New approach could reverse liver failure

Liver Disease Survivors Guide

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

Liver Disease Survivors Guide Summary

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Rate of Progression to Cirrhosis

HBV co-infection in chronic hepatitis C has been associated with a higher prevalence of cirrhosis, as well as an accelerated evolution to cirrhosis (8,23,30,53). A similar observation was noted in those with occult HBV co-infection (25). Patients with hepatitis C infection, who were HBV DNA-positive, had worse Knodell scores, attributed to more severe piecemeal necrosis and fibrosis, compared to those who were HBV DNAnegative (15,23). This implies that the persistence of HBV replication plays an important role in disease progression. On the contrary, Colombari et al. (33) and Liaw et al. (34) reported that the prevalence and time to development of cirrhosis in co-infected patients were not different from those who were infected with only a single virus. Furthermore, the effect of dual infection with HBV and HCV on the long-term outcome of the disease was thought to be insignificant.

Complications Of Cirrhosis

Portal pressure is a function of resistance in the portal venous system and the flow of blood through it. In cirrhosis, portal venous resistance is increased, and inflow of blood is increased by splanchnic vasodilatation and elevation of cardiac output. Variceal bleeding is increasingly likely as the pressure gradient between the portal and systemic venous systems rises beyond 12 mmHg. Pharmacological therapy. Nonselective p-blockers, e.g. propranolol or nadolol, reduce cardiac output (Pj receptor antagonism) and induce splanchnic vasoconstriction (p2 receptor antagonism allowing unopposed a-adrenergic vasoconstriction). Recurrent bleeding is reduced by about 40 . As propranolol is extensively extracted in a single pass through the liver, its systemic availability may be unpredictable in patients with cirrhosis and portal hypertension due to variations in hepatic blood flow and portal systemic shunts. Ideally, the dose of propranolol (given b.d.) should be adjusted by measuring the...

Outcome After Decompensation Of Cirrhosis

The natural history and the prognostic factors in hepatic cirrhosis have been extensively studied, but several aspects remain unclear, and prognostic factors have not been validated fully (47,112-134). Certain clinical problems, such as development or complications of ascites, predict a poor prognosis (Fig. 7). Patients with compensated cirrhosis who develop ascites have a 2-yr survival of 50 and 5-yr survival of only 20 (116-118). Various proposed scores and models combine biochemical, clinical, and histology data to give an estimate of prognosis (119-122). One of these, the CTP score, is a simple and valid index for assessing the severity of disease and prognosis in patients with cirrhosis. The majority of the clinical consequences of chronic liver disease are related to progressive hepatic fibrosis, which produces portal hypertension and progressive decline in functioning hepatic mass. Portal hypertension develops in earlier stages of cirrhosis, and the amount of functioning...

Risk Of Decompensation In Childs A Cirrhosis

Patients who progress to cirrhosis may remain compensation without deterioration in liver function or clinical status, for many years. Fattovich et al. (112) reported outcomes in 384 European patients with compensated cirrhosis (Childs-Turcotte-Pugh score CTP < 7) caused by CHC. The mean length of follow-up was 5 yr, but some patients were only followed for 6 mo and others for over 12 yr. By actuarial analysis, the risk of decompensation (ascites, variceal bleed, or encephalopathy) was 18 and risk of HCC was 7 (Fig. 5), at 5 yr follow-up (Fig. 5). 13 of the cohort died, with 71 of deaths related to liver disease. Overall survival was 91 at 5 yr, and 79 at 10 yr. Patients who experienced Fig. 5. Actuarial plot demonstrating risk of developing complications is shown for patients with hepatitis C and compensated cirrhosis. Risk was 18 at 5 yr and approx 35 at 10 yr. (Adapted with permission from ref. 112.) Fig. 5. Actuarial plot demonstrating risk of developing complications is shown...

Cirrhosis

Fifty-five cirrhotic patients, 6 with primary biliary cirrhosis, 14 with alcoholic cirrhosis, and 38 with posthepatic cirrhosis who were referred for liver transplantation, underwent bone density testing of the PA spine and proximal femur with DXA (Lunar DPX-L) (31). The subjects were 39 men and 19 women with an average age of 50 7.6 years. Compared to age and sex-matched controls, 15 patients had spine z-scores of -2 or poorer, whereas only 5 had z-scores in the femoral neck that were -2 or poorer. An additional 13 patients were found to have fractures in the spine that were judged to be atraumatic. The authors observed that the more severe the liver dysfunction, the greater the reduction in femoral bone mass. A significant number of patients were found to have vitamin D deficiency, reduced serum parathyroid hormone levels, and hypogonadism.

Robert L Carithers Jr MD

There are striking epidemiological and clinical parallels between hepatitis B and hepatitis C virus infections . Each virus can be transmitted by bloodborne routes, such as transfusions or injection drug use. Acute infections often are asymptomatic, but can result in persistent viremia and chronic liver injury. Finally, chronic infection with either virus may cause minimal symptoms for decades, but ultimately can progress to cirrhosis and hepatocellular carcinoma (HCC). have an inordinately high risk of developing chronic hepatitis B and suffering the sequelae of cirrhosis and HCC later in life. Over 90 of infants who acquire hepatitis B at birth develop chronic infection. Children exposed to the virus within the first 5 yr of life have a 25-50 risk of developing chronic infection. By contrast, acute hepatitis B can be severe in older individuals, but no more than 5 of adolescents and adults develop chronic infection (6). Maternal-fetal transmission of hepatitis B is virtually...

Role Of Liver Transplant In Hepatitis B

Despite advances in the understanding of the immunopathogenesis of HBV, and development of new treatment strategies, there are approx 4500 deaths yr in the United States, attributable to HBV infection. As mentioned, there is only a 14 5-yr survival among patients with decompensation HBV cirrhosis. Although full consideration of liver transplant for hepatitis B is beyond the scope of this chapter, the availability of liver transplant has the potential to reduce the impact of progressive hepatitis on mortality. Among patients who would otherwise succumb to end-stage cirrhosis or fulminant hepatitis resulting from HBV infection, liver transplant can lead to long-term survival 80 at 1 yr, and 65 at 5 yr, comparable to survival figures for liver transplant in nonviral liver disease. Such excellent outcomes, however, would not be possible without effective antiviral strategies to prevent recurrent infection in the allograft.

Disease Progression In Chronic Hepatitis

The major determinant of clinically significant liver disease in patients with CHC is the progressive accumulation of hepatic fibrosis (27,33,4453). The rate of progression in fibrosis is highly variable, generally requiring 20-40 yr from initiation of infection to result in death from cirrhosis (1,19,20,25-33,35,43). Yano et al. have suggested that the degree of necrosis, inflammation, and fibrosis on liver biopsy predicts risk of pro-gres-sion to cirrhosis (Fig. 4) (48). Studies examining progression of fibrosis, Fig. 4. Graph showing that patients with more severe inflammation and necrosis on baseline liver biopsy were at greatest risk to develop cirrhosis in long-term follow-up. (Adapted with permission from ref. 48.) Fig. 4. Graph showing that patients with more severe inflammation and necrosis on baseline liver biopsy were at greatest risk to develop cirrhosis in long-term follow-up. (Adapted with permission from ref. 48.) In the study by Poynard (47), in which risk factors for...

Monitoring of renal function

Is a demonstrable rise in the serum creatinine concentration. A rise in the serum creatinine concentration that just exceeds the normal range may reflect as much as a 50 decline in the GFR. The failure of the serum creatinine to accurately reflect the degree of renal injury is particularly evident in patients with decreased muscle mass or those with chronic liver failure. Crea-tinine is produced from the metabolism of creatine in skeletal muscle. In turn, creatine is derived from the liver. In the setting of chronic liver disease or malnourished patients with decreased muscle mass creatinine synthesis becomes impaired. As a result more profound decreases in the GFR may occur before the serum crea-tinine concentration begins to rise above normal values 53 . By contrast, the serum creatinine concentration is a sensitive indicator of changing renal function in patients with chronic renal failure. In these patients a small decline in the GFR is associated with a large increase in the...

Thyroxine Binding Globulin

Acquired TBG deficiency, which can be caused by protein malnutrition, is encountered frequently in chronic diseases and debilitative states, in liver failure, and in calorie malnutrition. In patients with the nephrotic syndrome, TBG is lost through the glomerular filtrate. The cause of the decrease in TBG concentration associated with glucocorti-coid or androgen administration is not clear, but it is believed that the effect is transcriptionally mediated, although cleavage of the protein may also play a role in increasing its clearance.

Hiv Coinfection Accelerates Natural History Of Hcv Disease

Greater than half of immunocompetent, HCV-infected patients develop chronic hepatitis, and about 20 develop cirrhosis after 10-20 yr of infection. Approximately 15 ofpatients with HCV-related cirrhosis will develop hepatocellular carcinoma. Immunosuppression caused by HIV significantly alters the natural history of HCV infection. Hepatic damage resulting from HCV infection is believed to be predominantly caused by direct viral cytotoxicity, with contributions from the host immune response. Cell-mediated immunity, T-helper 1 (TH1) clones that recognize multiple core epitopes of HCV, are important in immune clearance of HCV, through elimination of virally infected hepatocytes (8-10). The decline in CD4 cells associated with progressive HIV infection appears to permit greater HCV replication, with more hepatic spread of HCV, and therefore vast hepatocyte injury. Co-infection with HIV also probably A number of studies have suggested that the presence of HIV infection accelerates the...

Hepatitis C Infection Limits Ability To Treat

HIV protease inhibitors have not been found to inhibit HCV replication (26). Additionally, the control of HIV to less than 400 copies by anti-HIV medications has no effect on the HCV viral load. Instead, initiation of HAART may transiently increase the level of aminotransferases, and even the HCV viral load for the first 3-4 mo of treatment, typically returning to baseline over the ensuing 3-8 mo (27). A number of studies have addressed whether the presence of HCV infection increases the liver toxicity associated with HAART. Many antiretroviral drugs are hepato-toxicity according to data found in the physicians' desk reference, the risk of hepatotoxicity of antiretroviral drugs is between 3 and 12 , depending on the therapeutic agent. Perhaps the earliest evidence of the true hepatotoxicity potential of these drugs was observed in 1995, when a hepatitis B treatment trial, using a fluorinated uridine nucleoside analog, fialuridine (FIAU), similar to those used in HIV treatment,...

Presence Of Hiv Does Not Alter Efficacy Of Antihcv Therapy

These initial responders, more than one-half relapse within 6 mo after termination of treatment. In all, IFN-a therapy induces a sustained response, with eradication of the virus and stable improvement of liver histology in less than 20 of treated patients. The rate is even lower in patients infected with HCV genotype 1b, who make up the majority of the infected patients in the United States. There are few studies that have reported long-term results of the so-called sustained responders, raising the question of how IFN-a affects the future development of the sequelae of hepatitis C, e.g., cirrhosis, end-stage liver disease. The incidence of hepatocellular carcinoma is reduced, even if treatment fails (34,35). Patients who clear HCV RNA after 6 mo of IFN-a, and whose HCV is genotype 1a or 1b, should be treated for at least 12, and perhaps 18 mo. with genotype 1, with high baseline viral load, or those with pretreat-ment cirrhosis or bridging fibrosis. The effect of IFN and ribavirin...

Protocol and Results of the Clinical Trial

Patients of viral hepatitis with cirrhosis (more than 90 of these individuals were hepatitis C virus-infected patients) were randomly divided into two groups (Table 1). Patients in group 1 (46 patients) were administered the carotenoid mixture in addition to conventional antisymptom-atic treatment. The daily dose of carotenoids was 20 mg in total. The carotenoid mixture contained lycopene 10 mg, -carotene 6 mg, a-carotene

Clinical Correlation

A patient's serum albumin level is compared with the reference range to determine if it appears to be abnormal. An elevated serum albumin level is indicative of dehydration, in which an insufficient amount of fluid in the blood causes some substances to appear relatively increased. Decreased serum albumin levels correlate with many types of diseases, including liver failure, extensive skin loss, and kidney diseases that cause loss of albumin via the urinary tract.

Improvement of Cancer Preventive Efficacy by Additional Use of Other Food Factors

Based on these clinical and experimental data, we have planned a new clinical trial. Since P-cryptoxanthin is rich in Japanese tangerine oranges, we decided to use them as a form of juice for a clinical trial. The experimental sample contained 3 mg of P-cryptoxanthin and 1 g of myo-inositol in 190 ml canned juice. Hepatitis C virus-infected patients with cirrhosis were ad-

Risk for HCC in those with Hepatitis C and past HBV Infection

There is a higher incidence of HCC, without underlying cirrhosis, in those who had past HBV infection, compared to those who only had HCV mono-infection, without any evidence of infection with HBV (39). Because HCC is known to develop occasionally in the absence of cirrhosis in chronic hepatitis B, it is possible that past HBV infection may have a role, as well, in the development of HCC, in the absence of cirrhosis, in patients with HCV. Moreover, the HCC found in patients with hepatitis C, who had past HBV infection, had a more aggressive histopathol-ogy, compared to those without past HBV infection (39).

Outcomes of Surgical Resection of HCC

Surgical resection of HCC in co-infected patients was associated with only a slight increase in postoperative morbidity and mortality, compared to those with either infection alone (44). The incidence of liver failure, ascites, and infection was higher in co-infected patients, although the differences were not statistically significant. The long-term survival rate after resection was lower in those with dual infection, but this was not statistically significant. Recurrence rate after surgery, however, was significantly lower in those with HBV and HCV co-infection, compared to the HBV mono-infected patients with HCC, but was significantly higher, compared to those with HCV-related HCC.

Durability of Response and Longterm Outcome of IFNTreated Patients

Increase in survival and decrease in risk of cirrhosis and HCC. Several studies found that HBeAg-positive patients, who cleared HBeAg, have improved survival, compared to patients who remained HBeAg-positive, suggesting that suppression of HBV replication can improve clinical outcome. In a long-term follow-up (median 8.2 yr) of 101 male patients who participated in a controlled trial of IFN-a therapy, Lin et al. (25) found that treated patients had a lower incidence of HCC, 1.5 vs 12 (P 0.04), and an improved survival, 98 vs 57 (P 0.02). In that study, IFN-a treatment was also associated with a lower rate of progression to cirrhosis, but the difference did not reach statistical significance. Similar data were reported by Niederau et al. (24). In their follow-up of 103 patients over a mean period of 50 mo, the length of survival, until liver transplant or death, was significantly longer in patients who had cleared HBeAg after IFN-a therapy.

Distinct Clinical Entities

It appears that the often fulminant hepatitis initiating the disease is caused by a non-A, non-B, non-C hepatitis virus. The hepatitis is associated with jaundice and an often pronounced rise in transaminases. It can result in fulminant liver failure. In patients who survive the hepatitic phase, transaminases, decrease and a latency period characterized by a period of a relative well-being follows. After a variable time period (often several months), pancytopenia develops with a clinical picture typical of severe AA. ATG therapy is effective and can often result in a complete remission. The time course of the syndrome is highly suggestive of virally induced hepatitis, which upon clearance of virus results in induction of cross-reactive T-cell response directed against hematopoietic stem cells.

Hydralazine and procainamideinduced autoimmunity

Methylation of deoxycytosine residues of gene promoters takes place during cell ontogeny and silences genes through fixation of methylcytosin binding proteins and changes in chromatin structures (developed in 64 ) this pattern is maintained through subsequent mitoses by methyltransferases. It was shown that antigen specific T-cell clones, incubated with inhibitors of these enzymes, overexpressed LFA-1 and became able to proliferate in the presence of autologous antigen presenting cells, even in the absence of the nominal antigen. Autoreactivity is probably the consequence of the increase in LFA-1 expression since antigen specific T-cells transfected with LFA-1 also became autoreactive 63 . The injection of T-cells rendered autoreactive by incubation with procainamide 65 or with hydralazine 66 or of T-cells transfected with LFA-1 63 into a non-irradiated syngeneic normal recipient triggers an autoimmune disease 66 . This disease is marked by anti-DNA antibody production,...

The Team Approach

Hyponatremia is caused by renal and nonrenal causes also. Salt-losing renal nephritis, renal tubular acidosis, or syndrome of inappropriate antidiuretic hormone secretion (SIADH) are common causes of renal loss of sodium and may be evaluated by testing for the presence of excess urinary sodium and hyperosmolar urine. Certain diuretics, such as thiazine, can cause renal loss of sodium.22 Increased urine sodium levels usually indicate sodium loss. Chronic renal failure can cause water overload due to inability to regulate water and results in hyponatremia, while nephritic syndrome can cause fluid imbalances and edema with resulting hypona-tremia. Urine sodium levels are usually normal or decreased in hyponatremia due to edema. Nonrenal causes of hyponatremia include psychogenic water overload, cellular shift changes from acidosis, and edema secondary to cirrhosis or congestive heart failure.14

Eukaryotic Protein Synthesis Is A Little More Complex

Hepatitis C is a particularly nasty virus because infected people can go on to develop liver cancer, cirrhosis, and other chronic liver disease. In the United States alone, 10,000 people die per year from hepatitis C infection. It is hoped that drugs can be developed that will prevent the host ribosome from binding to the viral IRES and so halt the production of new virus in an infected liver.

Who to Consider for Treatment

Do not correlate closely with histologic activity, and cannot be used as surrogates for liver biopsy (25,26). Liver biopsy confirms the cause of liver disease, and documents the degree of inflammation activity and fibrosis. The latter, specifically the presence or absence of cirrhosis, is essential in counseling the patient regarding long-term prognosis, and establishing a management plan to monitor for hepatic decompensation and development of hepatocellular carcinoma. Liver biopsy also provides a sense of the urgency of treatment and an estimation of the likelihood of response to treatment. The National Institutes of Health Consensus Development Conference on Hepatitis C (27), and the more recent European Consensus Conference (28), concluded that the need for treatment in patients with moderate or severe histologic inflammation activity, with or without fibrosis, was essential. Patients with mild inflammation on histology, or those with advanced cirrhosis, need to be considered for...

Combination Therapy with IFN Plus Ribavirin

The encouraging results ofthese early studies with combination therapy led to two large multicenter trials, one conducted in the United States (45), and the other conducted internationally, primarily in Europe (33). In the U.S. trial, 912 previously untreated patients were randomized 1 1 1 1 to receive either combination therapy (IFN 3 MU 3x wk subcutaneously with ribavirin 1000 mg for weight < 75 kg, or 1200 mg for weight > 75 kg in a divided daily dose) or IFN monotherapy plus placebo, for a duration of either 24 or 48 wk. The international trial randomized 840 treatment-naive subjects, and was similar in design, except there was no 24-wk IFN monotherapy arm. In both studies, subjects were stratified according to HCV genotype (1 or non-1), viral load (above or below 2 x 106 copies mL), and the presence or absence of cirrhosis. Study end points, for assessing treatment outcome, were similar in the studies, and involved biochemical, virologic, and histologic findings. The combined...

Other Laboratory Test Results That Correspond With Liver Disorders

Beta Gamma Bridging

Since the majority of proteins found in plasma are synthesized by the liver from amino acids, including serine protease coagulation factors, prothrombin time, serum albumin, and serum protein electrophoresis results can be used to indicate declining liver function. For example, serum albumin decreases and prothrombin time becomes prolonged with liver failure. Protein levels also reflect other disorders, such as those in which essential amino acids are not provided by the diet or in which proteins are lost by the kidneys or gastrointestinal tract. Figure 7-4. Protein electrophoresis pattern found in a patient with cirrhosis. Notice the beta-gamma bridge. Figure 7-4. Protein electrophoresis pattern found in a patient with cirrhosis. Notice the beta-gamma bridge. Serum protein electrophoresis results can also indicate inflammatory states of the liver in which there are elevated gamma globulin protein fractions, especially immunoglobulin A (IgA) and IgM levels. In cirrhosis, protein...

General Aspects Of Hgf And Met Structure And Activities

In parenchymal organs, HGF is expressed predominantly in mesenchymal or stromal cells while Met HGF receptor is expressed in epithelial cells (24, 27, 37, 38). HGF induces branching tubulogenesis of epithelial cells, as a mesenchymal-derived factor in several tissues, including kidney, lung, and mammary gland. Targeted mutation of HGF or the c-met gene results in impaired development of the liver, placenta, and skeletal muscles and diaphragm (39-41). HGF is essential for long-distance migration of myogenic precursor cells during development of skeletal muscles and the diaphragm. This is a pertinent example of the motogenic activity of HGF during normal biological processes. Physiologically, expression of HGF is regulated in response to tissue injuries and HGF supports regeneration of various organs such as the liver, kidney, lung, and vascular tissues (24, 26, 28). Thus, HGF exerts biological activities to construct or reconstruct normal tissue...

Role of Hypothalamic Neuroimmune Interactions

Similar data suggesting increased serotonergic activity in the presence of anorexia have been obtained in patients suffering from either chronic renal failure 11, 34, 46 or liver cirrhosis 59 , thus supporting the view that anorexia associated with different diseases shares a similar pathophys-iologic mechanism. It must be acknowledged that partial brain serotonin depletion and antagonism did not result in improved food intake of tumour-bearing animals 52, 60 . However, it is not clear

Nutritional Support

The objective of nutritional support in patients with liver cirrhosis is to provide adequate calories, protein, and other nutrients to ensure the availability of synthetic and energy substrates to hepatocytes without inducing hepatic encephalopathy (Table 6) 76, 77 . In general, cirrhotic patients without encephalopathy require no restriction of protein, but a diet high in complex carbohydrates and calories and supplemented with multivitamins, calcium, Table 6. Nutritional support for liver failure with cirrhosis. (Data from 77 ) Cirrhosis without encephalopathy No protein restriction (1.0-1.2 g kg per day) High complex carbohydrate, high-calorie diet (30-35 Kcal kg per day) Cirrhosis with acute encephalopathy Temporary protein restriction (0.6-0.8 g kg per day) until encephalopathy is ameliorated or resolved Substitute or supplement with BCAA for refractory encephalopathy or negative nitrogen balance Normal protein intake (1.0-1.2 g kg per day) as encephalopathy resolves Cirrhosis...

Metabolic Acid Base Disturbances

Hypotension secondary to dehydration, which leads to poor tissue perfusion, lac- perfusion - passage of blood tic acid formation, and fluid and electrolyte imbalance. Metabolic alkalosis can through the vessels of a partic-stem from vomiting or gastric suction, low potassium or chloride levels (electrolyte ular organ designated as Q imbalance), and liver cirrhosis with ascites, corticoid excess, and massive blood transfusion.5 These conditions are not categorized as acute or chronic.

Pretreatment Evaluation And Education

First, the authors like to establish the goals of therapy for each individual patient. The primary goal of therapy should be viral eradication that is sustained once treatment has stopped. Secondary goals of therapy include prevention of histological progression of disease and reduction of the risk of development of either liver failure or hepatocellular carcinoma. Education, so that the patient understands that the liver disease leads to significant morbidity and mortality, is of critical importance. The patient must understand that there is a significant benefit that can be obtained, even without viral eradication. This is particularly true for patients with advanced histological disease, who are at risk for the development of hepatocellular cancer.

Micronutrient Metabolism

Deficiencies of water-soluble vitamins, including vitamin C, and the B complex compounds, are particularly common in cirrhotic patients with active alcoholism. Similarly, low plasma concentration of fat-soluble vitamins (A, E, D, and K) may occur in patients with cirrhosis of any aetiology 72 . Abnormalities in vitamin activation, conversion, release, and transport by carrier molecules all result from hepatocellular injury. Low serum levels of some trace elements, such as zinc and selenium, have also been detected in cirrhotic patients 73 . In most patients with liver cirrhosis, while micronutrient deficiencies are clinically silent, the biological antioxidant effects of micronutrients are notably impaired. In liver cirrhosis, one of the most important micronutrients is zinc. Zinc deficiency can alter cognitive function, appetite and taste, immune function, and protein metabolism, and has been claimed to be a precipitating factor for hepatic encephalopathy 74 . Vitamin A and other...

Zellwegers Disease or Cerebrohepatorenal Syndrome

The cerebral pathology is distinguished by developmental abnormalities, such as disorders of neuronal migration pachygyria and microgyria along the Sylvian fissures, heterotopias of the Purkinje cells, and anomalous dentate and olivary nuclei. Other changes are variable neuronal losses, diminution and or breakdown of myelin, lipid deposits within macrophages, and degeneration of the optic nerves. Common visceral changes include liver fibrosis, often progressing to cirrhosis kidney cysts and lipid-containing striated cortical cells in the adrenals.

Symptoms and Complications

The majority of patients with acute HBV make a full recovery and develop immunity. After acute infection, approx 1 in 300 patients develop liver failure, which may result in death. asymptomatic. Adults may have only mild symptoms or may also be asymptomatic. Approximately 15-25 of chronically infected individuals (depending on age of acquisition) will develop cirrhosis over a number of years. This may also result in liver failure or other serious complications, including hepa-tocellular carcinoma, though the latter is rare. The overall mortality rate of HBV is estimated at less than 5 .

Therapeutic Potential Of Embryonic Stem Cells

Most of the enthusiasm relating to embryonic stem (ES) cells results directly from the perceived need for cell replacement therapy for a host of degenerative diseases. Indeed, disorders of organ failure are not reversible, and organ transplantation cannot meet the needs of an ever-aging population. Primary pump failure in the heart, alcoholic or viral liver failure, P-cell-deficient type 1 diabetes, and Parkinson's disease (PD) are frequently cited as examples of monocellular deficiency states that might be amenable

Causes Of Hyponatremia

Hepatic cirrhosis Hypervolemia is usually apparent as edema or elevated jugular venous pressure. It commonly occurs as a result of congestive heart failure, cirrhosis of the liver, or the nephrotic syndrome. In these edematous disorders, there is usually a total body excess of both sodium and water, yet arterial baroreceptors perceive hypoperfusion or a decrease in intravascular volume, which leads to an increase in the level of ADH and, therefore, retention of free water by the kidneys. Renal failure itself can lead to hypotonic hyponatremia because of an inability to excrete dilute urine. In any of these cases, the usual initial treatment of hyponatremia is administration of diuretics to reduce both salt and water excess. Thus, hypovolemic or hypervolemic hyponatremia is often apparent clinically and often does not present a diagnostic challenge. Euvolemic hyponatremia, however, is a frequent problem that is not so easily diagnosed. Once the clinician has diagnosed the patient with...

Clinical Features

The disease is transmitted as an autosomal recessive trait and can occur from childhood through adolescence. Cardinal clinical manifestations are hepatic, neurologic, and psychiatric. Acute or chronic hepatitis and liver cirrhosis are common. During the course of the disease, splenomegaly, kidney dysfunction, and clotting abnormalities develop.

Licorice Glycyrrhizin

One trial (20), which evaluated a glycyrrhizin-based compound against other herbs, included 193 hepatitis C patients, followed prospectively for 2-16 yr for evidence of progression to cirrhosis or the development of hepatocellular carcinoma. Although glycyrrhizin appeared to slow the histological progression of the disease, both groups appeared to progress to carcinoma more frequently than in similar patients treated with IFN. Side effects attributed to glycyrrhizin included hypokalemia in 11 and hypertension (HT) in 3.6 . In a single randomized control study of iv glycyrrhizin vs placebo, among 58 IFN nonresponders or patients unlikely to respond (cirrhotic patients with genotype 1), the herb resulted in lower ALT, with no effect on HCV RNA levels (21). The adverse effects of glycyrrhizin in humans are well-characterized. Glycyrrhizin inhibits 11- -hydroxysteroid hydrogenase in the kidney, inhibiting the conversion of cortisol to cortisone. This results in a...

Changes in the Gastrointestinal Tract

Diseases involving the GI tract contribute to delayed gastric emptying (GE) and delayed small-bowel absorption. Such diseases include linitis plastica, pathologies of the small bowel, such as lymphomas, lymphangectasia, sarcoidosis, Whipple's disease, celiac disease, viral enteritis, and haemangiomas of the gut. These processes influence malabsorption by lymphatic infiltration of the mucosal and submucosal tissues. Less obvious aetiologies of delayed GE and malabsorption include cirrhosis, psoriasis, ileitis, and ulcerative colitis 12 . Human studies 13 document the association of gastroparesis and abnormal small-bowel function, which contribute to the malabsorption associated with non-GI tumours, which ultimately leads to malnutrition and cachexia. These GI processes are independent of tumour site, size, or overt constitutional changes 14 , but are clinically manifested in advanced cancer, after weight loss, following chemotherapy or abdominal radiation 14 .

Antibiotic Prophylaxis

Antibiotics are not generally needed if the wound is more than 2 days old and there is no sign of infection or in superficial noninfected wounds evaluated early that can be left open to heal by secondary intention in compliant people with no significant comorbidity (58). Antibiotics should be considered with high-risk wounds that involve the hands, feet, face, tendons, ligaments, joints, or suspected fractures or for any penetrating bite injury in a person with diabetes, asplenia, or cirrhosis or who is immunosuppressed.

Hcv Infection And Malignancy

B 104 , Recently, Serfaty et al. 104 reported that the incidence of HCV in patients with hepatitis C cirrhosis is about 3 per year, an incidence which is higher than previously estimated. This risk is independent of the genotype responsible for infection 105 , In 1994, Nashitz et al. 109 reported on a patient with liver cirrhosis due to HCV infection in whom a B cell heptosplenic lymphoma has found. This was followed by other reports on primary malignant lymphoma of the liver 110 and spleen 111, 112 , Despite the epidemiological association between chronic HCV infection and malignancy, the precise underlying mechanism for this observation is largely unclear. HCV is an RNA virus with no DNA intermediate. Disruption of the host genome as a result of viral integration is therefore not possible. Furthermore, HCV is not known to carry oncogenes. Until recently, the most plausible explanation for the link between HCV and HCC was that the virus causes a chronic necroimflammatory process in...

Ultrasound Contrast Agents

Ultrasound Acoustic Windows

Drawbacks of Traditional Ultrasound Imaging The drawbacks in traditional UI and Doppler include blocking of the US beam by anatomical structures, for instance bones US beam attenuation or reflection by air and other substances, such as free air, intestinal loops, cirrhotic liver dense fat pads in the region of organ or site interrogated such as the abdominal fat pad, obese patients, liver enlargement, or hypertrophic muscle bundles artifacts created by organ movements such as vessels or intestinal loops and deteriorated patients lacking cooperation or poor patient compliance 24, 25 .

Approach To Suspected Hepatitis Viral Hepatitis

Cause of acute viral hepatitis in the United States. Hepatitis E is much less common and is found in Asia. Africa. Central America, and the Caribbean. Both hepatitis A and E infections usually lead to self-limited illnesses and generally resolve within weeks. Almost all patients with hepatitis A recover completely and have no long-term complications. A few may have fulminant disease resulting in liver failure. Most patients with hepatitis E also have uncomplicated courses, but some patients, particularly pregnant women, have been reported to develop severe hepatic necrosis and fatal liver failure. Hepatitis B is the second most common type of viral hepatitis in the United States, and it is usually sexually transmitted. It also may be acquired par-enlerally. such as by intravenous drug use. and during birth from chronically infected mothers. The outcome depends on the age at which the infection was acquired. Up to 90 of infected newborns develop chronic hepatitis B infection. which...

Malignancies Occurring Several Years After Onset Of The Vasculitis

Rinaldi et al. 20 studied 41 patients with cirrhosis alone, and 41 patients with cirrhosis and hepatocellular carcinoma. They showed that patients with cirrhosis are at high risk of developing hepatocellular carcinoma, especially when they have hepatitis B or C virus infection. They also demonstrated a strong association between hepatitis C virus infection and cryoglobulinemia in cirrhosis patients with and without hepatocellular carcinoma. Cryoglobulins were detected in 88 of patients with hepatocellular carcinoma and in only 58 of patients without hepatocellular carcinoma. Ferri et al. 21 reported on the development of hepatocellular carcinoma in 3 of 250 patients with cryoglobulinemic vasculitis (mixed cryoglobulinemia) after a period of 8 (2 patients) and 16 years (1 patient). Two of the patients had hepatitis C virus infection and the remaining patient had chronic hepatitis B virus infection. Thus, not only is the hepatitis C virus associated with cryoglobulinemic vasculitis, but...

EtOH and Increased Damage Caused by Iron Overload

Excessive iron (Fe) in the body is toxic to many cells. High Fe levels per se (as in hemochromatosis) can cause cirrhosis, liver failure, and hepatocellular carcinoma (13,14). There is also growing evidence that only mildly increased, or even normal, amounts of Fe can cause or enhance hepatic injury in the presence of alcohol. Evidence is now accumulating that Fe can also potentiate hepatotoxicity caused by other etiologies, such as chronic viral hepatitis (13). In addition, Fe overload may facilitate or exacerbate microbial infections, and suppress the ability of the host's immune system to overcome such infections. Abnormalities in serum parameters of Fe status (ferritin, transferrin saturation) are common in patients with chronic viral hepatitis, probably because of the release of Fe from injured hepatocytes. The increased, metabolically active Fe, in turn, may increase the severity of chronic viral hepatitis and the degree of hepatocyte damage (13). Some of the proposed mechanisms...

General factors decreasing hypoxic pulmonary vasoconstriction

Cirrhosis Thus hypoxic pulmonary vasoconstriction is least effective when the volume of hypoxic lung is large or when pulmonary vascular pressures are increased by disease, fluid overload, or left heart failure.26 The magnitude of the response to hypoxia is greatest in the newborn, varies between species and between individuals in any given species, and is reduced by hypothermia, sepsis,27 trauma to the lung, liver cirrhosis,28 smoking,29 and the action of many other drugs. Hypoxia increases the heterogeneity of flow and decreases the central to peripheral gradient of perfusion in lung lobes.30

Autoimmune Diseases

ANA specificity changed to HCC1 in a patient with liver cirrhosis who progressed to HCC 57 Cyclins and cyclin-dependent kinases (CDK) are a group of cell-cycle regulating proteins acting at different points of the cell-cycle progression. They are amplificated and overexpressed in many tumors 38 41 , Covini et al. 42 showed that AAb to cyclin Bl, cyclin A and CDK2 are present in sera of patients with hepatocellular carcinomas (HCC) in 15, 1 and 1 , respectively. Furthermore, anticyclin Bl antibodies could be found in patients with a higher risk of HCC development, e.g., in patients with chronic hepatitis (in 1 out of 70 cases) and cirrhosis (in 3 out of 70 cases), suggesting a predictive relevance of these AAb. To date, there are no reports about aberrant expression of cyclin B1 in HCC tissue. If an antigen-driven process caused by cyclin B1 overexpression results in AAb production, cyclin B1 antibodies should be also found in other tumors, such as leukemias, breast and colorectal...

Adjustments in Drug Doses in Chronic Viral Hepatitis or Other Chronic Liver Disease

In view of such complexities, and in absence of a simple, widely available, well-validated approach for estimating hepatic function, it is currently possible only to offer general guidelines for adjustments of drug doses in chronic viral hepatitis or other chronic liver diseases (Table 4). The need for care, and circumspection in prescribing, increases markedly as the severity of liver disease increases. Although patients with decompensated, end-stage cirrhosis have many symptoms, and often feel miserable, it is unwise to prescribe sedatives or strong analgesics, because of the risk of precipitating or worsening encephalopathy. Close observation and follow-up are mandatory for all such patients, but espe

Indications For Liver Transplantation

The selection and listing of patients with UNOS for liver transplantation has become more standardized over the past several years. The primary criterion for placement of a patient on the liver transplantation waiting list is an estimated 1-yr survival from chronic liver disease of less than 90 , which is the expected outcome with liver transplantation at most centers (3). This criterion is based on a Child-Turcotte-Pugh (CTP) score of > 7 for patients with cirrhosis, i.e., CTP class B or C. Cir-rhotic patients who have experienced gastrointestinal bleeding caused by varices, or a single episode of spontaneous bacterial peritonitis, have reduced survival, and are also considered to meet minimal criteria for transplant listing, irrespective of their CTP score.

Chronic Viral Coinfection

Patients with HBV and hepatitis D virus (HDV) co-infection demonstrate more rapid progression to cirrhosis, compared to patients with isolated HBV infection (4). However, after liver transplantation, the outcome is favorable in patients who are co-infected prior to liver transplantation, in part because HDV downregulates HBV replication. Patients who are co-infected with HBV and HDV usually develop HDV infection of the liver allograft early posttransplant, without markers of HBV infection (4). The course of isolated HDV infection after liver transplantation is indolent, and usually results in spontaneous resolution, except when HBV recurs.

Chronic Hepatitis B Virus Infection

Chronic hepatitis B is a major global public health problem. There are an estimated 350 million chronic HBV virus carriers worldwide. The prevalence rate of chronic hepatitis B is as high as 15-20 in some countries in Asia. Chronic HBV infection may cause advanced liver disease. Once decompensated end-stage liver disease develops, prognosis is poor, with 5-yr survival rates decreasing, from 84 in patients with compensated cirrhosis, to 14 in patients with decompensated disease (7). Moreover, patients with compensated chronic hepatitis B associated with active viral replication are more likely to have progressive disease and a poorer prognosis than patients with inactive replication. Ultimately, many patients with advanced HBV infection become potential candidates for liver transplantation.

Other Significant Birth Defects And Inborn Errors Of Metabolism

Tyrosinemia is also less common than PKU, but also has profound effects in the neonate if undetected and untreated. Infantile tyrosinemia (type I) is generally due to absence of fumarylacetoacetase, which causes multiple problems including liver and kidney disease that results in nodular replacement of normal functional tissue. If left untreated, tyrosinemia is generally fatal within the first 12 months of life, usually from liver failure. There are other types and causes of tyrosinemia as well, but infantile tyrosinemia is the main one detected in neonatal testing.

Liver Transplantation for HBV

The long-term outcome after liver transplantation for chronic HBV infection with cirrhosis is excellent, but this has not always been the case in fact, in the early 1990s, patients with chronic hepatitis B were generally regarded as poor candidates for liver transplantation. The initial experience with liver transplantation for hepatitis B was associated with a disappointing 50 survival after 3 yrs of follow-up (9). The reason for this relatively poor survival was that HBV re-infection with detectable hepatitis B surface antigen (HBsAg) occurred in 80 of patients, usually within the first year. In many instances, recurrent HBV infection had an aggressive course, with rapid progression to cirrhosis and death. Histologically, a pattern of fibrosing cholestatic hepatitis was recognized as an unusual, but rapidly progressive, and usually fatal, form of liver disease associated with HBV re-infection that occurred in some recipients after liver transplantation (10,11). High levels of...

Hepatitis B Immune Globulin Prophylaxis for HBV ReInfection

A major breakthrough was reported in 1993, when the European Concerted Action on Viral Hepatitis Study showed that patients who received prophylactic hepatitis B immunoglobulin (HBIg) perioperatively, and long-term, after liver transplantation, had a lower incidence of recurrent HBV and improved survival rate (13). This study showed that patients with evidence of active viral replication before liver transplantation, i.e., detectable serum HBeAg and or HBV DNA, were at an increased risk for recurrent HBV infection (Table 1). On the other hand, patients without active viral replication, transplanted for fulminant hepatitis rather than cirrhosis, or co-infected with HDV, had a lower incidence of HBV recurrence. Several studies from the United States later confirmed that the administration of high-dose intravenous HBIg, after liver transplantation, reduces the incidence of recurrence to 20-30 or less (14-17). The finding that some patients without recurrence of HBsAg, the routine test...

Treatment of Recurrent HBV Infection Posttransplant with LAM

Despite prophylaxis with HBIg, lamivudine, or a combination of these treatments, 10-30 of patients will develop recurrent HBV infection after liver transplantation, and a small percent of patients transplanted for other diseases develop de novo HBV infection (13,23). Based on historical data, recurrent HBV infection may be accelerated, leading to liver failure.

Chronic Hcv Infection

CHC with end-stage liver disease is the leading indication for liver transplantation in the United States (1,43). The World Health Organization estimates that 120 million people worldwide are infected with HCV, and that 20 of these will develop cirrhosis. Most cases of hepatocellular carcinoma not associated with HBV are caused by HCV. In the United States, 1.8 of the population, or 4 million Americans, have been infected with HCV, and about 8000 die each year from this infection. Approximately 25 of all liver transplantations in the United States are performed for end-stage liver disease secondary to HCV infection, and this percentage will increase, based on the large number of patients with CHC on the waiting list. Liver transplantation is the best treatment for decompensated cirrhosis caused by HCV infection, but HCV re-infection poses important clinical problems that may appear either early or late after liver transplantation (44,45).

Low Efficacy Diuretics

Spironolactone (Aldactone) is structurally similar to aldosterone and competitively inhibits its action in the distal tubule (exchange of potassium for sodium) excessive secretion of aldosterone contributes to fluid retention in hepatic cirrhosis, nephrotic syndrome and congestive cardiac failure (see specific use in chapter 24), in which conditions as well as in primary hypersecretion (Conn's syndrome) spironolactone is most useful. Spironolactone is also useful in the treatment of resistant hypertension, where increased aldosterone sensitivity is increasingly recognised as a contributory factor.

Protein Energy Malnutrition

Patients with chronic liver disease exhibit a progressive loss of fat and muscle mass, which leads to mixed protein-energy malnutrition. When investigating whole-body protein metabolism, protein synthesis, degradation, and amino acid oxidation have to be estimated in a specific manner. McCullough and Glamour reported that there appear to be few differences in protein turnover in stable cirrhosis patients and in healthy controls, while oxidation of amino acids in these patients was generally normal or reduced 60 . However, increased protein catabolism is thought to be an It continues to be debated whether body wasting in patients with liver cirrhosis is related to hypermetabolism or not. Resting energy expenditure (REE), estimated by use of indirect calorime-try, in stable cirrhotic patients is usually not significantly different from that in normal controls. However, Shanbhogue et al. reported that REE per g creatinine in 24-h urine in end-stage liver disease patients was...

Liver Transplantation for HCV

Like hepatitis B, the natural history of HCV infection in liver transplantation recipients is often accelerated, and the spectrum of recurrent disease ranges from asymptomatic mild hepatitis to severe chronic hepatitis and cirrhosis. Re-infection with HCV after liver transplantation is virtually universal, occurring in more than 95 of cases (44-46). Acute lobular hepatitis is seen in up to 75 of the patients, at a median of 4 mo after liver transplantation. Fortunately, approx 85 of patients with recurrent HCV generally do well, with only mild manifestations of re-infection, but an unpredictable 15 of patients have a more severe course, with rapidly recurrent disease and progression to cirrhosis. Most studies that have analyzed the survival of patients with recurrent HCV infection after liver transplantation have failed to show significant differences, compared to those transplanted for other causes of cirrhosis (44). However, the usual average follow-up in published studies has been...

Siadh Ratio Serum Urine Osmolality

Hyperosmolar, hypernatriuric urine is associated with many conditions, including secretion of excessive ADH, or syndrome of inappropriate antidiuretic hormone secretion (SIADH). Coupled with unrestricted fluid intake, the urinary output may be normal in SIADH, but fluid restrictions can cause oliguria and hypo-osmotic plasma, including hyponatremia. This relatively common syndrome results from a variety of causes including malignancy, pulmonary or chronic central nervous system disorders, and drug toxicity. Hypo-osmotic plasma and hyponatremia are common to many disorders, including congestive heart failure, nephrotic syndrome, cirrhosis, renal insufficiency, and to SIADH, so a differential diagnosis is important. In SIADH, urinary sodium levels often are elevated, urine-to-serum osmolality ratio is slightly greater than 1.0, and serum osmolality is usually less than 270 mOsm Kg. Unlike in SIADH, urinary sodium levels are generally normal in congestive heart failure, cirrhosis, or...

Treatment of Recurrent HCV

Unfortunately, in contrast to the success in preventing HBV re-infection after liver transplantation, there is as yet no effective antiviral treatment to prevent HCV re-infection. Recurrent HCV may be accelerated in immunosupressed liver transplantation recipients, progressing to cirrhosis in 8-16 of patients within 5 yr, in some reports (44). The rapid rate of progression to liver failure has been observed in a subset of HCV-infected transplant recipients who develop a cholestatic pattern of liver injury (42,56,57). Cholestatic hepatitis is an infrequent cause of jaundice in HCV-infected liver transplantation patients, and should be a diagnosis of exclusion (68). Cholestatic hepatitis C ranges in severity, and does not always signal impending graft failure. The natural history of cholestatic hepatitis C differs dramatically from that of cholestatic hepatitis B, which has been shown to lead to death or need for retransplantation within several weeks (9).

Inhibitory Effect Of Shosaikoto On Hepatic Fibrosis

In the injured liver, HSCs are regarded as the primary target cells for inflammatory and peroxidative stimuli, and are transformed into myofibroblast-like cells. These HSCs are referred to as activated cells, and this activation is accompanied by a loss of cellular retinoid, and the synthesis of a-smooth muscle actin (a-SMA) and large quantities of the major components of the ECM, including collagen types I, III, and IV, fibronectin, laminin, and proteoglycans. a-SMA is an activation marker of HSCs. It has been shown that, in vivo , HSCs express the genes that encode for enzymes such as matrix metalloproteinase (MMP)-1 and MMP-2, as well as a tissue inhibitor of metalloproteinase (TIMP)-1. The net effect of the production of proteins involved in matrix synthesis and degradation could be reduced matrix degradation, which could account for the marked increases in matrix deposition and nodule formation observed during hepatic fibrosis and cirrhosis (Shimizu, 2001).

Role of Brain Serotonin in Disease Associated Anorexia

Tryptophan is the precursor of serotonin, whose synthesis is strictly dependent on the availability of tryptophan 10 . In anorectic cancer patients, plasma and particularly CSF concentrations of tryptophan are increased when compared to controls and non-anorectic cancer patients 11, 12 . After tumour removal, plasma tryptophan normalises and food intake improves 13 . Similar data have been obtained in patients with liver cirrhosis. In this clinical setting, the presence of anorexia was associated with higher plasma levels of tryptophan than in non-anorectic patients with liver cirrhosis 14 . Also, brain tryptophan availability, which predicts brain tryptophan levels, was higher in anorectic than in non-anorectic patients. In uremic patients, persistently high brain serotonin levels appear to be related to the onset of anorexia and reduced food intake 15 . When considered together, these data suggest that brain serotonin could represent a key factor involved in the pathogenesis of...

Pharmacokinetic Changes In Liver Disease

Important changes in drug handling occur. Parenchymal liver disease e.g. chronic viral or alcoholic liver disease, has more impact on hepatic drug-metabolising enzyme activity than primarily cholestatic conditions, e.g. primary biliary cirrhosis, although clearance of drugs eliminated mainly by biliary excretion will be impaired in the latter.

Hepatic Blood Flow And Metabolism

Complex changes in blood flow occur with liver disease. Resistance to hepatic portal blood flow rises in cirrhosis, and portasystemic and intrahepatic shunts reduce drug delivery to hepatocytes. The pattern of change caused by disease relates to the manner in which the healthy liver treats a drug and there are two general classes

Autoimmune Active Chronic Hepatitis

This chronic inflammatory disease of the liver is characteristically associated with circulating autoantibodies and high serum immunoglobulin concentrations. Untreated, it progresses to cirrhosis, but the condition responds well to immunosup PRIMARY BILIARY CIRRHOSIS (PBC)

Stem Cells and Regenerative Medicine

Advances in medicine and medical technology have resulted in a tremendous improvement in health and welfare. However, we are still faced with various diseases that are difficult to treat using contemporary medicine. For organ failures (heart failure, renal failure, liver failure) and neurodegenerative diseases (Parkinson's and Alzheimer's disease), there is at present no effective treatment other than the transplantation of organs from human donors or cells from a fetus. In the case of transplantation, there are many problems such as immunological rejection, infectious diseases, and a lack of donors, and the development of a novel treatment method has been desired. During the past decade, regenerative medicine has appeared as a key technology for the next generation of medical care 6-12 . Cell therapy and organ repair using stem cells have become very attractive in regenerative medicine.

Hypoglycemic Encephalopathy

Hepatic encephalopathy in a 53-year-old chronic alcoholic man with severe liver cirrhosis. Alzheimer type 2 astrocytes in basal ganglia display (A) large vesicular nuclei, scanty chromatin, and prominent nucleoli (HE), and (B) positive immunostaining for S-100 protein (Immunostain). C. The subcortical white matter shows focal spongiosis (HE). Hepatic encephalopathy in a 53-year-old chronic alcoholic man with severe liver cirrhosis. Alzheimer type 2 astrocytes in basal ganglia display (A) large vesicular nuclei, scanty chromatin, and prominent nucleoli (HE), and (B) positive immunostaining for S-100 protein (Immunostain). C. The subcortical white matter shows focal spongiosis (HE).

Vaccination Strategies

Patients with chronic liver disease, e.g., chronic hepatitis C (CHC), are also candidates for the HBV vaccine, if serologic markers of HBV infection are absent, since super-infection by HBV may result in increased morbidity and high case-fatality rates. Limited data (9) indicate that vaccine responsiveness may decline with advancing disease, and that patients with cirrhosis awaiting transplantation are among the least responsive. Hence, early immunization, after the diagnosis of chronic liver disease, seems appropriate. Although, in a recently reported European study (10), patients with CHC were less responsive to a non-U.S.-approved recombinant vaccine than were healthy controls, conflicting data (11) have been

Sex gonadal hormones and antagonists steroid hormones

In hepatic cirrhosis degradation of oestrogens in the liver may be impaired, leading to raised blood concentrations of oestrogen with f minisation androgens may help such patients. They may also stop the itching of biliary obstruction. Androgens may also help in some cases of anaemia due to bone marrow failure. Androgens are now little used in metastatic breast cancer because of their virilising effects.

Prevention of HAV Superinfection in Chronic Hepatitis B and CHC

HAV super-infection of individuals with chronic hepatitis B virus and chronic hepatitis C virus infection may exacerbate the liver disease, and, in some instances, may lead to acute liver failure (19,20). This concept has not been accepted by all workers in the field (21), but the recommendation that HAV-susceptible patients with chronic liver disease should be targeted for vaccination with one of the inactivated, whole HAV vaccines seems reasonable, and has become standard practice in many hep-atology centers. HAV vaccination of patients who have received liver transplants is also reasonable. Information about the immunogenicity of HAV vaccines in patients with chronic liver disease remains limited, but, in general, the immune response to the vaccines appear to be adequate in those with mild to moderately severe disease. In one study, the immune response to inactivated HAV vaccine among Chinese HBV-carrier children appeared to be reduced, compared to that in noncarrier children, but...

Isoflurane versus halothane

Debaene et al41 induced cirrhosis in rats by bile duct ligation and then compared the influence of anaesthetic drugs on liver blood flow during mild haemorrhage (removal of 20 of estimated blood volume). One MAC (1-3 inspired in rats) isoflurane anaesthesia maintained hepatic arterial flow (measured by radioactive microspheres) at prehaemorrhage values. One MAC (1-0 inspired in rats) halothane anaesthesia caused a significant decrease in hepatic arterial flow during haemorrhage.

Classification of human acute renal failure

When it comes to assessing whether HBOCs decrease the likelihood of acute renal failure or cause acute renal failure, the important question is 'what is acute renal failure ' Simply defined, acute renal failure has occurred when there is an increase in serum creatinine of 8-125 mol l (0.3-0.5 mg dl) above baseline within 48 hours of an intervention however, no one has shown an association of transient changes in serum creatinine with morbidity or with likelihood of long-term recovery (Mehta and Chertow, 2003). Mehta and Chertow (2003) used epidemiological data to classify human acute renal failure under four domains (S) susceptibility (I) insult (R) response and (E) end-organ consequences. Susceptibility relates to the severity of pre-existing chronic kidney disease and risk factors. Risk factors include diabetes mellitus with micro-albuminuria, dehydration, multiple myeloma, congestive heart failure, and decompensated cirrhosis. Insult is rated as known or unknown, and by proximity...

Approach To Jaundice History and Examination

Hep Igg And Igm

The social history is of critical importance in a patient with jaundice. The abuse of alcohol is the most common cause of cirrhosis. IV drug use or unsafe sexual practices can lead to infection with hepatitis B or C. Hepatitis is also associated with getting tattoos if unsterili .ed equipment is used. Travel history, especially the location and timing of any international travel, can lead to the consideration of hepatitis A. Abdominal examination must include, among other things, evaluation of the general contour of the abdomen, the presence of any ascites, the presence of organomegaly, and any tenderness. Hepatomegaly may or may not occur as a part of liver disease. Right upper quadrant tenderness can be associated with acute hepatitis but also with gallstone disease. Splenomegaly could suggest portal hypertension from cirrhosis or could be caused by malignancy. Hepatitis B virus infection is transmitted via contact with contaminated blood or body fluids. Sexual contact and needle...

951 IL6 Knockout and Transgenic Mice

When sections of the liver were cut away, the mice would deteriorate and die. However, when the mice were pretreated with IL-6, hepatocyte proliferation returned to normal and liver damage was prevented. Thus, IL-6 therapy may be of benefit in patients undergoing liver transplant, or in those suffering from cirrhosis or chronic hepatitis, which are characterized by liver degeneration. The possible role of IL-6 in autoimmune disease is made apparent with trans-genic mice that overexpress the cytokine and show an increase in agalactosyl IgG (499). This immunoglobulin is increased in a variety of autoimmune diseases such as RA, Crohn's disease, type I diabetes, and pulmonary TB (500-502). Transgenic overexpression of IL-6 in the CNS can lead to significant neurodegeneration and subsequent motor uncoordina-tion, ataxia, and tremor (503).

Transmission of Infectious Agents

Exposure to Infected Body Fluids As you learned in Chapter 9, AIDS is caused by exposure to infected blood. Hepatitis is another disease caused by contact with infected blood. There are at least six different hepatitis viruses, but the most dangerous is the virus known as hepatitis C. Exposure to hepatitis C leads to chronic liver diseases such as cirrhosis (irreversible, potentially fatal scarring of the liver), liver cancer, and liver failure. Hepatitis C ranks second to alcoholism as a major cause of liver disease and is the leading reason for liver transplants in the United States.

Antiserotonergic Therapies Targeting Anorexia and Cachexia

Anorexia significantly improved after 3 days of treatment only in cancer patients receiving BCAA, leading to a significant improvement of energy intake. These encouraging results must be considered as preliminary, since they were obtained in a small population during a short study period, and need to be validated in larger trials. However, they confirm the feasibility of interfering with hypothalamic neurotransmission to influence energy intake. Indeed, more fascinating results were later obtained in uremia and in liver cirrhosis.

Chronic Infection With Normal Alt Carrier

CHC in patients with persistently normal ALT. Mathurin et al. (39) performed a case-control study of 102 patients with positive hepatitis C virus antibody and normal ALT and 102 patients with positive hepatitis C virus antibody and abnormal ALT. HCV RNA was positive in 66 and 97 , respectively. Histology grade (0.6 vs 1.38 P < .0001) and stage of fibrosis (.95 vs 1.8 P < .001) were much lower in the normal ALT group. Patients with normal ALT, who were positive for HCV RNA, had histology scores as low as those with negative HCV RNA. In addition, patients with normal ALT had much slower rates of disease progression than the patients with abnormal ALT, regardless of HCV RNA status (fibrosis progression of .05 vs .13 (F-METAVIR) U yr. The only patients with normal ALT who developed severe fibrosis or cirrhosis were those with a history of heavy alcohol consumption. One is left to conclude that the natural history of hepatitis C has not yet been fully defined (43). Current data suggest...

Risk for Development of HCC

Dual infection with HBV and HCV may accelerate the progression of chronic liver disease to cirrhosis and HCC (35-38). In one study of patients with HCC, the presence of both anti-HCV and HBsAg was found in 12 of cases (38). 45 did not have HBsAg, but integrated HBV DNA was detected in the tumor tissue. The relative risk of developing HCC was highest in those with HBsAg and anti-HCV positivity (RR 40.05), compared to those who are positive for only anti-HCV (RR 27.12) or HBsAg (RR 13.96), and those who were negative for both markers (RR 1.00). In a multivariate analysis of cirrhotic patients, male gender, older age, alcohol abuse, and dual positivity for HBsAg and anti-HCV were determined to be independent risk factors for the development of HCC. Benvegnu et al. (35) suggested that HBV might act as the initiating factor, by altering the arrangement of the hepatocyte genome, and that HCV is the promoting factor, by virtue of its contribution to continuing liver injury and regeneration.

Optic Neuropathies of Malnutrition Definition

An optic neuropathy of malnutrition is one caused by a dietary deficiency. In the developed parts of the world, this is most commonly a deficiency of vitamin Bi2. Such cases are uncommon, and are most often caused by macrocytic anemia. Vitamin Bi2 and folate levels are easily measured. Other risk factors for malnutrition include intestinal bypass or gastric stapling for weight loss and the hepatic cirrhosis of alcoholism. Treatment should include intramuscular injections of high doses of hydroxycobolamine.

Safe Limits For Chronic Consumption

Alcoholics with established cirrhosis have usually consumed about 23 units (230 ml 184 g) daily for 10 years. It has long been thought that total consumption accumulated over time was the crucial factor for cirrhosis. Heavy drinkers may develop hepatic cirrhosis at a rate of about 2 per annum. The type of drink (beer, wine, spirits) is not particularly relevant to the adverse health consequences.

EtOH and Increased Methotrexate Toxicity

Methotrexate (MTX) may induce liver damage. The pathogenesis of hepatotoxicity with MTX is poorly understood. Some patients may develop fibrosis or cirrhosis, following long-term treatment with MTX. However, several studies, with serial liver biopsies during continued treatment, have shown that MTX-induced liver cirrhosis is not of an aggressive nature. Alcohol has been cited as a major contributing factor to development of cirrhosis in patients treated chronically with MTX (10,11). There is a strong association with previous or concurrent heavy EtOH intake and host susceptibility to injury by MTX (12). Pre-existing hepatic injury, as may be seen with chronic viral hepatitis, may also contribute to injury with MTX (12). Whenever chronic MTX use is contemplated, discontinuation of alcohol use should be recommended.

Alcohol and Chronic Viral Hepatitis

The most common form of nonalcohol-induced liver disease seen in patients with alcoholism is CHC (7). In patients with CHC, chronic alcoholism has been shown to cause more severe and rapidly progressive liver disease. This can lead more frequently to cirrhosis of the liver and hepatocellular carcinoma. Alcohol intake in excess of 10 g d has been associated with increased serum hepatitis C viral RNA and amino-transferase levels (7). The mechanisms of these increases are poorly understood, but, as mentioned, Fe may enhance viral replication and or reduce immune-dependent viral killing. The histological picture in hepatitis C patients with chronic alcohol abuse is usually indistinguishable from that in CHC patients who do not use EtOH. In alcoholic patients, compared with nonalcoholic patients, IFN therapy has been shown to be less effective, even after a period of abstinence. Alcohol intake should be restricted to 10 g d or less in patients with CHC. If cirrhosis is present, or IFN...

Acquired Generalised Lipodystrophy Lipoatrophic Diabetes or Lawrence Syndrome

Lipo Dostrophy Images

Acquired generalised lipodystrophy (AGLD) is a rare, juvenile-onset lipodystrophy, first fully described by Lawrence in 1946 1 , who reported on a young female subject with 'lipodystrophy, and hepatomegaly with diabetes, lipaemia and other metabolic disturbances.' To date, approximately 80 patients with AGLD have been reported 2 . Like others LDs, AGLD is prevalent in females. Lipoatrophy develops over a number of years, in childhood or in adolescence, so that the onset of the condition is later than that of congenital generalised lipodystrophy (CGLD). Extended areas of subcutaneous fat are involved, including the face, arms, and legs. Less frequently mesenteric, retroperitoneal, perirenal and mediastinal fat depots are involved, while retroorbital fat seems to be spared. Muscle mass, evaluated by dual energy X-ray analysis (DEXA), is preserved or even increased compared to age-, sex- and body mass index (BMI)-matched subjects. Therefore, in spite of the generalised atrophy of fat...

Pleural Fluid Appearance

Clear yellow Transudative, e.g., secondary to CHF. cirrhosis, nephrotic syndrome To appreciate the pathophysiology of the formation of a transudate versus an exudate is to understand the differential under each category. Approximately 10 mL of pleural fluid is formed every day by the visceral pleura and absorbed by the parietal pleura (capillaries and lymphatics). Processes that disturb this equilibrium lead to fluid accumulation. Clinical settings in which the hydrostatic pressure is increased, for example. CHF and constrictive pericarditis the oncotic pressure is decreased, for example, nephrotic syndrome and cirrhosis or the intrapleural pressure is reduced, for example, atelectasis, lead to the formation of a transudate. In contrast, exudates are more a result of local inflammation, for example, infection, malignancy, and connective tissue diseases. which cause a protein leak into the pleural space. Less commonly, impaired lymphatic drainage, as occurs in chylothorax, or...

Agnogenic Myeloid Metaplasia Ammmyelofibrosis With Myeloid Metaplasia

As the disease progresses, the spleen gradually enlarges, as may the liver. Anemia becomes more severe and is complicated both by iron deficiency owing to bleeding from esophageal varices and by relative folic acid deficiency. The high portal blood flow due to the enlarged spleen may cause forward liver failure, portal hypertension, and ascites. Thrombosis of the hepatic vein and development of the Budd-Chiari syndrome have been recognized. Eventually, the spleen may occupy the entire abdomen. Ascites may develop.

Surrogate Endpoints

Use of a surrogate endpoint is often considered when direct measures of clinical benefit arise (are available) only after a lengthy period of observation. For example, the principal clinical sequelae of chronic hepatitis C are the development of end-stage liver failure, hepatocellular carcinoma, or death. These outcomes typically occur many years to decades after diagnosis, therefore using them as endpoints to assess new treatments for chronic hepatitis C would require very lengthy trials. In the trials of interferons for treatment of chronic hepatitis C infection, decreases in levels of circulating liver enzymes, improvements in liver histopathology, and, more recently, loss of detectable virus in the plasma have been used as surrogate endpoints because these types of improvements are thought to indicate a decreased likelihood of serious, long-term clinical sequelae. Similarly, in trials of antiviral agents for the treatment of patients with early HIV infection, effects on CD4+...

Electroencephalographs Studies of Chronic Substance Abusers

It is a logical fallacy to unquestionably attribute an EEG EP ERP difference between one group of substance dependent patients and a group of healthy, non-drug-abusing volunteers to an effect of substance abuse. Collectively, substance-dependent patients are known to exhibit higher-than-normal rates of comorbid psychopathology, polydrug abuse, medical disorders (e.g., cirrhosis,

Detection Of A Malignant Disease

P53 autoantibodies were also detected although with a low frequency (4 ) in patients with chronic liver diseases and in patients with liver cirrhosis. All of these patients were free of a hepatocellular carcinoma and they were carefully investigated for another underlying malignancy which was not found. Thus, these results might suggest that p53 autoantibodies are not exclusively detectable in patients with a malignant disease 35 .

Neuropsychiatric Manifestations

The selective serotonin reuptake inhibitors (SSRIs) are the antidepressants of choice for treating IFN-induced depression. First, these agents appear to be well-tolerated and safe in patients with liver disease. Fluoxetine has a positive impact on the mental slowing associated with IFN, and venlafaxine and buproprion have stimulating effects that also help the mental slowing associated with IFN. Sertraline is easy to titrate, and very safe in liver disease, and citalopram has minimal drug-drug interactions. The clinician should become familiar with one or two the SSRIs, and use these, once depression is diagnosed. Tricyclic antidepressants, with their anticholinergic activity, are not recommended, particularly for patients with cirrhosis, since they may exacerbate cognitive dysfunction. Counseling and psychiatric consultation are advisable for all patients with more than mild depression.

Clinical Aspects of Diuretics

In a healthy human subject, changes in dietary intake or variations in the extrarenal loss of fluid and electrolytes are followed relatively rapidly by adjustments in the rate of renal excretion, thus maintaining the normal volume and composition of extracellular fluid in the body. Edema is an increase in extracellular fluid volume. In almost every case cf edema encountered in clinical medicine, the underlying abnormality involves a decreased rate of renal excretion. One of the factors influencing the normal relationship between the volume of interstitial fluid and the circulating plasma is the pressure within the small blood vessels. In diseases of hepatic origin (e.g., cirrhosis), the pressure relationships are dis

Anorexia Nausea and Vomiting

Anorexia is common in patients on IFN, with loss of appetite and associated early satiety. Patients are frequently told to expect a 5-10 weight loss while on treatment with IFN. In overweight patients with hepatic steatosis, this weight loss can actually be beneficial, but some patients, particularly those with cirrhosis and catabolic malnutrition, do poorly with this degree of weight loss. Frequent small meals and use of high-calorie nutritional supplements are occasionally necessary. If patients lose more than 10 body wt, or have any associated symptoms suggestive of more serious disease, then a clinically appropriate workup for occult malignancy may be necessary.

Chronic Infection And Sequelae

The prolonged time-course of disease progression after acute hepatitis C was suggested by two older studies. Kiyosawa (26) studied 231 patients with transfusion-related hepatitis C. 96 had chronic hepatitis without cirrhosis, 81 had cirrhosis, and 54 had HCC. The time of acquisition of infection was presumed to be the time of transfusion. Using Clinical Outcomes After Infection with HCV A. Rates of progression to cirrhosis and HCC Cirrhosis (yr) HCC (yr) B. Risk of developing cirrhosis, HCC, or death related to liver disease Clinical Outcomes After Infection with HCV A. Rates of progression to cirrhosis and HCC Cirrhosis (yr) HCC (yr) B. Risk of developing cirrhosis, HCC, or death related to liver disease Cirrhosis these assumptions, they estimated that development of cirrhosis required 21.2 yr, and development of HCC required 29 yr of chronic infection. Tong (27) used similar analyses to determine that the time to development of cirrhosis and HCC were 21 and 28 yr, respectively. In...

Risk Factors

The current incidence of hepatitis C in the United States is on the decline, because of effective means of screening for HCV in the blood donor population, and changes in behavior of injection drug users related to awareness of AIDS and hepatitis (14). The CDC estimates that there were approx 180,000 new infections yr in the mid 1980s, but that the incidence had dropped to 28,000 cases yr by 1995 (Fig. 1). Currently, it is estimated that there are 30,000-40,000 new infections annually. Given the relatively slow progression in liver disease of 20-30 yr, large numbers of patients who were infected in the 1970s and 1980s are just now beginning to report to physicians with advanced liver disease and hepatocellular carcinoma (HCC). Worldwide incidence of hepatitis C is unknown, but the World Health Organization estimates that about 3 of the world population is chronically infected with hepatitis C these 170 million individuals are at risk for cirrhosis and liver cancer (15).

Host Factors

For management of CHC, examined patients for factors associated with disease progression. Most of the patients had established liver disease, 16.8 had cirrhosis on entry, and 7.4 died during a mean follow-up of 26.9 mo. Death resulting from complications of liver disease, including liver failure and HCC, occurred only in cirrhotics and accounted for half of the total deaths. Risk of death was increased in patients with cirrhosis, long duration of disease, alcohol consumption, injection drug use, and older age. Acquisition of infection at a young age was associated with higher risk of dying from liver disease. Risk of death was decreased by use of interferon. As expected from the above discussion, these cases represented later-stage disease with 20 of patients who underwent liver biopsy demonstrating cirrhosis. Cirrhosis was more common in patients who acquired hepatitis C via blood transfusion, had longer duration of disease, were heavy users of alcohol, and had co-infection with...

Extraneous Factors

Most studies have suggested that chronic heavy consumption of alcohol is an important co-factor in progression of CHC to cirrhosis and hepatoma. Early epidemiological surveys (80,81) established the relationship between HCV infection and alcohol liver disease. Subsequent investigations indicate that chronic heavy alcohol use may promote HCV replication (82,83). In numerous epidemiologic studies, alcohol is often identified as a major factor in promoting progression of liver disease (84-88). An Australian study of 234 patients with CHC, who underwent liver biopsy, demonstrated cirrhosis in 21 , and that the risk of cirrhosis was related to two primary factors patient age, and total lifetime alcohol consumption (89). One could conclude that, in general, alcohol intake, especially exceeding 50 g d, promotes progression of fibrosis, accelerates liver disease, and is also linked to an increased risk for HCC (90). Two case-control studies (91) from Italy are consistent with the fact that...

Survival

Diabetes mellitus, chronic liver disease (including cirrhosis), cerebrovascular disease, and congenital anomalies (Table 1.2) 8 . In females, deaths caused by cancer occur at more than twice the frequency of the second leading cause of death caused by disease (Table 1.2).

Summary

Although much has been learned about the natural history of hepatitis C, gaps in knowledge and understanding of this chronic liver disease remain. Older, primarily retrospective studies, based in referral centers for liver disease, painted a grim picture of high rates of chronicity, moderate disease progression, and excessive rates for development of cirrhosis and HCC. Newer, prospective studies suggest a more benign outcome, with higher rates of spontaneous clearance of virus after acute infection, slower rates of progression to chronic liver disease, and reduced risk of liver cancer. Identifiable risk factors for disease progression include acquisition of infection by transfusion, long duration of disease, male gender, use of alcohol, and co-infection with hepatitis B or HIV. Cirrhotic patients, and those with HCC caused by hepatitis C, will represent an increasing burden and challenge to liver centers and programs in liver transplantation for several years to come (160). The peak...

Abstract

Since the incidence of hepatocellular carcinoma in chronic viral hepatitis patients with cirrhosis is very high, it is valuable to develop effective methods for its prevention. In the present study, the effect of a carotenoid mixture on hepatocellular carcinoma development was examined. Patients were randomly divided into two groups and treated with a carotenoid mixture in addition to conventional antisymptomatic treatment, or antisymptomatic treatment alone. Cumulative incidence of hepatocellular carcinoma development was periodically analyzed using the Kaplan-Meier method. Significantly lower incidence was observed in the carotenoid-treated group compared with the control group in the analysis at year 4.

HCV tropism

Oncogenic potential of the chronic HCV infection. (SS Sjogren's syndrome, MC mixed cryoglobulinemia, CH chronic hepatitis cirrhosis). Figure 1. Oncogenic potential of the chronic HCV infection. (SS Sjogren's syndrome, MC mixed cryoglobulinemia, CH chronic hepatitis cirrhosis).