low-resistance systemic venous circuits, making flow greater for the same driving pressure. Thus inspiration may increase, decrease, or have no effect on venous return depending on which of these factors is predominant. Inspiration will increase venous return in volume-overloaded states, whereas venous return will decrease in hypovolemic states and hepatic cirrhosis.

The Concept of Conditional Essentiality

Some patients with cirrhosis of the liver require supplements of cysteine and tyrosine to maintain nitrogen balance and normal plasma levels of these amino acids. Plasma taurine concentration also declines in adults with low plasma cystine levels. Insufficient synthesis of these nutrients in cirrhotic patients has been attributed to impairment of the synthetic pathway in the diseased liver. In some cancer patients, plasma choline concentrations declined by 50 when they were maintained on TPN. This was attributed to precursors of choline bypassing the liver during feeding by TPN ( 18).

Other causes of haemosiderosis

Dietary iron overload may also occur as a result of chronic over-ingestion of iron-containing traditional home-brewed fermented maize beverages peculiar to sub-Saharan Africa, which overwhelms physiological controls on iron absorption. Iron stores may 50g and iron is initially deposited in both hepatocytes and Kupffer cells but when cirrhosis develops, accumulates in the pancreas, heart and other organs. Over-ingestion of medicinal iron may possibly have a similar though less dramatic effect but is certainly harmful to patients with iron-loading disorders. The excessive iron absorption seen in patients with chronic liver disease is associated with accumulation in Kupffer cells rather than hepatic parenchyma. Rare congenital defects associated with iron overload have been reported.

The routes and risks of addiction

The route of use also affects risk, most notably with the risk of infection from intravenous use, especially when needles are not cleaned or are shared. The majority of current intravenous users are hepatitis C positive and we can therefore expect cirrhosis to become a major cause of their death in the next decade or so. This also raises ethical and economic issues interferon treatment significantly reduces the progression of the disease but is costly and its routine use in addicts would be massively expensive and likely to cause public disquiet. The other main infections are hepatitis B and AIDS. The frightening rise of AIDS in drug abusers, where it occurred faster than in any other group, was the main impetus to the harm-reduction approach becoming the treatment style of the 1990s. Needle-exchange programmes and increased methadone availability were both proven to reduce the spread of AIDS and have become the cornerstone of treatment in many countries.

Characteristics of the alcoholmisusing population

The evidence concerning help-seeking in ethic minority groups is complex (see Ch.a.ptei 7.10.3). Harrison et al 64) have recently provided a review of the evidence. In the United States, Hispanics tend to be under-represented and African-Americans are over-represented in alcohol treatment compared with the general population prevalence. However, interpretation of the evidence is complicated by the fact that household surveys tend to under-represent socially disadvantaged individuals from ethnic minorities. In the United Kingdom, surveys such as the General Household Survey do not examine ethnicity, and estimates of prevalence tend to be based on indirect indicators of alcohol misuse such as cirrhosis mortality. For example, Marmot et al 65 found that cirrhosis mortality rates were elevated compared to the national average for men from the Asian subcontinent and from Ireland, but lower than average for African-Caribbean men. In women, cirrhosis mortality was lower than average in Asian...

Regulating the availability and conditions of use

With a general prohibition, typically the consumption of alcohol does fall in the population, and there are declines also in the rates of the direct consequences of drinking such as cirrhosis or alcohol-related mental disorders.(1 22) But prohibition also brings with it characteristic negative consequences, including the emergence and growth of an illicit market, and the crime associated with this. Partly for this reason, prohibition is not now a live option in any developed society, although it is in some other societies.

The effectiveness of specific types of regulation of availability

Generally, consumers show some response to the price of alcoholic beverages, as of all other commodities. If the price goes up, the drinker will drink less data from developed societies suggests this is at least as true of the heavy drinker as of the occasional drinker. (13) Studies have found that alcohol tax increases reduce the rates of traffic casualties, of cirrhosis mortality, and of incidents of violence. (2 ,29 Rationing the amount of alcohol sold to an individual potentially directly impacts on heavy drinkers, and has been shown to reduce levels both of intoxication-related problems such as violence, and of drinking-history-related problems such as cirrhosis mortality. (2,29 But while a form of rationing the medical prescription system is well accepted in most societies for psychoactive medications, it has proved politically unacceptable nowadays for alcoholic beverages in developed societies.

Multiple systems organ failure

Although abnormalities of liver blood tests are the most obvious manifestation of multiple systems organ failure, there is increasing evidence of a wide range of more subtle changes in hepatocellular metabolic function that may be of profound prognostic importance. The initial response to sepsis is associated with increased gluconeogenesis and a reprioritization of hepatic protein synthesis. The former is driven in part by increased glucose counter-regulatory hormones (cortisol, glucagon, and epinephrine (adrenaline)), but increased uptake of alanine for gluconeogenesis is also important. In bacteremic burns patients, hepatic glucose output doubled and alanine uptake by the liver rose fivefold. Protein anabolism and catabolism both increase, with peripheral release of amino acids available for hepatic uptake and acute phase protein synthesis. This enhanced acute phase protein synthesis and concomitant reduction in albumin synthesis is mediated by the release from Kupffer cells of a...

Chapter References

Fulminant and subfulminant hepatic failure definition and causes. In Acute liver failure improved understanding and better therapy (ed. R. Williams and R.D. Hughes), pp. 6-10. Mitre Press, London. O'Grady, J.G., Schalm, S., and Williams, R. (1993). Acute liver failure redefining the syndromes. Lancet, 342, 373-5. Wendon, J., Harrison, P., Keays, R., and Williams, R. (1994). Cerebral blood flow and metabolism in fulminant liver failure. Hepatology, 19, 1407-13.

Transplantation and other treatment options

Transplantation remains the treatment of choice for a subgroup of patients with a poor prognosis. A variety of models have been developed, including assessment of liver volume (volumes below 700 cm3 resulting in transplantation), assessment of percentage necrosis on biopsy (complicated by sampling error), and a variety of prognostic models. These need to be simple to apply in the clinical setting and to achieve a high level of sensitivity and specificity in discriminating survivors and non-survivors. Two models are commonly used in Europe. In the first, criteria for poor outcome in non-acetaminophen-induced liver failure have been established as the findings of coma or confusion in association with a factor V level below 20 per cent of normal in patients less than 30 years of age, or below 30 per cent of normal in those aged 30 years or above. In the second, the criteria separate acetaminophen and non-acetaminophen patients. For acetaminophen, the criteria are an arterial pH below 7.3...

Reduced plasma proteins

Reduced plasma drug binding will increase the volume of distribution by making more of the drug available for equilibration with extracellular tissues. This change will alter drug elimination half-life, irrespective of metabolism (t05 elim ln2 * VJC where t05 elim is the half-life, Vd is the volume of distribution, and Cl is clearance), thus making half-life a measure of little use in liver failure. The increase in the elimination half-life of lorazepam is purely a result of reduced binding.

Selection Criteria And Listing Process

The decision to proceed with transplantation requires a careful assessment of the etiology and staging of liver disease, the complications of cirrhosis, potential contraindications, and a comprehensive psychosocial evaluation. The results of the work-up may not be clear-cut and a determination to exclude a candidate can be difficult, especially when the alternative outcome to the patient is certain death. A Multidisciplinary Transplant Review Board, composed of all individuals involved in the different aspects of care of the transplant recipient, needs to weigh dispassionately the pros and cons of each candidate in order to reach a rational decision. Input from consulting physicians, psychiatry, ethicists and social workers is critical to resolve specific situations. Each candidate must have an advocate who presents his her case to the selection committee and the vote to proceed must be unanimous. The patient needs to meet minimal listing criteria before placed in the waiting list...

Assessing renal function

Serum creatinine is produced at a constant rate and has relevant characteristics that allow it to be used in the estimation of glomerular filtration rate. This equation should be used only when serum creatinine is stable and there are not continuing changes in renal function. The Cockroft and Gault equation is subject to significant error in patients with diminished muscle mass (the elderly, those with hepatic cirrhosis, and malnourished patients) (St. Peter 1993). In unstable patients, the estimated glomerular filtration rate is often an educated guess based on individual patient characteristics.

Effect of nutrition supplementation on patient outcome

Because malnutrition increases complications, one would theorize that providing nutrition support would improve nutritional status and therefore clinical outcomes. However, there are factors that interfere with improvement of nutritional status. First, achieving adequate nutrient intake can be difficult because the symptoms of liver failure (e.g., ascites, encephalopathy) impair a patient's appetite and food tolerance. In addition, there are potential impairments in nutrient absorption and metabolism induced by liver disease or associated complications such as infection. Nutrition supplementation, whether by the oral, tube feeding or parenteral route, may be necessary for individuals with serious liver disease to achieve adequate nutrient intake.

Was the substance truly blood Was it the patients blood

Variceal bleeding is rare in infancy, although gastroesophageal varices associated with portal hypertension are the most common cause of significant GI bleeding in older children. Gastroesophageal varices form in children with intrahepatic or extrahepatic causes of portal hypertension rarely in association with congenital heart disease or vascular malformations. Portal vein thrombosis is a common cause of extrahepatic obstruction. Risk factors include omphalitis, history of umbilical vein cannula-tion, and dehydration. Intrahepatic portal hypertension is caused by hepatic parenchymal disorders. More common associated diagnoses include biliary cirrhosis with biliary atresia, hepatitis, congenital hepatic fibrosis, ( -antitrypsin deficiency, and cystic fibrosis.

Oral Nutrition Supplementation

If a patient's nutrient intake is inadequate, he she should be counseled to eat small, frequent meals of nutrient-dense foods. If oral intake is still inadequate, oral nutrition supplements should be considered. Several studies evaluated the effect of oral nutrition supplementation on liver disease outcomes 26-28 . Cunha et al. attempted to improve nutrition status in 29 patients with alcoholic cirrhosis 27 .

Adr Reports Review Practices At The

After a case series is assembled and follow-up completed, it is analyzed for drug-relatedness. Several factors are important to this assessment. Temporal association describes the relationship between drug exposure and event. If the adverse effect preceded the drug exposure, the drug cannot have caused the effect. If the reaction resolves with the withdrawal of the drug, the dechallenge is positive if the reaction reoccurs with the re-initiation of the drug, the rechallenge is positive. Dechallenge is often cited as evidence of drug-relatedness. However, the lack of resolution (negative dechallenge) should not be viewed as evidence against an association. Many adverse effects, once initiated, follow a course of their own. This is especially apparent with certain blood dyscrasias, serious skin reactions and acute liver failure. Positive rechallenge has traditionally been cited as strong evidence of drug association. Our experience suggests that the absence of reoccurrence should not be...

Vitamins and Minerals

Because the liver is involved in the transport, storage and metabolism of micronutrients, it is reasonable to assume that liver disease could result in abnormal micronutrient activity and levels. Plasma and erythrocyte trace elements were measured in 50 patients with nonalcoholic liver disease 45 . Compared with controls, patients with cirrhosis had reduced serum levels of iron, zinc and selenium erythrocyte levels of glutathione and selenium were also low. Trace element decrease was not related to the degree of liver function impairment however, glutathione levels were related to the degree of failure. Micronutrient losses and needs are often dictated by the type of liver disease and specific conditions associated with liver failure. For example, alcoholic liver disease can create deficiencies of B vitamins. Deficiency of folate or B12 can cause macrocytic anemia B1 B6 and B12 deficiencies can cause neuropathy. In addition, Wernicke's encephalopathy is linked to thiamine deficiency....

Function tests should be obtained in any symptomatic child or

Cholestasis or gallstone formation can be seen. Liver disease associated with CF can progress to cirrhosis. About one quarter of patients with CF have liver involvement therefore, all patients need screening laboratory evaluations. Treatment with ursodeoxycholic acid seems to improve cholestasis but may not influence natural progression of disease.

The Hepatic Microvascular System

The portal blood represents a route through which infectious gut-derived organisms can enter the liver. Specific mechanisms have evolved to instigate and regulate inflammatory responses against invading pathogens. The close proximity and cross-talk between the different cells within the liver dictates that many of the hepatic cells are involved in an inflammatory response. Unfortunately the development of an inflammatory response, if uncontrolled, can manifest in permanent liver injury. Indeed, there is irrefutable evidence for the involvement of inflammatory cells in a large number of known liver diseases, including alcoholic hepatitis and cirrhosis, viral hepatitis, ischemia-reperfusion injury (transplantation, tumor resection, shock), sepsis- or endotoxin-induced liver injury, acute and chronic rejection, primary biliary cirrhosis, and primary sclerosing cholangi-tis. Following is an overview of the inflammatory cells, molecules and mechanisms used by the liver to combat and...

Differential Diagnosis

And precise treatment of HCC in cirrhotic liver. One study found no significant difference in the number of Kupffer cells between well-differentiated HCC and surrounding liver tissue (Tanaka et al., 1996). It should thus be noted that phago-cytic activity might overlap among borderline lesions. Another study reported that the ratio of the intensity of tumorous lesion to that of non-tumorous areas on SPIO-enhanced MR images (SPIO intensity ratio) correlated inversely with the Kupffer-cell-count ratio in HCCs and dysplastic nodules and increased as the degree of differentiation of HCCs decreased (Imai et al., 2000). This indicates that the uptake of SPIO in HCCs decreased as the degree of differentiation of HCCs declined.

Liver Transplantation

In patients with acute or subacute liver failure requiring urgent transplantation there is little time to do an extensive preoperative evaluation. Most patients however have to wait a significant amount of time for their transplant, and therefore evaluation should be complete. Anesthesiologists should be part of the multidisciplinary team determining appropriate candidacy for transplantation for patients with severe liver disease.

Special Issues In Organ Transplantation

The most salient psychosocial issue and controversy in liver transplantation is the transplantation of patients with alcoholic liver cirrhosis. There is slowly emerging data on the most important questions initially asked about liver transplantation in alcoholics. These scientific questions have always existed in the context of the larger questions of ethics, moralization and the reality of public perception. The scientific questions have been about survival, return to drinking and quality of life. The ethical question goes as follows if we have a scarce resource like donor livers should we allow alcoholics who presumably shoulder a greater responsibility for their illness to receive equal consideration for transplantation The fact is that alcohol cirrhosis and recently hepatitis C, which in some cases is the consequence of IV drug abuse, are the most common causes for cirrhosis. As the waiting lists rise, it will be important to have data to support the rationale in transplantation...

Psychopharmacological treatments

The liver is the major organ for biotransformation and elimination of psychotropic drugs. Any dysfunction may result in drug accumulation and alteration of pharmacological effects. Drug elimination by the liver depends on its intrinsic activity, on hepatic blood flow, and on the extent of drug binding to plasma proteins. Acute inflammatory disease impairs metabolizing activity, whereas blood flow is reduced in cirrhosis. Decreased metabolizing activity affects poorly extracted drugs (e.g. benzodiazepines and barbiturates), whereas reduced blood flow decreases hepatic clearance of highly extracted drugs (e.g. tricyclic antidepressants). Decreased protein synthesis and drug binding to plasma proteins may increase the free fraction of psychoactive drugs. The drug classes most affected by liver disease are barbiturates, 2-keto-benzodiazepines (chlordiazepoxide, diazepam, and flurazepam), and tricyclic antidepressants.

Bloodborne Pathogens In the Workplace Debra L Hunt Jerry J Tulis MD

Hepatitis B virus is transmitted parenterally, sexually, and perinatally, and is the major cause, worldwide, of acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. High risk groups in industrialized countries include intravenous drug users, homosexual men, and those with multiple sexual partners (113). Others at substantial risk of infection include hemodialysis patients, institutionalized patients, and healthcare workers with occupational exposure to blood (114).

Hepatitis C Virus RNA

HCV is the major cause of parenterally transmitted non-A, non-B hepatitis (Choo et al., 1989). Until the virus was characterized, diagnosis was made by exclusion of all other known causes of hepatitis. Antibody against HCV is found in over 80 of patients with well-documented non-A, non-B hepatitis. Chronic HCV is characterized by fluctuating alanine aminotransferase (ALT) levels and recognizable changes in liver histology, which may lead to cirrhosis and hepatocellular carcinoma (Alter et al., 1990). Therapy with interferon-a has been approved by the Food and Drug Administration (FDA) and can be effective in eliminating the virus. However, less than half of HCV-infected individuals respond to treatment, and relapse is common (David et al., 1989).

Ethical considerations

The appropriateness of allocating finite resources to the terminally ill is frequently challenged, and as AIDS is a progressive disease and has no cure many health care workers have questioned the validity of decisions to allow HIV-infected patients to receive intensive care. Patients with AIDS have the same right of access to intensive care as non-HIV-infected patients with conditions such as cirrhosis with varices, severe chronic heart failure with angina, or unresectable non-small-cell lung

Epithelioid haemangioendothelioma

Suggestion of a relationship to oral contraceptive use has not been validated 1270 . Epithelioid haemangioendothe-lioma causes systemic symptoms (weakness, malaise, anorexia, episodic vomiting, upper abdominal pain, and weight loss) and hepato-splenomegaly 807, 1150 . Some patients develop jaundice and liver failure. Uncommon modes of presentation include the Budd-Chiari syndrome 2040 or portal hypertension. Macroscopy. Macroscopically, lesions are usually multifocal ill-defined lesions scattered throughout the liver vary from a few millimeters to several centimeters in greatest dimension. They are firm, tan to white on sectioning, and often have a hyperaemic periphery calcification may be evident grossly.

Exposure to Manganese

More recent neuroimaging studies of symptomatic patients in CMI showed prominent involvement of the globus pallidus, sparing the dopaminergic system 116 , while a recent study of a woman with severe liver failure and symmetric hyperintensity of the globus pallidus in MRI images showed increased serum manganese levels, and neuropathological examination of the globus pallidus was consistent with manganese neurotoxicity 117 . Recent positron emission tomography (PET) studies in chronic Mn intoxication, using 99mTc-TRODAT-1, a tracer of dopamine transporter binding, showed a mild decrease of its uptake in the putamen and the ratio of putamen and caudate when compared with normal controls. Although the 99mTc-TRODAT-1 shows a slight decrease in the putamen of manganese patients, the data indicate that the presynapic dopaminergic terminals are not the main target of CMI 118 .

Clinical features

Ness, hepatic pain, jaundice, anorexia, and weight loss. Constitutional symptoms, such as malaise, fatigue, and fever may be present. On examination, nodules or a mass are felt in up to 50 of the cases, and a friction bruit may be heard on auscultation. Unfortunately, symptomatic presentation is associated with bulky, rapidly progressive tumours with a poor prognosis 2035 . Rarely, patients present with fulminant hepatic failure, obstructive jaundice, or intraperitoneal haemorrhage. Functioning neuroendocrine tumours produce syndromes of hormonal excess. 'Carcinomatous cirrhosis' with jaundice, ascites, and bleeding varices due to diffuse infiltration of the liver, usually by metastatic breast carcinoma, has been described 174 .

IIA General Aspects of NO in the Liver

Cells in the liver can be divided into the hepatic parench-ymal cells (hepatocytes) and the hepatic nonparenchymal cells, which are further subdivided into endothelial cells, smooth muscle cells, Kupffer cells, and hepatic stellate cells. Both hepatic parenchymal cells and hepatic nonparenchymal cells can express iNOS, whereas eNOS is constitutively expressed in hepatic endothelial cells. Although iNOS is not thought to be expressed constitutively in healthy liver, it is readily upregulated in the liver under a number of disease conditions, including ischemia-reperfusion injury, cirrhosis, hepatitis, and liver regeneration (1-4). The iNOS is also upre-gulated in vitro in hepatocytes and Kupper cells in response to endotoxin, proinflammatory cytokines, such as tumor necrosis factor-a (TNF-a), interleukin-1 (IL-1 ), and interferon , as well as their combinations (5). These stimuli often act synergistically to induce iNOS expression however, IL-1 alone is an effective stimulator of iNOS...

Prevention and Treatment

Hepatitis B, formerly known as serum hepatitis, represents over 40 of the cases of viral hepatitis in the United States. Approximately 240,000 new cases occur each year, and as many as 1 to 6 of the infected adults will become carriers of the disease. About 1.25 million people in the United States have chronic hepatitis B and therefore an increased risk of death from cirrhosis and liver cancer. Hepatitis B infects at least 5 of the world's population and is the ninth leading cause of death worldwide.

Clinical aspects of PMPS

PMPS usually presents within the first few months of life with hypoproliferative SA, variable cytopenias and pancreatic exocrine dysfunction. Bone marrow examination reveals, in addition to ring sideroblasts, striking vacuolation of the erythroid and myeloid precursors (Plate 12.1). Metabolic acidosis is another frequent manifestation, and renal disease, liver failure, hypoparathyroidism and diabetes mellitus may also occur. Despite treatment with blood products, pancreatic enzymes and various vitamins (e.g. coenzyme Q), about half of the patients do not survive beyond the third year of life. Of the patients who do survive, most develop complications in other organs, particularly ophthalmoplegia, pigmentary degeneration of the retina and cardiomyopathy that is, the features originally described as the Kearns-Sayre syndrome (KSS). The overlap between PMPS and KSS is not surprising, since similar genetic lesions are found in both conditions (see below).

IIIB Biological Functions of Three Products of HO1

The bile pigment biliverdin is produced as a consequence of the heme degradation by HO and is then reduced to biliru-bin. Cytoprotection by bilirubin is not an intuitively intriguing concept to most hepatologists, and, as a sign in liver damages, removal of bile pigments is a potential beneficial factor of modern supportive treatment strategies in acute liver failure, such as albumin dialysis (35). On the other hand, cells primed by a wide variety of toxic compounds, such as heavy metals, develop tolerance to subsequent, otherwise lethal injury. Moreover, there is good evidence to suggest a significant role for bile pigments as a cellular antioxidant system (36).

Chronic Liver Disease in taut Mice

Taurine was identified as an important organic osmolyte in hepatic parenchymal and nonparenchymal cells with impact for immune functions such as phagocytosis, prostanoid, and cytokine formation (Peters-Regehr et al., 1999 Warskulat et al., 1997 Weik et al., 1998). Plasma taurine levels are decreased in liver cirrhosis (Weisdorf et al., 1987 Yamamoto, 1996).

Tumourassociated antigens

AFP is a 70 kDa glycoprotein found in the circulatory system of the developing foetus. It is synthesized primarily by the yolk sac and (foetal) liver. AFP is present only in vanishing low quantities in the serum of adults (where it is replaced by serum albumin). Elevated adult serum levels of this marker are often associated with various cancers of the liver, as well as germ cell tumours. It is also sometimes expressed by gastric and pancreatic cancer cells. Although a useful tumour marker, increased serum AFP levels also often accompany cirrhosis and some other non-cancerous liver diseases.


The lactate level at any time is a balance between its production and its elimination. Overproduction of pyruvate, and hence of lactate, occurs primarily as the result of inadequate oxygenation as outlined above, although some can be produced from protein catabolism. Therefore excessive muscle breakdown, as seen in critical illness, could contribute to raised lactate levels. Since elimination occurs primarily in the liver, liver failure might be expected to cause abnormally high lactate levels. Patients with stable cirrhosis maintain relatively normal levels, but the presence of liver disease can certainly magnify levels already raised due to circulatory failure and slow down their return to normal once resuscitation is complete.

Conformational Diseases

In a-1-antitrypsin deficiency, a mutation hinders the proper folding of the protein in the ER of liver cells. The misfolded protein tends to form oligomers that are targeted for degradation (Carrell and Lomas 2002). In heterozygous carriers and in homozygous patients with the lung form of the disease, the capacity of degradation components of the protein quality control system is sufficient to cope with the accumulated protein. However, owing to a yet unexplained decrease in the degradation capacity found in 10 -15 of ho-mozygous patients, the protein aggregates cannot be eliminated in the liver cells of such individuals and they develop cirrhosis-like liver damage and hepatocellular carcinoma (Wu et al. 1994).

Galactose elimination capacity

Galactose is eliminated from the liver via a phosphorylation pathway involving galactokinase. When this enzyme is saturated, the hepatic galactose clearance follows zero-order kinetics and can be used as a determinant of hepatic function. It has been shown in animals to be proportional to the functioning mass of hepatocytes. In this test 0.5 g kg of galactose is injected intravenously (Iygstrup.J966) and galactose levels are then measured in the serum to determine clearance between 20 and 50 min following injection. Values below 2 mg kg min are incompatible with survival and probably relate to extrahapatic galactose clearance. This test has been shown to be able to predict survival in patients with primary biliary cirrhosis and to correlate with outcome following interferon treatment for hepatitis B.

Indocyanine green clearance

Therefore interpretation of this test must take into account the varying effects of both liver blood flow and hepatic extraction. In order to quantify the extraction ratio in patients with liver dysfunction, it is necessary to sample indocyanine green concentrations across the liver from the hepatic vein and a peripheral artery. When high levels of indocyanine green are given, the uptake process becomes saturated and the maximal clearance, which equates to the functioning mass of hepatocytes, can be calculated. Reports have suggested that this test can be used as an independent variable in the assessment of prognosis for patients with cirrhosis, in patients awaiting liver transplantation, and in the assessment of potential donor grafts.

Mechanically ventilated patients

The main problems during analgesia and sedation occur in patients who are ventilated for more than 5 days. Sepsis, acute respiratory distress syndrome, renal and liver failure, specific procedures such as the prone position, weaning problems, and sympathetic hyperactivity syndromes (e.g. withdrawal from chronic alcohol abuse) may significantly complicate the control of adequate analgesia and sedation. In general, there seems little sense in using ultra-short-acting substances in patients with an expected duration of treatment of several days or even weeks. Sufentanil may be an exception due to its higher affinity with the opioid receptor, lower tolerance development, and less pronounced withdrawal symptoms. Clonidine may be added if initial signs of tolerance development occur or even earlier to facilitate the control of analgesia and sedation. It should be also considered if sympathetic hyperactivity syndromes (agitation, tachycardia, hypertension) develop during the weaning phase....

Liver DiseasesA Variety of Conditions

There are numerous reasons for impairment of the hepatic function. In the western world, chronic alcohol abuse is one of the main causes of liver disease and can cause steatosis, alcohol hepatitis, and cirrhosis. Cirrhosis is not a disease in itself but a stage in the course of inflammatory liver diseases. Cirrhosis can be caused by liver damage resulting from alcoholism, hepatitis B and hepatitis C, drugs, metabolic disorders, prolonged cholestasis, etc. Cirrhosis is characterized by increased presence of fibrous tissue, destruction of the lobular architecture and sinusoidal network, and nodular degeneration. The hepatic synthesis of proteins such as albumin, prothrombin, and enzymes is decreased. Cirrhosis often gives rise to portal hypertension. In portal hypertension, the blood flow coming from the intestine through the liver via vena porta is reduced while the arterial blood flow is increased relative to the portal flow. Many cirrhotic patients have portacaval shunts, where a...

Estimates of Liver Function

Child-Turcotte classification is an empirical but commonly accepted way to estimate the grade of cirrhosis even though it is not known to what extent it may be used to estimate hepatic function. In 1973, Pugh used Child's classification system but added the prothrombin time when he wanted to classify patients in a study with regard to the risk related to surgery of the oesophagus 32 . Since then, the degree of liver dysfunction is determined mainly by ranking the patient according to the Child-Pugh classification. Using this classification, the patients are grouped into mild, moderate, or severe impairment based on both two clinical symptoms of liver disease (encephalopathy and ascites) and three clinical chemistry parameters (S-albumin, S-bilirubin, and prothrombin time) (Table 1).

HFEassociated hemochromatosis

The most common form of hemochromatosis was classically described as the triad of cirrhosis, diabetes and skin melanosis ('bronze diabetes'). It is a late-onset disorder, which is inherited in an autosomal recessive pattern and characterized by iron deposition in parenchymal cells of the liver, pancreas and heart. Macrophages of the reticuloendothelial system are relatively spared. This disorder results from a small but chronic increase in intestinal iron absorption, averaging about two-to three-fold above the normal level. Over time, the presence of iron causes damage by promoting the formation of toxic oxygen radicals, which attack cellular structures and thereby cause reactive fibrosis. The earliest manifestation of HFE-as-sociated hemochromatosis is increased transferrin saturation, often approaching 100 before tissue iron deposition is noted. The treatment for hemochromatosis is phlebotomy, and this has been used effectively for more than half a century. Initially, blood is...

Toxicity in Either

Androgen administration to male or female adults, especially at high dosages, results in erythrocytosis and polycythemia, fluid retention, and it may produce or exacerbate edema. This can be serious when associated with congestive heart failure, cirrhosis of the liver, or nephrotic syndrome. Since androgens stimulate the activity of sebaceous glands, oily skin and acne are found in some individuals who are receiving androgen therapy. A change in cholesterol levels can result from androgen therapy, such as decreased levels of high-density lipoprotein cholesterol and increased levels of low-density lipoprotein cholesterol. This change in the distribution of cholesterol may contribute to increased risk of atherosclerosis and coronary artery disease, especially in athletes who are exposed for long periods to high levels of anabolic steroids.

Selection of sedatives and modes of administration

The selection of an appropriate sedative drug in ICU patients depends on the comorbidity of the patient, on wanted and unwanted effects of the drug, and on the expected duration of therapy. Benzodiazepines should be chosen for short- and intermediate-term sedation, particularly if anxiolytic and anticonvulsive effects are desired. Haloperidol or other butyrophenones are preferable in psychotic patients and in delirium. Owing to its pharmacokinetic properties, propofol may be favored in liver failure and in situations when rapid recovery from sedation is desired. Finally, the remarkable costs of sedative drugs should be taken into account.

Survey of Recombinant Viral Vaccines Currently under Development 6211 Herpes viruses

Hepatitis C virus (HCV) is thought to be the major causative agent of non-A, non-B hepatitis, which can lead to cirrhosis, liver failure and liver cancer (Flint & McKeating 2000). Currently 170 million people are infected worldwide, and the only available treatment (interferon-a with ribavirin) is expensive and only moderately effective. A vaccine is thus a high priority, but efforts are hampered by the lack of a small animal model and the inability to routinely support HCV replication in vitro in cultured cells. Conventional neutralizing assays cannot, therefore, be performed, although there are conflicting reports that vesicular stomatitis virus (VSV) HCV pseudotyped virus expressing combinations of E1 and E2 glycoproteins can be produced by transfected BHK cells (and possibly primary hepatocyte and human hepatoma cell lines) and be neutralized by homologous antisera (Buonocore et al. 2002 Lagging et al. 1998 Matsuura et al. 2001).

Hepatocellular Carcinomaintroduction

Multifokal Hcc

Spread transmission of viral hepatitis, specifically of types B and C, during the 1970s and early 1980s, when illicit use of intravenous narcotics, needle sharing, unsafe sexual activity, and transfusion of unsafe blood and blood products were common practices (Bruix et al. 2001). Patients with liver cirrhosis are at greatest risk for developing HCC and should be monitored every 6 months to detect the tumor at an asymptomatic stage (Bruix and Llovet 2002). The Barcelona-Clinic Liver Cancer (BCLC) group has developed a system that stratifies patients into four categories based on performance status, severity of liver dysfunction caused by the underlying cirrhosis, and the kind of tumor involvement, thus simultaneously setting prognosis and guiding treatment (Llovet et al. 1999a). In the BCLC staging classification, patients who have early-stage HCC, who have a good performance status, Child-Pugh class A or B cirrhosis and an asymptomatic single tumor smaller than 5 cm or as many as...

Distribution in Pathologic States

Alcoholic Liver Cirrhosis We did not identify myofibroblast proliferation in the duct walls of the pancreas of alcoholic liver cirrhosis patients without CP. Myofibroblasts uniformly proliferated in the periacinar space (fig. 5), where fibrosis was observed, in pancreas tissues obtained from autopsy cases with alcoholic liver cirrhosis 57 . These cells are thought to be derived from pancreatic stellate cells similar to Ito cells in the liver. Moroboshi et al. reported that periacinar fibrosis accompanied with no inflammatory changes were observed in the pancreata of hard drinkers, and suggested the existence of not only secondary fibrosis due to parenchymal inflammation but also primary fibrosis 22 . In the livers of cases Fig. 5. Myofibroblasts, a-SMA-positive cells, proliferating in the periacinar area of a patient with alcoholic liver cirrhosis. Immunostain for a-SMA. X200. Reproduced with permission 23 . with alcoholism, similar fibrosis in absence of hepatitis, which is called...

Distribution of Pancreatic Fibrosis


The distribution of fibrosis mostly corresponds to or is based on individual causes, as shown in table 1. Pancreatic fibrosis or chronic pancreatitis due to pancreatic duct obstruction is known as chronic obstructive pancreatitis (COP), which is characterized by both inter- and intralobular fibrosis and lobular acinar atrophy. Autoimmune pancreatitis (AIP), recently a focus of attention, shows a similar fibrosis pattern to COP, except that it is accompanied by marked lymphoplasmacytic infiltration 8 . Fibrosis due to biliary diseases such as gallstones or choledochal cysts is distributed in the interlobular and periductal areas 9 . Fibrosis after acute pancreatitis includes surrounding areas of both necrosis and lobules the latter is called perilobular fibrosis 4 . Fibrosis in hemochromatosis or severe hemosiderosis is found in diffuse intralobular and periinsular areas 6 . However, as for chronic alcohol abuse, which is the most common cause of pancreatic fibrosis, it remains...

Microvascular Actions of CO

Hifas Aseptadas

Demonstrated intrahepatic distribution of two major HO isozymes immunohistochemically, with the finding that the two isozymes have distinct topographic patterns HO-1, the inducible form, is expressed prominently in Kupffer cells, while the constitutive HO-2 is abundant in hepatocytes 11 . CO derived from HO-2 is necessary to keep sinusoids in a relaxing state through mechanisms involving sGC in hepatic stellate cells (HSC), also known as Ito cells, that constitute microvascular pericytes in this organ. HSC cultured on silicon membrane-coated dishes exhibited wrinkling formation through their intercellular connection of cytoplasmic processes and can respond to micromolar levels of CO to reduce the density of wrinkles, suggesting a relaxing response (Figure 2). Considering the microanatomical orientation of the liver cells in and around sinusoids, HO-2 in parenchyma stands in a reasonable position for the gas reception by HSC where CO released from hepatocytes can directly access to the...

Association of Polymorphisms in DME and Drug Transporters with Disease Susceptibility and Progression

Biliverdin Ixa

Deaths from chronic liver disease have increased threefold in the United Kingdom during the last three decades (8). The mortality can largely be attributed to alcoholic liver disease and viral hepatitis. Two-thirds of deaths from liver cirrhosis occur in patients under the age of 65 years (8). Alcohol is a major contributor to death, injuries, and illness, accounting for 10.3 of disability adjusted life years among established market economies, compared with 11.7 for tobacco and 2.3 for illicit drugs. The U.S. Veterans Administration Twin Panel Study showed a higher concordance for cirrhosis in monozygotic twins (17 ) compared with dizygotic twins (5 ), indicating that genetic factors contribute to susceptibility although most of the liability for cirrhosis occurs due to the shared risk for alcoholism (9,10). The strongest genetic association with alcoholism has been shown to be with genes encoding alcohol-metabolizing enzymes. An estimated 0.5 to 1 of the U.K. population and 170...

Agnogenic Myeloid Metaplasiamyelofibrosis

Hepatic myeloid metaplasia (extramedullary hematopoiesis) also commonly occurs in patients with agnogenic myeloid meta-plasia-myelofibrosis and may occupy up to 30 percent of the hepatic lobule134 (Plate 3-1O-Q). The basic liver architecture is preserved, but erythroblasts and megakaryocytes occupy the hepatic sinusoids and granulocytic precursors reside in the portal tracts. This distribution mimics normal mammalian embry-otic hematopoiesis. As the disease progresses, the hematopoiesis becomes more immature but neoplastic invasion of the liver does not occur. Hepatic fibrosis is generally minimal, although patients with portal hypertension and cirrhosis have been described.134,135 Such severe complications may be due to postsi-nusoidal obstruction (Budd-Chiari syndrome), presinusoidal thrombotic obstruction, or sinusoidal obstruction secondary to EMH coupled with a high portal blood flow.135

Structures by Inflammation

Varicose Veins Splenic Hilum

In our histopathological study of surgical and autopsy specimens from 12 patients with chronic alcoholic pancreatitis, fibrosis in the pancreatic parenchyma continuously extended to the wall of the splenic vein in 11 specimens 5 patients showed organized thrombus formation with recanalization, 4 presented with phlebosclerosis and in 2 there were no apparent changes. In 2 of the 5 patients with organized thrombus formation in the splenic vein, localized portal hypertension had been clinically diagnosed these patients had shown splenomegaly and varicose veins in the fundus of the stomach, but not liver cirrhosis.

Immunological Response To Cancer

Orbital Tumor

Tumor-associated antigens (TAAs) The TAAs can be found in both normal and cancer cells, but their expression is greatly increased in tumors. They include the so-called oncofetal antigens, usually present during embryonic and fetal development, but either absent or present at very low levels in normal adult tissue. The two most important antigens of this group are represented by the carcinoembryonic antigen (CEA) (colon, pancreas, lung, breast, and prostate cancers, cirrhosis of the liver, chronic lung disease, and serum of heavy smokers), and a-fetoprotein (AFP) (liver and testicular cancer).7

Hcv Rna Detection and Quantitation

HCV viral load testing is useful in pretreatment evaluations of patients being considered for therapy, since a viral load of less than 2 x 106 copies ml (800,000IU ml) is one of several predictors of achieving a sustained virological response.51,52 Other factors associated with achieving a sustained response to therapy include the absence of cirrhosis, age less than 40 years, female gender, white race, and viral genotype other than 1. Viral load testing also can be used in an early assessment of viral kinetics in patients treated with IFN alone or with pegylated IFN plus ribavirin.42,43 Patients who fail to achieve less than a 2 logi0 decline in viral load with treatment have little chance of achieving a sustained virological response to these therapies.

Why Mystinia Gravis Exhibits Greater Toxicity With Aminoglycosides

Once the drug is within the lysosomes, it will bind to anionic phospholipids, inhibiting lysosomal phospholi-pase A2. This leads to lysosomal distension, rupture, and release of acid hydrolases and the aminoglycoside into the cytosol. Free aminoglycoside then binds to other cellular organelles. Gentamicin accumulation in mitochondria displaces Ca++, leading to mitochondrial degeneration and cell necrosis. The necrotic cellular debris then sloughs off and is passed in the urine, leaving a denuded basement membrane. The development of toxicity depends upon the duration of aminoglycoside therapy and the mean trough blood plasma drug concentration. Nephrotoxicity is more likely in aminogly-coside-treated patients with gram-negative bacillary bacteremia than in those with staphylococcal bac-teremia. Nephrotoxicity is most common and most severe in patients with extrahepatic biliary obstruction, hepatitis, or cirrhosis.

Chronic Alcoholic Pancreatitis

In the early stage of the disease, mild interlobular fibrosis is seen the original interlobular stroma becomes lengthened or widened with fibrosis (fig. 1a). When this interlobular fibrosis progresses, and protein plugs or stones are formed in the pancreatic duct, atrophy of the lobules commences atrophy and loss of acinar cells are seen 3 . So called 'nodular pancreatitis' is observed in some cases, in which severe inflammatory and repair reactions leave some lobules island-like, or nodular 7, 8 . In the advanced stage, most parenchyma is lost, leaving ducts and Langerhans islets isolated. Even in such severe cases, the shapes of the lobules usually retain their nodular, or so-called cirrhosis-like, appearance (fig. 1b, c). It is worth noting that, in chronic alcoholism or heavy drinkers, fibrosis is distributed intralobularly, in particular, periacinarly 5, 11 . Hence, the pathology of chronic alcoholism is quite distinct from CAP. Clinically, patients with chronic alcoholism also...

Mechanisms Of The Effects Of Oxidants And Antioxidants On Inflammation And Immune Function

Oxidant damage to cells will indirectly create a pro-inflammatory effect by the production of lipid peroxides. This situation may also lead to upregulation of NFkB activity, as the transcription factor has been shown to be activated in endothelial cells cultured with linoleic acid, the main dietary n-6 poly-unsaturated fatty acid, an effect inhibited by vitamin E and NAC (36). The interaction between oxidant stress and an impaired ability to synthesize glutathione that results in enhanced inflammation is clearly seen in cirrhosis, a disease that results in high levels of oxidative stress and an impaired ability to synthesize GSH (37). In this study, an inverse relationship between glutathione concentration and the ability of monocytes to produce IL-1, IL-8, and TNF-a was observed. Furthermore, treatment of the patients with the GSH prodrug, oxothiazalidine-4-carboxylate (procysteine), increased monocyte GSH content and reduced IL-1, IL-8, and TNF-a production (Fig. 5.5). Thus,...

Complications and comorbidities

Alcohol becomes an increasingly potent neurotoxin with age.(4) Alcohol intoxication and withdrawal can both be more severe in elderly people than in younger adults. Cognition is often impaired in recently detoxified alcoholics of all ages, but deficits are greater and more long lasting in older patients, with improvements noted as long as 5 years after initiation of abstinence. In non-amnesic chronic alcoholics, alcohol neurotoxicity is suggested by a number of deficits in neuropsychological performance and by brain imaging studies demonstrating atrophy of both grey and white matter in the cerebral cortex, especially in frontal areas. (9,19 Cortical changes occur in older alcoholic individuals beginning in about the fifth decade, and are over and above the changes associated with normal ageing. Dementia associated with chronic alcoholism accounts for as many as 20 to 25 per cent of cases in dementia cohorts. It lacks the dense amnesia found in Wernicke-Korsakoff syndrome and may be...

Mediators of Hepatic Inflammation

Prostaglandins and leukotrienes are ubiquitous mediators of liver function and disease. In the inflamed liver, Kupffer cells produce prostaglandins to modulate hepatic glucose metabolism. Upregulation of glucose correlates with the increasing demand for energetic fuel by the inflammatory cells such as leukocytes, sinusoidal endothelial cells, and Kupffer cells. Studies have also demonstrated a protective role of PGE2 in viral hepatitis as it abrogates the induction of TNFa, attenuating the expression of antigens on hepato-cytes, and may inhibit viral replication. By contrast, in cirrhosis and fulminant hepatic failure a dysregulation of prostaglandin metabolism has been noted. Leukotrienes (e.g., LTB4) have vasoconstrictive and metabolic effects in the liver. These mediators have been shown to cause liver injury in ischemia-reperfusion and endotoxemia.

Sex Hormonebinding Proteins

SHBG levels are known to be influenced by a variety of clinical conditions. In females, the high estrogen levels of pregnancy or the use of oral contraceptives result in increased SHBG concentrations. In males, elevated levels of SHBG are seen most commonly in individuals with liver cirrhosis or during normal aging. Elevated SHBG levels are also seen in hyperthyroidism and hypogonadism. All of these conditions are associated with elevated estrogen levels, which result in increased hepatic SHBG synthesis. SHBG levels are suppressed by androgen replacement or chronic glucocorticoid therapy. Elevations of SHBG do not necessarily result in a fall in free testosterone levels. When assessing the androgenic status of an individual, whether male or female, it is necessary to measure both total and free testosterone plasma levels.

Table 52 Some Key Definitions for Hazard Identification

2.4.3 Assessing the Toxicological Significance of Observed Effects In some instances, the risk assessor must evaluate the toxicological significance of the observed effects, for example when the effect is reversible. A reversible change is often an adaptive or compensatory response to stress or may be an overt adverse response that the body can repair. Reversible changes return to normal or within normal limits either during the course of or following exposure. An irreversible change persists or may progress even after exposure ceases (22). It must be recognized that although a change may be reversible when exposure is terminated, it still may be adverse to an organism. In fact, depending upon the changes observed at the various dose levels tested, a potentially reversible change may well be selected as the critical effect in the dose-response assessment because reversibility often depends on the magnitude of the dose and the duration of exposure. The longer the test species receives...

Analytical Epidemiology

Combined high dietary intake of iron and manganese may result in an increased risk for PD (85). Dietary intake of manganese alone does not seem to have toxic effects, except in individuals with liver failure (86). Further complicating the study of metals as risk factors is the finding that certain exposure combinations may be associated with increased risk, while each single exposure at a similar level is not.

Pharmacokineticsdrug disposition

Nandrolone Decanoate Kinetics Curve

After oral administration drugs go via the portal circulation to the liver. If hepatic metabolism is extensive, a large amount of drug will be removed during this first passage through the liver. Thus, even if a drug is extensively absorbed, first-pass removal will reduce its systemic availability. For example, clomethiazole has extensive first-pass metabolism in the liver, and its systemic availability is low (about 40 per cent) thus, intravenous doses are considerably lower than oral doses. In severe liver disease, such as cirrhosis, or when there is arteriovenous shunting, this presystemic metabolism is reduced and the systemic availability increases up to 90 per cent oral doses of clomethiazole should be reduced in liver disease. (6)

Giuseppe Barbanti Brodano

Important causes of human tumors are biologic and environmental agents, mostly of a chemical and physical nature, that act by genotoxic mechanisms which induce alterations in the cell genome such as chromosomal deletions, rearrangements, and mutations. In the complex multi-factorial pathogenesis of cancer, viruses often participate as biologic cofactors that cooperate with chemical and physical agents in both the initiation and progression of tumors. Thus, the detection of a tumor virus in a given tumor does not establish causation. Moreover, the genetic background of an individual and his her immune status at the time of infection or during viral latency may influence susceptibility to various carcinogens, especially viral carcinogens. Often, it appears that oncogenic viruses act at the beginning of tumor development, inducing in the host cell a number of genetic alterations and immortalizations that can lead to tumor growth. Viruses at other times can be oncogenic only upon...

The availability of alcohol treatment services

The availability of alcohol services is likely to affect the overall impact of public health measures to reduce alcohol use disorders. There is some evidence that the availability of alcohol treatment services has an effect on the prevalence of alcohol use disorders at a population level. Mann et al.(80) found that increased treatment services in Ontario, Canada, were associated with decreased hospital discharges for liver cirrhosis. A similar study in North Carolina examining the 20-year period between 1968 and 1987 found an association between increased alcohol treatment admissions and decreased cirrhosis mortality. Further, Mann et al 1 found a relationship between AA membership and alcohol-related problems including cirrhosis rates in the United States, Canada, and other countries. They estimated that a 1 per cent increase in AA membership was associated with a 0.06 per cent decrease in cirrhosis mortality. These studies of course demonstrate associations rather than causal links...

Effects of Impaired Liver Function on Pharmacokinetic Parameters

The hepatic blood-flow may be decreased in cirrhosis but predictions of the effect on pharmacokinetic parameters are ambiguous. Reduced blood flow and shunting can both increase the bioavailability of drugs subject to hepatic first pass metabolism and also reduce the systemic hepatic clearance of drugs depending on their extraction ratio 3 . Drug metabolism catalyzed by cytochrome P450 enzymes is generally decreased in cirrhosis whereas it may, at present, be less predictable and have been less investigated in other liver diseases. The reduced metabolism in cirrhosis is probably due both to reduced viable cell-mass and as well as reduced enzyme synthesis in the hepatocytes. Decreases have been observed in mRNA-level and protein-level as well as in enzyme activity 34, 35 . The sensitivity to liver disease appears to vary between enzymes 38 . Drug metabolism catalyzed by CYP2C19 appears to be markedly decreased in patients with cirrhosis while the CYP2D6 activity seems less affected 39...

Diagnosis of pleural effusions

Although radiographic studies and a careful physical examination will usually confirm the presence of a pleural effusion, determining the etiology of the effusion often requires thoracentesis. Pleural fluid analysis categorizes effusions as either transudates or exudates. Transudates are effusions resulting from an imbalance in the Starling force. Systemic disease states, such as congestive heart failure, cirrhosis, and nephrotic syndrome, alter forces governing fluid exchange across pleural surfaces. Exudative effusions, in contrast, occur as the result of pleural membrane disease such as neoplastic and inflammatory processes. Abnormal protein clearance by pleural lymphatics and increased permeability of protein and fluid into the pleural space result in exudative effusions. Pleural fluid with a protein concentration of 3 g dl and a specific gravity of 1.016 or more is usually considered to be an exudate. Additional tests of pleural fluid are of diagnostic value. Analysis of pleural...

Prevalence of Malnutrition

Malnutrition prevalence depends in part on the parameters that were chosen to determine nutritional status. For example, when 50 patients with cirrhosis were assessed according to subjective global assessment (SGA), prognostic nutritional index (PNI) and handgrip strength (HG), malnutrition was diagnosed in 28 based on SGA, 18.7 by PNI and 64 by HG. HG was superior in predicting poor clinical outcome when compared with SGA and PNI 4 . In another study, Figueiredo et al. 5 measured body cell mass (BCM) by isotope dilution in 69 patients awaiting liver transplantation. Patients were also evaluated based on SGA, anthropometry, HG dynamometry, laboratory tests and dual-energy X-ray absorptiometry (DXA). Only one-half of the patients in The prevalence of malnutrition also depends on the type of liver disease (see Table 4.3). Over 15 years ago, DiCecco et al. 6 evaluated the rate of malnutrition in patients undergoing liver transplantation based on diagnosis (chronic active hepatitis,...

Aminophylline and Theophylline secondline therapy

-Aminophylline load dose 5.6 mg kg total body weight in 100 mL D5W IV over 20min. Maintenance of 0.5-0.6 mg kg ideal body weight h (500 mg in 250 mL D5W) reduce if elderly, heart liver failure (0.2-0.4 mg kg hr). Reduce load 50-75 if taking theophylline (1 mg kg of aminophylline will raise levels 2 mcg mL) OR -Theophylline IV solution loading dose 4.5 mg kg total body weight, then 0.40.5 mg kg ideal body weight hr. -Theophylline (Theo-Dur) PO loading dose of 6 mg kg, then maintenance of 100-400 mg PO bid-tid (3 mg kg q8h) 80 of total daily IV aminophylline in 2-3 doses.

Chronic Diseases Epidemiology And Audit

Disease in Tayside for research purposes only. This disease register has a range of liver diseases that affect the whole organ including viral hepatitis (A, B and C) (Steinke et al., 2000b), autoimmune hepatitis, alcoholic liver disease (Steinke et al., 2000c), primary biliary cirrhosis and hepatocellular carcinoma (Weston et al., 2000) and complications of liver disease like ascites. The ascertainment of liver disease by electronic record-linkage was maximised because of the unique integration of multiple sources of data to create a patient-specific information system. The specificity of virology, immunology and biochemistry tests increase the completeness of the data. Accurate incidence and prevalence rates of liver disease and its complications are used to ensure that hepatology services run effectively and efficiently.

Dan D Hershko and Michael M Krausz

Tance, as it too depends on the etiology and mechanism leading to its formation. Noninflammatory edema fluid, such as accumulates in heart failure, cirrhosis of the liver, and various renal diseases, is protein-poor in nature and is termed a transudate. In contrast, the inflammatory edema fluid, which is termed an exudate, is protein- and leukocyte-rich and is associated with increased endothelial permeability. Thus, when characterizing the pathophysiology of edema formation, it is convenient to differentiate between the inflammatory and noninflammatory (hemodynamic) derangements that lead to edema formation.

Pathophysiology Of Chronic Liver Disease

The pathophysiology of advanced liver disease results in two cardinal pathophysiological abnormalities hepatocellular failure and portal hypertension. In acute liver failure, portal hypertension is seldom a clinical problem while in cirrhosis, an increased portal pressure may give rise to complications while hepatocellular function is preserved. The importance of these two factors is recognized in the Child-Turcotte-Pugh classification, a prognostic tool in patients with cirrhosis.(Table 9.7) Portal pressure rises as a result of both a high hepatic vascular resistance and an increased portal venous inflow. The anatomical site of the increased vascular resistance in the liver will vary with different etiologies of cirrhosis15, the hepatic sinusoids being the critical site for alcoholic cirrhosis. A functional component to this resistance may also be present, as transformed stellate cells in the sinusoids may respond to vasoconstrictive stimuli, such as endothelin. Once a critical level...

Cause of Malnutrition in Liver Disease

It is theorized that energy expenditure may be elevated in patients with liver failure, thus contributing to a malnourished state. However, in one study comparing energy expenditure in 74 patients with cirrhosis and 9 healthy controls, the energy expenditures were not different between the groups except when the patients were stratified based on the level of malnutrition. Those patients with cirrhosis who were considered malnourished had a lower basal energy expenditure than did the controls 14 . Even then, if the energy expenditures were evaluated according to BCM, there were no differences. Refer to the section on calorie needs for a full review on energy expenditure and liver disease. Psychosocial factors also influence nutritional status. Santolaria et al. 16 studied 181 hospitalized alcoholic men. Malnutrition was related to intensity of alcohol intake, development of social or family problems, irregularity of eating habits and presence of cirrhosis and ascites. The skid row...

Decline In Antioxidant Defenses And Increased Oxidant Damage Follows Infection And Injury

Were shown to fall precipitately in spleen, lymph nodes, and peritoneal macrophages (14). In asymptomatic HIV infection, substantial decreases in glutathione concentrations in blood and lung epithelial lining fluid have been noted (15). In patients undergoing elective abdominal operations, the glutathione content of blood and skeletal muscle fell by over 10 and 42 , respectively, within 24 h of the operation (16). Blood concentrations returned rapidly to preoperative values however, concentrations in muscle were still depressed 48 h after the operations. A diverse range of clinical treatments and diseases, all of which involve the inflammatory process, have been shown to lead to a decrease in tissue anti-oxidant concentrations. These include hepatitis C, ulcerative colitis, and cirrhosis. In patients with malignant melanoma, metastatic hypernephroma, and metastatic colon cancer, plasma ascorbic acid concentrations fell from normal to almost undetectable levels within 5 days of...

Hepatitis C Viruses Introduction

Infection by HCV (family Flaviviridae, genus Hepacivirus), the cause of most cases of non-A, non-B viral hepatitis, is a major cause of chronic hepatitis, resulting in liver cirrhosis and hepatocellular carcinoma worldwide146 and infects 175 million people globally. More than 80 of infected patients develop chronic disease while remaining essentially asymptomatic.147 In the United States, an estimated 2 to 3 million people are currently infected and more than 150,000 new cases of HCV infection occur per year. The sequelae of HCV-induced and serious chronic liver disease result in 8,000 to 10,000 deaths annually.147 Since the first report of viral genomic sequences from HCV in 1989, a greater understanding of the HCV infection has been achieved.

Juvenile hemochromatosis

Iron accumulation in the parenchymal cells of the liver, heart, pancreas elevated transferrin saturation relative paucity of iron in macrophages. Clinical manifestations include liver fibrosis, cirrhosis, markedly increased incidence of hepatocellular carcinoma, cardiomyopathy, diabetes and untreated patients typically die from cardiomyopathy by age 30 years. Liver cirrhosis and failure are uncommon. There are several possible explanations for this pattern. Firstly, experience with patients who develop siderosis from

Clinical course of acetaminophen overdose

The majority of overdoses are of small quantities of acetaminophen and the patients are not unwell. Thus the presence of symptoms or signs should be treated as an indicator of hepatotoxicity. Nausea and vomiting occur within a few hours of ingestion, soon followed by diffuse abdominal pain and hepatic tenderness. Liver function tests start to become deranged from 12 h with the AST peaking at 72 h. Jaundice becomes biochemically apparent at 24 h and rapidly deepens. A coagulopathy can be demonstrated only a few hours after overdose, with the prothrombin time being prolonged and continuing to rise until day 3. Oliguric or polyuric renal failure occurs in 11 per cent of severe overdoses, with or without the presence of acute liver failure, and is best monitored with the plasma creatinine as urea production is impaired in hepatic dysfunction. The renal failure can result from prerenal hypovolemia as well as a direct nephrotoxic effect of the acetaminophen. Once acute liver failure has...

Principles of management

An International Normalised Ratio (INR) between 1.5-2.5 and or platelet count of (20-40) x 109 l do not usually require correction if the patient is not bleeding or at high risk e.g. active peptic ulcer, recent cerebral haemorrhage, undergoing an invasive procedure. 5-10 units of platelets will raise the count by only 10-20 x 109 l. The effect is often transient (50 x 109 l. A target INR

Glycogen Storage Diseases Molecular Basis of the Disease

GSD IV, also known as Andersen disease, is caused by glycogen branching enzyme deficiency that results in glycogen that is abnormal and insoluble. Intracellular accumulations occur in the liver, brain, heart, skeletal muscles, and skin fibroblasts. Neonates with GSD IV appear normal at birth but develop hepatomegaly and failure to thrive in the first year of life. Patients develop progressive cirrhosis and usually die of liver failure by 2 to 5 years of age. Mutations in the branching enzyme (a-1,4 to a-1,6) have been identified in a limited number of patients.

Derangement of the systemic circulation

The hemodynamic disturbances seen in AHF are similar to those of sepsis, i.e. elevated cardiac output and lowered systemic vascular resistance. Relative hypovolemia secondary to vasodilatation is frequent, and a pulmonary artery flotation catheter is often required to optimize fluid replacement. Colloid loading is almost inevitably required, usually to a greater degree than initially considered. Crystalloid is also necessary both to cover maintenance requirements and maintain euglycemia. The basis for microcirculatory dysfunction seen in liver failure is poorly understood, but evidence is accumulating to suggest the importance of

Local Anesthesia

Lidocaine is the most commonly used amide-type agent. The maximum subcutaneous dosage of lidocaine is 7 mg kg or less than 500 mg in a healthy adult. Two percent lidocaine contains 20 mg mL therefore, the maximum dose in the 70-kg adult is 25 mL of 2 , or 50 mL of 1 lidocaine. As a general rule, 2 lidocaine is preferred except when the clinical question is infection, where 1 is utilized. The lidocaine effects usually last for approximately 0.5 to 1 hour, but may be prolonged in elderly patients or those with liver failure (5).

Produce Samples and

Lm is a Gram-positive, facultative intracellular pathogen acquired most often through the consumption of contaminated food. Listeriosis is a serious illness that can cause a variety of symptoms including septicemia, liver failure, meningitis, and spontaneous abortion and death 152,153 .


Various demographic and clinical factors have been related to the probability of a fatal outcome. Age has been shown to be independently associated with mortality, although its relative importance appears to be lower than other prognostic factors. Male gender may also be related to death probability, but to a low degree. Chronic debilitating diseases such as diabetes mellitus, chronic obstructive pulmonary disease, alcoholism, hepatic cirrhosis, chronic heart failure, renal insufficiency, neuralgic or mental disease, malignancy, and immunosuppression have been shown to be clearly related to mortality. As shown in TabJeJ , different clinical features at presentation, and also some laboratory and radiographic findings, have been associated with pneumonia outcome in univariate and multivariate studies. Finally, some etiologies, particularly Staphylococcus aureus, Gram-negative enteric rods, and Legionella pneumophila, present a higher probability of a fatal outcome when compared with...

Replacement fluid

A buffered balanced electrolyte solution is given to buffer acidaemia and achieve the desired fluid balance. Buffers include lactate (metabolised by liver to bicarbonate), acetate (metabolised by muscle), and bicarbonate. Acetate causes the most haemodynamic instability and is rarely used in the critically ill. Bicarbonate solutions may be more efficient than lactate at reversing severe metabolic acidosis, but outcome benefit has yet to be demonstrated from its use and care is needed with co-administered calcium since calcium bicarbonate may crystallise. In liver failure a lactate buffer may not be adequately metabolised. Similarly, in poor perfusion states, the muscle may not be able to metabolise an acetate buffer.

Natural history

Cirrhosis and hepatocellular carcinoma are the most common causes of death in patients with haemochromatosis and are due to hepatic iron accumulation. Cirrhosis does not usually develop until the hepatic iron concentration reaches 4000-5000jg g of liver (normal 50-500jg g). Hepatocellular carcinoma is the cause of death in 20-30 but does not occur in the absence of cirrhosis which increases the risk over 200x. If venesection can be commenced prior to the development of cirrhosis and other complications of haemosiderosis the life expectancy is that of a normal individual. Reduction of iron overload by venesection has only a small effect on symptomatology which has already developed skin pigmentation diminishes, liver function may improve, cardiac abnormalities may resolve, diabetes and other endocrine abnormalities may improve slightly, arthropathy is unaffected.

Role in Fibrosis

These cells have been shown to be present in normal and pathologic situations of various organs, such as the liver, the kidney, and the heart 2-17, 29 . Ito cells, which are also called hepatic stellate cells or fat-storing cells, and which store vitamin A, play a central role in fibrogenesis of the liver 31 . These cells contain fat droplets which are rich in vitamin A in their cytoplasm. They activate and transdifferentiate into myofibroblast-like cells, and synthesize collagens during liver cirrhosis 32 . Recent reports have revealed that periacinar myofibroblasts, which are similar to Ito cells in morphology and functions, play a important role in pancreas fibrosis 18-22, 33, 34 . However, the detailed mechanisms of myofibroblast activation in pancreatic diseases are not known.

Alcohol problems

Alcohol problems can be related to the acute or chronic consumption of alcohol. A fractured ankle sustained by falling over while acutely intoxicated is an example of the former category. Cirrhosis of the liver is an example of a chronic problem. An individual who drinks in binges will experience different problems compared with someone who drinks the same amount of alcohol spread out over a week or a month or a year. The way in which a person behaves while intoxicated is another important factor determining the nature of alcohol-related problems. The social consequences of drinking such as job loss, imprisonment, marital and family break-up, and drink-driving have profound effects on the well being of the drinker, their family, and society. (37)


In transplantation patients, nutritional assessment and education are beneficial in both the pre- and post-transplantation periods 124 . Nutritional support can prevent continued symptoms of end-stage organ failure by, for example, implementing dietary sodium restriction and fluid retention in ESRD patients or branched-chain amino acids supplementation in patients with severe cirrhosis. A small intervention study using oral supplementation in liver transplant candidates reported that the benefit in reducing the frequency of hospitalizations before transplantation could be partly due to increased energy consumption 130 . The post-transplant nutritional goal is to provide adequate nutrition to promote wound healing and anabolism, to prevent infection, and to minimize side effects of medications. Nutritional intervention is documented to be able to provide adequate nutrition and to treat underlying malnutrition, but it is also important to prevent excessive weight gain, as both...

Cerebral management

Encephalopathy is characteristic of the syndrome of AHF. Patients may progress from being mildly confused through aggressive and unmanageable to deeply comatose over a matter of 24 h. Patients with AHF are also at risk of developing cerebral edema in association with deep levels of coma, a complication not seen in chronic liver failure. Increases in intracranial pressure may be caused by increases in volume of any of the three main components within the skull, namely brain tissue, cerebrospinal fluid, and cerebral vessels. An increase in the volume of brain tissue is reported to occur in up to 80 per cent of patients progressing to grade IV encephalopathy, although more recent work suggests that the incidence of cerebral edema in AHF has fallen to approximately 40 per cent.

Folate Antagonists

5fu Mucositis Mechanism

High-Dose Therapy High-dose MTX yields therapeutic concentrations in the CSF. Nephrotoxicity, manifested as oliguria and azotemia, is the major adverse effect of high-dose MTX therapy. Although MTX may be a direct tubular toxin per se, nephrotoxicity arising from high-dose therapy is mainly attributed to intratubular precipitation of MTX and its less-soluble metabolites, 7-OH MTX and 2,4-diamino-N-10-methyl pteroic acid (DAMPA), in acidic urine. Vigorous hydration and urine alkalinization can diminish such complication. Some myelosuppression and mucositis may occur. Leucovorin rescue (described next) reduces the likelihood of systemic tox-icity. Acute transient transaminase elevations commonly occur after high-dose therapy, but late occurrence of liver failure or cirrhosis has not been reported. Repeated courses of high-dose MTX therapy can result in encephalopathy, dementia, paresis, and seizures.

Immune competence

Many factors non-specifically alter delayed cutaneous hypersensitivity in the absence of malnutrition viral, bacterial, and granulomatous infections uremia, cirrhosis, hepatitis, trauma, burns, and haemorrhage drugs such as steroids, immunosuppressants, and cimetidine general anesthesia and surgery. Although anergy resulting from malnutrition can be reversed by nutritional support, delayed cutaneous hypersensitivity is valueless in assessing the state of nutrition as one or more of the above factors are generally present in critically ill patients. However, simply draining an abscess can reverse anergy. Hence, measuring delayed cutaneous hypersensitivity is not recommended in assessment of nutritional status.