Alternative Ways to Treat Liver Disease

Liver Tracker

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

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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.

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

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.

Substrates of glutathione transferases

Quinones (ortho- and para-) and quinoneimines are structurally very similar to a,b-unsaturated carbonyls. They react with glutathione by two distinct and competitive routes, one of which is a reduction to the hydroquinone or aminophenol, where GSH does not react covalently with the substrate but emerges in the oxidized form (GSSG). The other route is relevant to the present context, being a nucleophilic addition to form a conjugate. The reaction has physiological significance since endogenous metabolites such as quinone metabolites of estrogens are conjugated to glutathione. A medicinal example is provided by the toxic quinoneimine metabolite (71, Figure 23 see 5.05 Principles of Drug Metabolism 1 Redox Reactions 5.08 Mechanisms of Toxification and Detoxification which Challenge Drug Candidates and Drugs) of paracetamol (30). Its glutathione conjugate (71) is not excreted as such in humans dosed with the drug, but as the mercapturic acid (67, Figure 22). The reaction is one of major...

Mary Ann Cohen and David Chao

In 1967 Lipowski provided a classification of commonly encountered problems at the medical-psychiatric interface that is still relevant to AIDS psychiatry today. These problems (with a modification of the fifth item, discussed in Chapter 1 of this book) include psychiatric presentation ofmedical illness, psychiatric complications of medical illnesses or treatments, psychological response to medical illness or treatments, medical presentation of psychiatric illness or treatments, and comorbid medical and psychiatric illness. These five problems have been illustrated with casevignettes in Chapter 1. Somepersons withHIVand AIDS have no psychiatric disorder, while others have a multiplicity of complex psychiatric disorders that are responses to illness or treatments or are associated with HIV AIDS (such as HIV-associated dementia) or co-morbid medical illnesses and treatments (such as hepatitis C, cirrhosis, or HIV nephropathy and end-stage renal disease). Persons with HIV and AIDS may...

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.

Immunogenetic markers as determinants of outcome following paracetamol overdose

The nature and magnitude of the inflammatory immune response to tissue injury is an important element in the development of multiorgan failure (MOF) in the critically ill. In some cases, the immune response may be far greater than that required to deal with the original insult and promote tissue injury rather than resolution and healing. Patients respond very differently to paracetamol overdose once the critical threshold of 15 g has been exceeded. Outcome may vary from self-limiting coagulopathy to rapidly progressing MOF and the syndrome of hyperacute (fulminant) liver failure (POD-ALF). Evidence that immune activation occurs after paracetamol overdose is mainly based on the observation that high circulating levels of the cytokines IL-1, IL-6 and TNF-a can be detected at this time (reviewed in 21 ). Not only do these cytokines profoundly affect events close and distant to their release, but experimental evidence suggests that they may also impair liver regeneration 22 .

Immunogenetic markers as determinants of outcome and fibrogenesis in alcoholic liver disease

Alcoholic liver disease (ALD) progresses to liver cirrhosis in less than 10 of heavy drinkers. This clinical variability, and disappointing results from studies of genes involved in alcohol metabolism, has led to considerations that cirrhosis, fatty liver and alcoholic hepatitis are determined to some degree by genetic factors which regulate the immune system. An immune hypothesis for alcoholic cirrhosis has been suggested, although there is some evidence for a dose response. Twin studies suggest that genes do play a role in determining progression beyond simple alcoholic steatohepatitis, and candidate associations have been sought either with HLA or with other immunoregulatory genes. More recently, attention has focused on the cytokine genes. Ongoing studies at the Centre for Liver Research in Newcastle, UK, have linked TNF-238 and IL-10-627with alcoholic cirrhosis but not with alcoholic hepatitis 36, 37 . The IL-10 gene promoter encodes three SNPs which have been linked with...

Medical Complications Of Alcoholism Gastrointestinal Tract and Pancreas

Alcohol causes decreased peristalsis and decreased esophageal sphincter tone, which leads to reflux esophagitis with pain and stricture formation (Bor et al., 1998). The Mallory-Weiss syndrome refers to a tear at the esophageal-gastric junction caused by intense vomiting. Another source of bleeding from the esophagus is esophageal varices secondary to the portal hypertension of cirrhosis.

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.

Selection of toxicogenetic biomarkers lessons from paracetamol toxicity

Paracetamol (acetaminophen)-induced hepatotoxicity provides a useful illustration of the potential for toxicogenetic variants to determine outcome following overdose with a drug and these are currently under investigation in the author and colleagues' laboratories. Paracetamol is a safe and effective analgesic when used in the recommended doses (four X 1 g daily) but is considered the archetypal, predictable, iatrogenic hepatotoxin if excessive amounts are ingested 5 . Approximately 150 deaths from acute liver failure occur annually in the UK following paracetamol overdose. Considerable differences exist in the severity of liver damage, as well as in the outcome. For example, there are contrasting case reports of fatality after 6 g 6 , but an absence of toxicity with repeated daily doses of 20 g sustained for 5 years 7 . While liver transplantation offers a final treatment modality, the early and accurate prediction of patients requiring this expensive and limited resource are...

Incidence and aetiology

The single most common cause of ALF is paracetamol intoxication, accounting for 50 of the ALF patients in UK and Denmark and for 20 of ALF patients in the USA. Acute viral hepatitis B is the predominant cause of ALF in central and southern Europe, with acute viral hepatitis E a frequent cause of subacute liver failure in India. Other causes of ALF include mushroom intoxication, drug-induced hepatotoxicity (ecstasy, halothane, valproate and disulfiram), autoimmune hepatitis, cardiac failure, and inherited metabolic diseases.

Aetiology sex and age

In a multivariate statistical analysis of more than 500 patients with ALF, aetiology was found to be the single most important independent predictor of outcome 4 . Fatality rates are invariably 100 in ALF due to Wilson's disease and may exceed 70 in cases due to hepatitis nonA-E and drug-induced liver failure without liver transplantation. In contrast, patients with ALF due to acute viral hepatitis A and B have survival rates of 40-70 . Females with acute fatty liver of pregnancy and patients with paracetamol-induced ALF are those with the best prognosis 3, 4 .

Etiologies of Hypoglycemia

Pathophysiological Endocrinopathy (Addison's disease, Sheehan's syndrome) neoplasms (insulinomas, multiple endocrine adenomatosis MEA type I) liver disease (alcoholism, cirrhosis) chronic renal failure (CRF) and hemodialy-sis miscellaneous (AIDS, autoimmune diseases, pregnancy).

Prognosis by diagnosis

The natural course of hepatic disorders is determined by age, gender, the type of the disorder and its biological activity. The resulting prognosis is greatly variable, as shown in Table 20.1. The worst prognosis is observed in paediatric liver diseases such as extrahepatic biliary atresia 2 , and some transporter defects 3 , and hepatic metabolic disorders 1 . The later the manifestation of a hepatic disorder, the longer its natural course will be. In general, chronic end-stage liver disease in PBC, PSC or hepatitis B and C is only observed after 10-20 years 4, 5 . In acute liver failure, both children and adults have a poor prognosis of only a few days. In both age groups, the absolute prothrombin time (PT) or its international normalized equivalent (INR) have been shown to be the best prognostic predictors a PT result below 20 of normal indicating almost no chance of spontaneous survival (Table 20.1) 11 .

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...

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...

Growth factors and priming

Levels of HGF are detected in patients with acute liver failure. In these cases, plasma HGF levels have an inverse relationship with patient survival. Under these circumstances, it is not possible to determine whether high HGF levels in these patients constitute a marker for proliferative activity in the liver or whether they are a consequence of liver damage.

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 .

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.

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.

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 .

Host Defense and Viral Infection Mechanisms

Hepatitis C virus (HCV) is the major cause of posttransfusion and community-acquired hepatitis in the world. The majority of HCV-infected individuals develop chronic hepatitis that may progress to liver cirrhosis and hepatocellular carcinoma. The HCV structural proteins comprise the core protein and the two envelope glyco-proteins E1 and E2 (43). Several lines of evidence have demonstrated that the HCV envelope proteins may play a crucial role in the initiation of infection by mediating virus-host cell membrane interaction. E2 is thought to initiate viral attachment, whereas E1 may be involved in virus-cell membrane fusion (44-46). A comparative structural analysis of the E2 protein of various HCV isolates demonstrated that positively charged amino acid residues are highly conserved in the N-terminus of E2 hypervariable region 1 (47), thereby suggesting the negatively charged cell surface GAG, heparan sulfate, as an HCV receptor. Heparin directly interacts with E2 and binding of E2 is...

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.

The Pathophysiology of Benign Prostatic Hyperplasia

The prostate of aging males can be stimulated to undergo excessive growth. This is characterized by a number of cellular and molecular alterations leading to increased cell proliferation and reduced apoptosis in the prostate epithelium and stroma. The 'remodeling' that occurs as a result of these processes can permanently alter the appearance of the prostate, and may result in symptoms, long-term damage, and prostate cancer. It is not clear why these changes occur in some males, although it has been suggested that they are linked to a number of risk factors such as smoking, racial differences, obesity, liver cirrhosis, cardiovascular risks, and genetic predisposition. The pathogenesis of BPH is discussed in this section.

Gastrointestinal Function

C was the major risk factor for late development of cirrhosis of 16 patients with cirrhosis, 15 had disease attributable to hepatitis C 113 . Hepatitis B has largely been eliminated in populations treated after 1972 The true incidence of hepatic pathology is undoubtedly higher than current numbers suggest because the presence of cirrhosis is seldom reflected by abnormal liver function tests or hepatomegaly, because hyper-transaminasemia may be asymptomatic, and because liver biopsy procedures or liver scans are not routinely recommended after therapy. Thus, it is difficult to suggest foolproof guidelines for long-term follow-up. Patients at risk for gastrointestinal complications should be monitored by history or physical examination for hepatomegaly, icterus, and malabsorption. Especially for those patients with acute hepatotoxicity during therapy and for patients treated with hepatec-tomy, methotrexate, or hepatic radiation, the potential consequences of excessive alcohol and other...

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...

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.

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,

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.

Definition Classification and Diagnosis of Hypertension

Hypertension is usually systemic, but it may be limited to certain organs. The term 'pulmonary hypertension' is used to describe a selective elevation of pressure in pulmonary arteries. Portal hypertension, a persistent elevation of pressure in portal veins, is usually a secondary hypertension that often occurs as a consequence of liver cirrhosis.

Risk Factors and Etiology

HCCs appear to result from complications of previous hepatic damage due to metabolic or inflammatory disorders. Chronic infection with hepatitis B virus is the leading cause of HCC in children, adolescents, and young adults in Asia and Africa. However, in the Western countries, less than one-third of the adolescent or young adult patients diagnosed with HCC have an identifying cause such as hepatitis or other inflammatory liver disease 4, 5 . This is in marked contrast to older adults, in whom almost 90 of the cases are cirrhosis related, secondary to viral infection or alcohol consumption 6 . The prevention of a carrier state in children by a universal program of hepatitis B immunization has shown a dramatic decrease in the preva Less frequently, HCC is associated with congenital diseases such as hereditary tryosinemia, biliary cirrhosis, glycogen storage disease, and alpha 1-antitrypsin deficiency 8-11 . Prolonged exposure to anabolic steroids, toxin-contaminated foods (aflatoxin),...

Genetic and Molecular Mechanisms of Hepatocarcinogenesis

Recent publications have summarized the vast data now available on the genetic and molecular pathogenesis of human HCCs 36, 44, 45 . Briefly, the development of HCC is a slow, multistep process that is associated with changes in genomic expression that lead to alterations of the hepatocellular phenotype and the appearance and progression of a tumor. The development of HCC may take many years, and starts in the setting of chronic hepatitis or cirrhosis, with destruction of hepatocytes and inflammatory changes that alter the matrix and the microenvironment of the liver.

Clinical Presentation and Diagnosis

The symptoms associated with HCC are usually of short duration, and most often patients present with an enlargement of the abdomen and an associated palpable right upper quadrant mass. Anorexia, weight loss, and abdominal pain are frequently seen in association with advanced disease. Rarely, it may present as an acute abdominal crisis secondary to tumor rupture. Jaundice, vomiting, fever, and pallor are rare. On physical examination, hepatomegaly is common, and a palpable hard mass is frequently found. If the tumor is associated with pre-existing inflammatory or metabolic diseases of the liver, signs associated with cirrhosis of the liver can be found, including splenomegaly and spider angiomata. Most frequently there is extensive involvement of the liver by the tumor, and often the tumor is multifocal in origin. The presence of ascites may suggest intraabdominal extension, and at least one-third of patients present with metastatic involvement, with the lungs being the most common...

Natural history of HCV infection

Recently, a new form of HCV infection called occult HCV infection'' has been described in patients with abnormal liver function tests of unknown etiology (patients were anti-HCV and serum HCV-RNA negative, did not have markers of HBV infection and did not have clinical or biochemical evidences of autoimmunity, genetic or metabolic disorders, alcohol intake or drug toxicity). By analyzing liver biopsies from 100 patients with the above mentioned characteristics, Castillo et al. (2004) found HCV-RNA in the liver of 57 of the cases. Furthermore, the negative HCV-RNA strand was detected in 48 out of the 57 cases (84.2 ), indicating that the virus was replicating in the liver of patients with occult HCV infection. The clinical importance of this finding lays in the fact that the percentage of patients with occult HCV infection who had necroinflammation and fibrosis in the liver biopsy was statistically higher than that of patients without detectable HCV-RNA in liver. In fact, 5 of patients...

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.

Acquired Generalised Lipodystrophy Lipoatrophic Diabetes or Lawrence Syndrome

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...

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).

Fields Of Expertise Within Toxicology

Cirrhosis of the liver is one of the most well-known adverse effects of chronic alcohol abuse. The cholesterol-lowering, life-prolonging statin drugs must be monitored routinely for hepatotoxicity and rhabdomyolosis. A Google search on the terms statins, hepatotoxicity, and review produced over 22,000 hits indicating this is a very active field of interest.

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...

The need for biomarkers

There is a clear need for specific biomarkers that can be used in research studies for the testing of both novel artificial and bioartificial devices. In acute liver failure, there is considerable interest in prognostic markers (see Chapter 18) to predict outcome in patients - particularly in relation to selection for liver transplantation. Transplant criteria currently used at King's College Hospital are based on the presence of encephalopathy, the prothrombin time (alone or standardized as the international normalized ratio INR ), blood bilirubin and creatinine levels. These and other prognostic markers can be used to evaluate the effect of the device on the patient. When developing a device, in vitro experiments are performed to evaluate the activity of the device, usually with the measurement of basic liver functions such as production of a specific protein, e.g. albumin, metabolism of ammonia to urea or drug metabolizing cytochrome P450 (CYP) activity for lignocaine....

Risk Factors and Cancer

Alcohol and tobacco smoking are the main cause of cancers of the upper respiratory and gastrointestinal tracts. Alcohol by itself plays a role in liver cancer (cirrhosis) and possibly in a proportion of colon and breast cancer.36 Poverty is associated with increased exposure to tobacco smoke, alcoholism, poor nutrition, and certain infectious agents. Thus, poverty can act as a carcinogen, which suggests that fighting cancer also requires fighting poverty.

Time from jaundice to HE

Fulminant hepatic liver failure was defined as a form of ALF with an onset of HE within 8 weeks of the first clinical symptoms of liver disease, e.g. malaise, nausea, right abdominal discomfort or jaundice 1 . For a subgroup of patients with a longer interval to the development of HE, the terms subfulminant hepatic failure 2 or late-onset fulminant hepatic failure were adopted. Although this subgroup of patients may not develop severe HE, the prognosis is as poor as in patients with fulminant hepatic failure where a fatality rate of 82 has been reported. As the time from jaundice to development of HE is of prognostic value, a redefinition of patients with ALF into subgroups with hyperacute, acute and subacute liver failure has been proposed 3 .

Patterns of Psychoactive Substance

Traditional patterns of psychoactive substance use in most societies were episodic, coming at times of personal celebrations (e.g., birth and marriage), rituals (e.g., arrivals, departures, and changes in status), and seasonal celebrations (e.g., harvest and New Year). Exceptions to this pattern were daily or at least occasional use of alcohol as a foodstuff and use of various stimulants (e.g., betel-areca, tea and coffee, and coca leaf) in association with long, hard labor (e.g., paddy rice or taro farming and silver mining). Daily beer or wine drinking was limited to Europe, especially the para-Mediterranean wine countries and central grain-beer countries. Such daily or titer use is not without its problems, even when socially sanctioned. Hepatic cirrhosis and other organ damage (e.g., to brain, bone marrow, neuromuscular system, and pancreas) may result from long-term, daily use of more than 2-4 ounces of alcohol, depending on body weight (Baldwin, 1977). Daily use of stimulants,...

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

Pretransplant survival

Acute liver failure Paediatric chronic liver failure Paediatric chronic liver failure Adult chronic liver failure Paediatric and adult chronic liver failure Adult chronic liver failure Paediatric chronic liver failure Since liver blood flow measurements have become possible using noninvasive methods such as Doppler ultrasound, their influence on MEGX formation has been studied in more detail. Despite shortcomings in the accuracy of blood flow measurements using the Doppler technique, there is a disappointing lack of correlation between liver blood flow and MEGX formation in vivo or in microsomal preparations. There is also no correlation of blood flow with the mRNA expression of the CYP responsible for MEGX formation, CYP3A4, or its protein concentration in patients with compensated and decompensated paediatric liver cirrhosis 21 . There is, however, a significant difference between in vivo MEGX fomation, microsomal MEGX formation, mRNA expression of CYP3A4 and its protein...

Adaptive Immunity to Parasites

Adaptive immune responses to parasites can also contribute to tissue injury. Some parasites and their products induce granulomatous responses with concomitant fibrosis. Schistosoma mansoni eggs deposited in the liver stimulate CD4+ T cells, which in turn activate macrophages and induce DTH reactions. DTH reactions result in the formation of granulomas around the eggs an unusual feature of these granulomas, especially in mice, is their association with TH2 responses. (Granulomas are generally induced by TH1 responses against persistent antigens see Chapter 18.) Such TH2-induced granulomas may result from the process of alternative macrophage activation that is induced by IL-4 and IL-13 (see Chapter 10). The granulomas serve to contain the schistosome eggs, but severe fibrosis associated with this chronic cellmediated immune response leads to cirrhosis, disruption of venous blood flow in the liver, and portal hypertension. In lymphatic filariasis, lodging of the parasites in lymphatic...

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.

Kava Piper methysticum

Kava is an herb native to the South Seas, where it is valued for its calming and sedative properties. Double-blind studies in humans have shown efficacy for treating anxiety (8). Kava also appears to have analgesic, muscle-relaxing, and anticonvulsant effects, though these have not been scientifically proven in humans. The anticonvulsant potential of kava may be mediated via an enhancement of GABA within the brain, or possibly via blockade of sodium and calcium channels, similar to the actions of several standard AEDs (8). Rare instances of abnormal movements, acute hepatitis, liver failure, and rash (8) have been reported with kava. This herb is contraindicated in depressed patients because the danger of suicide may be increased (8).

Differential Diagnosis

(up to 25 of patients meet criteria for a current depressive disorder and up to 70 have elevated scores on depression rating scales), and cognitive dysfunction (up to 82 impairment on some measures) (Crone and Gabriel, 2003). Compared to patients with HIV alone, patients with comorbid HIV and hepatitis C are more likely to have disturbances in executive function and dementia (Ryan et al., 2004). The pattern of cognitive impairment associated with hepatitis C is similar to that of HIV. Patients with mild liver disease tend to have impairment in attention and concentration, and patients with more severe liver fibrosis have problems with learning, psychomotor speed, and cognitive flexibility. Patients with end-stage liver disease and cirrhosis experience superimposed delirium ( hepatic encephalopathy ). Combination pegylated interferon alpha 2a and ribavirin treatment for hepatitis C is well known to be a cause ofdysphoria, suicidal ideation, anxiety, sleep disturbance, fatigue, mania,...

Risk Based Healthcare of Survivors

Faced with these risks and challenges, how can the healthcare delivered to survivors be optimized It is important to recognize that there is a window of opportunity to modify the severity of health outcomes by prevention or early intervention. Early diagnosis and intervention or preventive care targeted at reducing risk for late effects can benefit the health and quality of life of survivors 6 . The outcomes of the following late effects can be influenced by early diagnosis and early intervention second malignant neoplasms following radiation therapy (breast, thyroid, and skin), altered bone metabolism and osteoporosis, obesity-related health problems (dyslipidemia, hypertension, diabetes mellitus, cardiovascular disease), liver failure secondary to chronic hepatitis C following blood transfusion, and endocrine dysfunction following chest mantle or cranial radiotherapy. Primary, secondary, and tertiary prevention, including tobacco avoidance cessation, physical activity, low-fat diet,...


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).


In interpreting the results of a neuropsychological evaluation, it is important to be cognizant of the multifactorial etiology of any identified impairment. Not only do alcohol and other drugs act directly on the brain but their habitual consumption may also induce organ-system injury, which in turn disrupts integrity of the brain. For example, cirrhosis, independent of alcoholism, causes hepatic encephalopathy, Thus, neuropsychological deficits commonly found in alcoholics may be, in large part, the result of advanced liver disease (Tarter, Van Thiel, & Moss, 1988). This fact is not inconsequential, because treatment of low-grade hepatic encephalopathy caused by alcoholic liver disease has been tentatively shown to improve cognitive capacities (McClain, Potter, Krombout, & Zieve, 1984). Thus, medically significant problems that potentially disrupt brain functioning should be recorded and incorporated into the treatment plan.

Cze Instrumentation

Because -lipoproteins and fibrinogen cannot be seen with the CZE method, the interpretative clues to hyperlipidemia, diabetes mellitus, neph-rosis and some coagulinopathies are not as clear. Also due to the short separation time the gamma globulin area may be somewhat narrower than on HRAGE, making it more difficult to recognize and interpret the p-y bridging normally seen in cirrhosis. In addition certain amino acids and contrast dyes that may absorb at 214 nm can interfere, resulting in poor scans (27).

Native Americans

Alcohol-related motor vehicle fatalities are highest in the Native American population, with a 68.1 rate compared to 44.2 for whites (National Highway Traffic Safety Administration, 1999). Cirrhosis is the sixth leading cause of death in Native Americans (Stinson, Grant, & Dufour, 2001).

African Americans

A 1996 report by the Group for the Advancement of Psychiatry (GAP) on alcohol abuse among African Americans found little difference in the lifetime prevalence of alcoholism between African Americans and whites. The alcoholism prevalence for African Americans is low in the young adult group and then increases, in contrast to the alcoholism prevalence for whites, which starts at moderately high levels in the young group and then decreases. Deaths from alcohol-induced causes are about 2.5 times higher in the black population than in the white population. Cirrhosis death rates for African American males are 45.3 compared to 34.7 for whites (Caeteno & Clark, 1998b). Motor vehicle fatalities are essentially equal between blacks (45.2) and whites (44.2 ) (National Highway Traffic Safety Administration, 1999).

Hispanic Americans

Hispanic American men drink more than Hispanic American women regardless of age. Mexican American men drink more and abstain less than either Puerto Rican or Cuban American men. Hispanic American men and women drink more as their income increases (Group for Advancement of Psychiatry, 1996). Surveys in 1984 and 1995 revealed that alcohol-related problems increased in Hispanic males but remained stable in women of all ethnicities, and stable in black males and white males (Caetano & Clark, 1998b). Mexican Americans have a motor vehicle alcohol-related mortality rate of 54.6 , while that of Cuban Americans is 36.6 (National Highway Traffic Safety Administration, 1999). Cirrhosis rates for Hispanic males are 61.8 per 100,000, which is higher than that found in black or white males. The notion that machismo is related to drinking in Mexican American males is dispelled by statistics showing equal machismo influences in white and non-Hispanic minorities (Caetano & Clark, 1998a).

Nervous System

Rological effects, alcoholic dementia and Wernicke-Korsakoff syndrome were discussed earlier. Hepatic encephalopathy occurs in the setting of severe liver failure as a result of either severe alcoholic hepatitis or cirrhosis. Early manifestations of encephalopathy include inappropriate behavior, agitation, depression, apathy, and sleep disturbance. Confusion, disorientation, and depressed mental status develop in the advanced stages of encephalopathy. Physical examination may demonstrate asterixis, tremor, rigidity, hyperreflexia, and fetor hepaticus. Treatment requires the elimination of the offending condition, dietary protein restriction, and removal of nitrogenous waste from the gut with osmotic laxatives and antibiotics (lactulose and neomycin, respectively) (Adams & Victor, 1989).

Liver Cancer

Although not a major cause of cancer in Western societies, primary hepatocellular carcinoma is a huge problem in a number of areas of the world, especially Southeast Asia and Africa. Worldwide, about 560,000 new cases occur annually.23 Liver cancer is extremely difficult to treat and overall, 5-year survival (all stages) is only about 7 in the United States and even lower in developing countries. The primary risk factor in parts of the world where liver cancer is prevalent is hepatitis B infection. Other risk factors include infection with hepatitis C virus, chronic liver cirrhosis, alcohol abuse, aflatoxin exposure, and parasitic infections.

Pancreatic Cancer

Pancreatic cancer is primarily a disease of developed countries. About 216,000 cases occur annually worldwide. Risk factors include smoking, obesity, physical inactivity, chronic pancreatitis, diabetes, liver cirrhosis, and high-fat diet.4 Familial genetic risk appears to account for about 10 of cases. K-ras and p53 gene alterations are the most common ones observed. As can be surmised from the poor survival rates, no effective treatment currently exists.


Becker, U., Gronbaek, M., Johansen, D., & Sorensen, T. I. (2002). Lower risk for alcohol-induced cirrhosis in wine drinkers. Hepatology, 35, 868-875. Stinson, F. S., Grant, B. F., & Dufour, M. C. (2001). The critical dimension of ethnicity in liver cirrhosis mortality statistics. Alcohol Clin Exp Res, 25, 1181-1187.


Figure 19.2 The balance of endogenous factors involved in liver regeneration in acute liver failure. HGF is hepatocyte growth factor TGF-a is transforming growth factor-a EGF is epidermal growth factor TGF- is transforming growth factor- and IFN-y is interferon-y. Figure 19.2 The balance of endogenous factors involved in liver regeneration in acute liver failure. HGF is hepatocyte growth factor TGF-a is transforming growth factor-a EGF is epidermal growth factor TGF- is transforming growth factor- and IFN-y is interferon-y.


Figure 19.3 Assay to detect inhibitory substances in acute liver failure serum based on incorporation of 3H-thymidine into HepG2 cells. Horizontal bars show median values 15 . Figure 19.3 Assay to detect inhibitory substances in acute liver failure serum based on incorporation of 3H-thymidine into HepG2 cells. Horizontal bars show median values 15 . control nonELAD-treated patients 14 . This surprising result was found to be due to the administration of heparin as anticoagulant for extracorporeal circulation, which displaces HGF from endothelial binding sites. It is unclear whether there is any biological significance in further increasing HGF in ALF. Transforming growth factor p1 (TGF- 1) is an endogenous inhibitor of DNA synthesis which may control liver size. Plasma TGF- 1, which is only slightly increased in acute liver failure, remained at similar levels in both ELAD and control patients. The data from the use of the ELAD in acute liver failure were obtained with the original...


Alcohol is thought to interact with smoking in the causation of certain cancers, particularly oral and esophageal cancers. Alcohol appears to be synergistic with tobacco in causing cancers of the mouth, pharynx, larynx, and esophagus, but not that of the lung.64,65 In liver cancer, there is good evidence that alcohol consumption sufficient to cause cirrhosis of the liver increases the incidence of liver cancers, perhaps secondary to the chronic damage to the liver caused by alcohol abuse. Pure alcohol is not by itself carcinogenic in animals and may exert its carcinogenic effect secondarily to tissue damage, as in the case of hepatic cirrhosis, or by facilitating uptake of carcinogens by exposed tissues, as may be the case for oral and esophageal cancer.51 Other potential mechanisms include (1) a carcinogenic effect of other chemicals such as N-nitrosamines in alcoholic beverages (2) a solvent action that facilitates absorption of carcinogens found in tobacco smoke and (3) a...

Hepatitis B Virus

HBV can infect pregnant women but does not cause more severe disease than seen in the general population. Chronic carriers of the virus usually have uncomplicated pregnancies unless evidence of liver failure is present. The importance of HBV infection during pregnancy is the significant risk of transmission to the infant (2,3,5). If the mother is known to be HBV infected and is acutely infected or a chronic carrier, the infant is at risk not only for infection, but also to become a chronic HBV carrier.

Hepatitis C Virus

HCV is spread primarily by blood-borne contact with infected blood. The most common risk factors identified are intravenous drug use and blood transfusion or transplantation prior to 1992. Sexual acquisition of the virus is a very inefficient form of transmission and has not been proven definitively in the absence of confounding risk factors. The prevalence of HCV infection in the United States is approx 2 , and in 1999 chronic HCV infection and subsequent liver failure were the leading indications for liver transplantation (8,9).

Wound Healing

Repair occurs when the wound involves mesenchymal connective tissue. The predominant matrix component of connective tissue is collagen and the major cell type is the fibroblast. Skin, the largest organ in the body, is composed of both ectodermally and mesodermally derived layers. The dermis is derived from the mesoderm and when the dermis is damaged it will attempt to heal by the process of repair. The outcome of repair is scar tissue. This is obvious in the skin and produces both deformity and disability. Scarring does, however, have widespread effects throughout the body resulting in an extensive range of morbidity. Connective tissues, which produce the scaffolding for specialized organ tissues, can be deformed and distorted by the process of scarring and can result in respiratory dysfunction due to lung parenchymal fibrosis, liver dysfunction due to cirrhosis, renal dysfunction due to post-glomerulonephritic scarring, adhesions in the bowel after surgery,...

Reyes Syndrome

This rare disease, predominantly of young children, usually develops acutely after a viral infection. Salicylate toxicity as a precipitating factor has been implicated in some cases. It manifests with fever, vomiting, enlarging liver, and rapidly progressing encephalopathy leading to death within days or a few weeks. High blood ammonia and low sugar levels are characteristic laboratory findings. Death occurs due to liver failure and raised intra-cranial pressure.

Oncofetal Antigens

AFP is a circulating glycoprotein normally synthesized and secreted in fetal life by the yolk sac and liver. Fetal serum concentrations can be as high as 2 to 3 mg mL, but in adult life, the protein is replaced by albumin, and only low levels are present in serum. Serum levels of AFP can be significantly elevated in patients with hepato-cellular carcinoma, germ cell tumors, and, occasionally, gastric and pancreatic cancers. An elevated serum AFP level is a useful indicator of advanced liver or germ cell tumors or of recurrence of these tumors after treatment. Furthermore, the detection of AFP in tissue sections by immunohistochemical techniques can help in the pathologic identification of tumor cells. The diagnostic value of AFP as a tumor marker is limited by the fact that elevated serum levels are also found in non-neoplastic diseases, such as cirrhosis of the liver.


The pathological role of abnormal matrix deposition with the exception of inherited metabolic defects has, until the last 15 years, been largely ignored. The study of MMPs and TIMPs in relation to disease is stimulating because it provides a focus for understanding morbidity and mortality in terms of deficient or excessive matrix deposition. Two examples of defective matrix deposition will be discussed alcoholic fibrosis, which leads to an increase in collagen deposition and to cirrhosis, and cardiac diseases including hypertensive fibrosis and unstable angina.

Tumor Staging

Since more than 70 of HCC in adults develop in cirrhotic livers, the conventional pre-treatment TNM staging system is clinically inadequate because it does not take in to consideration parameters of hepatic function. Instead, current staging systems used in adult liver cancer trials, such as the CLIP (Cancer of the Liver Italian Program) 68 , the BCLC (Barcelona Cancer of the Liver Committee) 69 , the CUPI (Chinese University Prognostic Index score) 70 and the Japanese Okemah system 71 , incorporate the extent of disease and liver function, as determined by the Child's-Pugh system 72 , to determine risk groups and for treatment planning. In contrast, since adolescents and young adults frequently develop HCC without pre-existing cirrhosis, it would seem appropriate to use a system least depenD I

Adults with HCC

Worldwide HCC represents the third largest cause of cancer-related death. Since the main risk factor for HCC is liver cirrhosis caused by alcohol consumption and or chronic infection by hepatitis B or C, primary prevention through vaccination (hepatitis B), implementation of adequate health standards, and antiviral treatment to prevent progression to cirrhosis (hepatitis C) may be the only effective ways to change this outcome. As discussed previously, a universal program of hepatitis B immunization has resulted in a decrease in hepatitis-B-virus-related HCC 7, 78 however, no therapy has been demonstrated to be efficacious once cirrhosis develops. Therefore, surveillance aimed at early detection of the tumor and implementation of effective therapy is the only option to diminish tumor-related mortality. The European Association for the Study of the Liver recommends that patients with cirrhosis who could undergo potentially curative treatment for HCC should have surveillance...

Future Perspectives

The overall survival for children and adults with HCC, with the exception of highly selected patients for whom complete tumor resection is feasible, continues to be dismal. In Western countries, where HCC in older adults is secondary to liver cirrhosis caused by alcohol consumption and or chronic infection by hepatitis B or C, primary prevention through vaccination (hepatitis B), implementation of adequate health standards and antiviral treatment to prevent progression to cirrhosis (hepatitis C) may be the only effective ways to change this outcome. In Asia, and African countries HCC is related to chronic infection with hepatitis B virus acquired at birth or at an early age. Universal hepatitis B immunization programs will continue to dramatically Liver cirrhosis reduce the incidence of HCC in these countries. Since no therapy has been demonstrated to be efficacious once cirrhosis develops, surveillance aimed at early detection of tumors and implementation of effective therapy is the...

Endocrine System

Alcohol interferes with gonadal function even in the absence of cirrhosis by inhibiting normal testicular, pituitary, and hypothalamic function. Testicular atrophy, low testosterone levels, decreased beard growth, diminished sperm count, and a loss of libido result. However, testicular atrophy does not occur in all male alcoholics but is associated with alcohol dehydrogenase polymorphism in the testes, as reflected by the genetic variant of an increased frequency of the ADH21 allele (Yanauchi et al., 2001).


The disease presents soon after birth with prolonged jaundice, vomiting, diarrhea, hepatomegaly, and anemia. Untreated patients develop ocular, neurologic, visceral, and metabolic disorders hepatomegaly progressing to nodular cirrhosis kidney dysfunction hypoglycemic episodes and lenticular cataract. Mental retardation, seizures, extrapyramidal and cerebellar symptoms, and The cerebral pathology is not specific some changes relate to the toxic effect of galactose whereas others are complications of multiple metabolic derangements, including liver cirrhosis. Grossly, the brain is small, the cerebral and cerebellar cortex is thin, and the hemispheric white matter is diminished and firm. The histol


An elevated serum bilirubin is the single most important indicator of outcome in patients with viral- or drug-induced ALF 18 . Its value is evident irrespective of aetiological group, although death may occur before bilirubin has increased significantly in those patients with hyperacute liver failure, e.g. paracetamol overdose. Table 18.1. Positive (PPV) and negative (NPV) predictive values for some reported prognostic markers in acute liver failure Table 18.1. Positive (PPV) and negative (NPV) predictive values for some reported prognostic markers in acute liver failure

Static tests

Chronic hepatitis, cirrhosis, follow course of the only direct marker of sinusoidal endothelial cell function and is a marker of liver perfusion. Serial determinations are useful in monitoring patients at risk of progressive fibrosis 2, 3 . Serum hyaluronic acid has been proposed as a noninvasive index of the severity of fibrosis in chronic viral hepatitis and as a measure of response to antiviral therapy. In one study 3 , hyaluronic acid showed a sensitivity and specificity for stage four and five fibrosis of 85 - exceeding those of alanine aminotransferase and glutathione S-transferase. In primary biliary cirrhosis and cirrhotic alcoholic liver disease, serum hyaluronic acid discriminates between early and advanced liver disease. In alcoholic liver disease, serum hyalu-ronic acid can be applied for the assessment of haemodynamic changes. In liver transplantation, early graft function can be predicted by this test 2 . Furthermore, hyaluronic acid has been proposed as a marker of...


In order to preserve normal intracranial compliance, treatment of patients with ALF has traditionally been based on the monitoring of intracranial pressure (ICP) for the calculation of cerebral perfusion pressure (mean arterial pressure minus intracranial pressure) 25 . Cerebral monitoring should focus on cerebral oxygenation in addition to intracranial pressure. Changes in CBF (assuming a constant metabolism) can be monitored by internal jugular vein oxygen saturation (SvjO2). A SvjO2 below 55 is associated with cerebral symptoms both in healthy individuals and patients with liver failure. A prolonged (measured in minutes) decrease in SvjO2 below 55 may result in cerebral hypoxia and oedema. Accordingly, mean arterial pressure should be increased instantaneously by volume expansion and or noradrenalin. In some patients, CBF increases during the course of ALF possibly due to gradual cerebral arteriolar vasodilatation, and SvjO2 may increase to above 75 8 .

NP in heart failure

ANP and BNP are activated to their greatest extent in heart failure however, they are also markedly increased in all oedematous disorders with a volume overload which leads to an increase in atrial or ventricular tension, or the central blood volume. Examples include systemic and pulmonary hypertension, renal failure and increases in NP found in patients with ascitic liver cirrhosis and some endocrine disorders 7 .

Dynamic tests

An important area for the clinical application of MEGX is the assessment of pre-transplant prognosis in patients with terminal cirrhosis. Shiffman et al. demon- Transplant candidates adults (cirrhosis) paediatric cirrhosis strated that MEGX declines in a stepwise fashion with advancing histology in patients with chronic liver disease 10 . Due to a wide interindividual variability, the MEGX test cannot be used to diagnose the initial stages of chronic hepatitis. MEGX test results, however, do relate to the histology activity index in patients with advanced liver disease. In patients with cirrhosis, MEGX decreases with worsening Child-Pugh score. Most patients with MEGX test results below 20 xg l had cirrhosis of Child-Pugh class C confirmed on histological evaluation. There is general agreement that MEGX concentrations of less than 20 xg l at 15 min reflect poor liver function. The problems of patient selection have been discussed in detail 9 . Patients awaiting transplantation may be...

Cystic fibrosis

Approximately 4 of children and up to 25 of adults with cystic fibrosis (CF) develop features of severe chronic liver disease including cirrhosis 39, 40 and this carries a poor prognosis. There is no association with any of the major CF gene mutations, DF508, G551D or R553X 41, 42 but familial clustering of liver disease and inappropriate immune responses may be responsible 43 . HLA A, B, DR and DQB typing performed at King's College Hospital in 247 CF children and adults, 82 of whom had chronic liver disease (Table 16.2), showed a greater prevalence of DQ6 in those with liver disease (66 versus 33 without). The study concluded that B7-DR15-DQ6 was associated with an increased risk of liver disease in CF patients, particularly males 13 .