Natural Liver Cirrhosis Treatment Ebook

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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Author: Grace Barrera
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Specific Problems In Patients With Cirrhosis

Although it is not inevitable that portal hypertension accompanies cirrhosis, some distortion in the normal portal flow is almost inevitable, and the secondary effects of shunting of portal blood around the liver have a major role in the subsequent cardiovascular, renal, electrolyte imbalance and fluid retention, and encephalopathic complications of portal hypertension. Nonetheless, the principal danger from portal hypertension is from gastrointestinal bleeding from the thin-walled varices that serve as conduits for portal blood around the scarred liver, as well as from an increased incidence of gastric and perhaps duodenal ulcer. Gastritis-related bleeding is also common, and some investigators believe that this is a complication of portal hypertension rather than being acid-peptic. The risk of bleeding varices after another, unrelated operative procedure is increased in patients with tight ascites. Therefore, these patients should be diuresed as much as possible to the point at...

Degree of Liver Failure

The degree of liver failure, which may be assessed by different parameters, such as Child-Pugh score, prothrombin activity, and serum bilirubin or albumin concentrations, has been related to the short-term prognosis of the SBP. The association of liver failure with mortality in SBP is not surprising, since SBP occurs usually in patients with advanced cirrhosis, and the prognostic value of these measurements of liver failure is well documented (7,8,25). In early series of SBP, the degree of liver failure was associated not only with hospital survival, but also with the resolution of SBP. In 1978, Weinstein et al. (24) found that hepatic encephalopathy, total serum bilirubin levels greater than 8 mg dL, and albumin levels lower than 2.5 g dL, respectively, were associated with poor prognosis in the group of 28 episodes of SBP in 25 cirrhotic patients studied. These findings suggest that the worse the liver function, the worse the prognosis of SBP. A few years later, Hoefs et al. (8), in...

Therapeutical Use of siRNA to Prevent and Treat Acute Liver Failure in Mice

As the first demonstrations of a therapeutic application of siRNA in vivo were done in mouse models of acute liver failure (ALF), the next paragraphs will give a brief introduction into this disease, followed by a discussion of the therapeutic use of siRNA to suppress apoptosis in this model. ALF is defined as a dramatic clinical syndrome in which a previously normal liver fails within days or weeks. Three subgroups of ALF can be distinguished, hyperacute, acute, and subacute liver failure. Despite the frequent occurrence of cerebral edema and renal failure in patients with hyperacute liver failure, prognosis without transplantation is relatively good. Survival rates in patients with acute and subacute liver failure, however, are at best 15 (20,21). The etiology of ALF shows marked worldwide variation in underdeveloped countries viral causes predominate, whereas drug-induced hepatotoxicity and seronegative hepatitis predominate in most countries of the Western world (22). To this day,...

Different Types Of Cirrhosis With

This pattern of4 'variations on a theme'' has continued, virtually every possible variable has been documented, and thus the syndrome has been broadened considerably. All of the first 29 patients, for example, had micronodular alcoholic cirrhosis. It was not difficult to predict that other types of cirrhosis would also be associated with SBP. These variations, some of which were observed in our series, but most of which have been reported by other investigators elsewhere, will be documented here. Initially the patients all seemed to have alcoholic cirrhosis, which was known then as Laennec's cirrhosis (1,2). That pattern changed quickly. Epstein reported SBP in posthepatitic cirrhosis, exclusively caused by pneumococci (7). The association of pneumococcal SBP that occurred only in patients with posthepatitic cirrhosis infection was short lived. Indeed, in most large series the pneumococcus is the second or third most frequent bacterial agent responsible (2) after E. coli and...

Viral Causes of Liver Failure

HEV is a water-borne, epidemic form of NANBH.55 HEV infection is enterally transmitted and self-limited, with no progression to chronicity. Epidemics have occurred in India, China, Africa and Mexico.56-60 Acute HEV infection has been documented in the United States among travelers returning from endemic areas.61,62 Acute HEV infection can be detected with a fluorescent antibody-blocking assay, anti-HEV immunoassays and PCR for HEV RNA.63-65 Mortality from acute liver failure due to HEV is greater in females than males and is highest among infected pregnant women.57 The increased HEV-associated mortality in pregnant women is thought to be related to host factors such as malnutrition or hormonal imbalance.66 Recent reports from India indicate HEV as the cause of FHF in more than 75 of patients.67 A report from Britain revealed that of 30 patients with an indeterminate cause of FHF, 5 had a positive PCR for HEV.39 In contrast, an American study showed no evidence for HEV using PCR and...

Liver Directed Cell Therapy for Acute and Chronic Liver Failure

Results of hepatocytes transplantation in animal models of acute liver failure and chronic liver disease have been mixed. These animal models often pose difficulties because of variable susceptibilities of individual animals to disease and the possibility of improved outcomes unrelated to hepatocyte regeneration (89). Nonetheless, more recent studies in better defined genetic animals models have begun to demonstrate that cell therapy could have therapeutic potential in acute liver failure (81,82). Clinical studies of hepatocyte transplantation in acute liver failure are limited (86,90,91). It is difficult to conduct controlled cell transplantation studies in acute liver failure because of emergency settings, the need to perform orthotopic liver transplantation whenever a donor liver becomes available, and a lack of unequivocal markers to assess metabolic and synthetic contributions of transplanted cells. End-stage liver disease with complications, such as hepatic encephalopathy and...


Cirrhosis is a chronic disorder characterized by liver fibrosis and nodule formation, which produce portal hypertension and hepatocellular failure. Cirrhosis is the end product of progressive liver injury resulting from diverse causes including toxins, drugs, viruses, and parasites. Clinical manifestations of cirrhosis vary with the underlying disease. In the West, cirrhosis is a cause of disability and death among middle-aged alcoholic males. Elsewhere, cirrhosis is predominantly an intermediate lesion in the evolution from chronic hepatitis B infection to primary hepatocellular carcinoma.

Massive Malignant Infiltration of the Liver

Massive infiltration of the liver with either metastatic adenocarcinoma1 or lymphoma can result in FHF or SFHF.132-135 Mechanisms of liver failure include ischemia from sinusoidal invasion of the tumor cells and cytokine release.133,136 In some cases of lymphoma, early chemotherapy can result in increased patient survival. Metastatic disease to the liver, lymphoma and primary hepatic tumors such as angiosarcoma and hemangioendothelioma are absolute contraindications for liver transplantation.137,138

General Considerations

Regardless of the underlying differences between acute and chronic encephalopathy, it is clear that alterations of blood flow and edema formation play a prominent role in the acute setting. Cerebral edema and intracranial hypertension occur in up to 80 of patients with acute liver failure.9 The two most immediate causes of death in this group include herniation from cerebral edema and sepsis. Cerebral edema is also of major concern perioperatively in patients who are candidates for orthotopic liver transplantation, and such patients may have substantial residual neurologic deficits after recovery.10

Cytokines and Inflammatory Factors

The release of toxic substances by necrotic liver cells is axiomatic and is strongly suspected to play some role in edema formation. This is supported by the clinical observation that patients with acute liver failure may respond to total hepatectomy with an immediate and significant lowering of ICP with improved overall hemodynamics.12 Candidate substances include the inflammatory cytokines, such as IL-1, IL-6 or TNF-a.2 The latter has, in fact, been shown to alter the permeability of the blood-brain barrier.13 It has also been suggested that various elements of the arachidonic acid cascade may also be important contributing factors. Unfortunately, in experimental anhepatic models, animals may still proceed to develop cerebral edema, suggesting a more complex etiology for edema formation.

Benzodiazepines GABA and Neurosteroids

Endogenous or exogenously ingested benzodiazepines may also play a role in the etiology of acute and chronic hepatic encephalopathy. In the past several years, dozens of basic science and clinical reports have appeared implicating these substances which enhance the inhibitory GABA-ergic tone. The gut flora has been postulated to contribute benzodiazepine ligand activity, which fits well with the general theory regarding the functional failure of hepatic clearance.37 Indeed, animal models of acute liver failure have demonstrated increased benzodiazepine receptor agonist activity.38 Clinical studies in patients with fulminant liver failure have documented an increase in benzodiazepine receptor ligands with enhanced GABA-ergic tone in all stages of encephalopathy.29,39 Increased densities of brain peripheral-type benzodiazepine receptors, and elevated levels of neurosteroids, have also been reported in animal models of acute liver failure.40,41 It is suggested that ammonia-induced...

Other Diagnostic Measures

As discussed earlier, there have been conflicting reports regarding the significance of cerebral blood flow (CBF) alterations in acute liver failure studies suggest both increased and decreased flows.29 Jugular venous oxygen saturation was suggested as an important tool for the diagnosis of cerebral hyperemia (when values are elevated above 75 ). Cerebral hyperperfusion has been documented immediately preceding brain death in patients with FHF. Electroencephalographs (EEG) monitoring has been advocated by some in patients with acute liver failure to avoid unrecognized seizure activity.29 However, the EEG per se shows no characteristic patterns diagnostic of hepatic encephalopathy, but rather only the diffuse changes of metabolic dysfunction. The EEG may be utilized as a confirmatory test when symptoms have progressed and brain death is suspected. Other confirmatory tests would include a nuclear medicine cerebral perfusion scan or angiography showing no cerebral perfusion.

Hepatocyte Transplantation

Transplantation of isolated hepatocytes has been shown to provide metabolic support and improve survival in various experimental animal models of acute liver failure (90 hepatectomy, D-galactosamine, dimethylonitrosamine, carbon tetrachloride, ischemia).25-29 Hepatocyte transplantation has also been shown to improve chronic encephalopathy induced by an end to side portocaval shunt in rats.30 Recently, we have demonstrated in an experimental model of FHF induced by a combination of liver resection and necrosis, that animal survival can be improved by intrasplenic transplantation of a small number of hepatocytes (2 of the native liver mass).31

Frederick D Watanabe Elaine Kahaku Achilles A Demetriou

Despite advances in critical care management, prognosis in fulminant liver failure (FHF) remains poor, with mortality between 70 and 90 .1 Introduction of orthotopic liver transplantation has improved outcome and increased patient survival. The paradigm of medical management of FHF focuses on patient stabilization and expectant management until either the patient's liver recovers or liver transplantation can be carried out. In this chapter, guidelines for the medical management of FHF patients will be discussed based primarily upon our own experience at the Liver Support Unit at Cedars-Sinai Medical Center in Los Angeles.

Patient Environment and Monitoring

Successful management of FHF requires near-fanatical diligence, accurate monitoring and rapid response to critical clinical situations. Rapid changes in a patient's status can occur without warning, necessitating early aggressive intervention. This degree of intensive monitoring and capacity to provide early, decisive therapeutic intervention, requires placement of patients in a specialized intensive care unit setting. In general, the clinical syndrome progresses into multisystem involvement requiring a coordinated multidisciplinary team approach to patient management.2,3 The complexity of the disease necessitates the involvement of adult and pediatric critical care nurses, hepatologists, transplant surgeons, transplant coordinators, intensivists, anesthesiologists, pulmonologists, respiratory therapists, nephrologists, cardiologists, neurologists, neurosurgeons, rehabilitation medicine specialists, infectious disease specialists, pathologists, radiologists and other experts as...

Definitions and Patient Selection

As discussed in earlier sections of the monograph, the definition of acute liver failure and its classification into fulminant versus subfulminant depends on the temporal relation between the initial onset of illness and manifestation of jaundice, encephalopathy and coagulopathy. One of the main problems is the difficulty to precisely determine the time of onset of the disease process and thus define the interval between disease onset and establishment of liver failure. The classic definition of Trey and Davidson is based on encephalopathy developing within 8 weeks from the onset of the illness.12 In a more recent classification, Bernuau1 defined FHF as acute hepatic failure (AHF) complicated by encephalopathy occurring less than 2 weeks after the onset of jaundice.3 Recognizing that the prognosis and clinical findings were different in those patients who developed encephalopathy later than 2 weeks, the term subfulminant hepatic failure (SFHF) was introduced to describe AHF...

Historical Perspective

For many years it has been assumed that the majority of toxins which cause coma in hepatic failure are small dialyzable molecules. As a result, most liver support systems and therapeutic regimens relied primarily on blood detoxification. However, the pathogenesis of acute liver failure is complex and many investigators, including ourselves, have argued that isolated viable hepatocytes should be used to construct a liver support system to provide not only detoxification, but also missing liver synthetic functions. This suggests that a clear distinction should be made between systems designed to strictly purify patient blood from toxins and devices incorporating liver tissue preparations to carry out detoxification and provide synthetic function. The former are based on the artificial kidney principle a classic example is hemodialysis, which was first applied by Kiley et al, and hemoperfusion, which was first tried by Schechter et al using cationic resins and several years later by...

In Vivo Animal Experiments

Ischemic liver failure in cats ischemic liver failure in dogs ischemic liver failure in galactosamine-induced liver failure various systems described here. Most of the experimental animal models used in these studies did not reproduce the full range of metabolic and physiologic derangements seen clinically in severe acute liver failure. In addition, there was significant variation in the physiologic, biochemical and survival effects noted in the untreated groups. The baseline variation in outcome, seen in control animals, makes evaluation of the effects of the various interventions difficult. The major experimental animal models studied include those utilizing hepatotoxins, i.e., acetaminophen, CCl4, D-galactosamine, and those with acute transient or permanent liver ischemia, sometimes in combination with partial liver resection. In both instances, however, it is difficult to standardize the degree of liver injury. Complete liver devascularization, although it appears to be more...

Past Accomplishments Clinical Studies

As mentioned, the first clinical report of use of a liver support system utilizing isolated hepatocytes is that of Matsumura, who converted a dialyzer to an artificial liver by adding a cryopreserved rabbit liver cell suspension to the dialysis chamber.11 In addition, he replaced the usual cuprophane membrane with a cellulose membrane permeable to middle range molecules, but not proteins. A 45-year-old man in hepatic failure due to unresectable cholangiocarcinoma underwent hemodialysis for 5 hours. Total serum bilirubin was reduced from 25.0 mg dl to 16.8 mg dl after the first treatment. Three days later, after a second 4 1 2 hour treatment, the total bilirubin level decreased from 18.0 mg dl to 8.0 mg dl. There was no evidence that the device affected the course of liver failure and outcome in this patient and there was no follow-up report on use of this system in a larger number of patients. A group of 59 patients with liver failure was treated in Latvia with daily six hour...

Achilles A Demetriou Frederick D Watanabe

As we have repeatedly emphasized throughout this monograph, severe acute liver failure (SALF) is associated with very high morbidity and mortality and represents one of the most challenging problems in clinical medicine. Historically, when faced with complex clinical problems, the medical community responded by developing specialized, multidisciplinary, focused programs to manage them. This has resulted in the development of Burn Units for managing major burns, Trauma Centers for treating severely injured patients and other such specialized Units. The rationale behind this strategy has been that managing these challenging problems requires a team approach crossing multiple discipline boundaries, commitment of substantial institutional resources, availability of a wide patient referral base and recognition that it will result in improved clinical outcomes.

Liver Support Unit Logistics

The dedicated site has to be the best Critical care Unit (Surgical, Medical, etc.) with a dedicated cadre of trained Nursing Staff. Eventually, with the success of the program, such a Unit will become exclusively dedicated to the care of patients with liver failure.

Helene Lilja Nikolaos Arkadopoulos Susumu Eguchi Raoul J Rosenthal David A Moscioni Achilles A Demetriou Jacek Rozga

Use of experimental animal models which are neither standardized nor validated and thus are difficult to reproduce (i.e., galactosamine-induced liver failure, temporary liver ischemia). result in early engraftment and allow transplantation of an adequate number of hepatocytes, and transplanted hepatocytes should express differentiated functions in vivo. We have developed methods of hepatocyte transplantation addressing and solving some of the problems outlined above and we propose a series of studies to attempt to resolve the remaining issues. Most of the work outlined here has dealt with the correction of specific genetic defects. This is an essential step toward development of methods of treating acute liver failure in animals. It provides a better experimental animal model for assessing the function of transplanted hepatocytes and quantitating their effects, and allows better assessment of engraft- ment and long term survival and differentiated function of these cells. Once these...

Hepatocyte Transplantation in Rats with Fulminant Hepatic Failure

We have developed a model of fulminant hepatic failure (FHF) in rats where resection of the anterior liver lobes (68 liver) is combined with ligation of the right lobe (24 liver) pedicle.29 In this setting, rat survival depends upon the ability of the residual omental lobes (8 liver) to function and regenerate. It was found that with hydration as the only supportive measure, more than 90 of these FHF rats die within 48 hours postoperatively from severe liver failure, with no signs of liver regeneration.12 Lack of a hyperplastic response in the remnant livers of these animals, was associated with delayed expression of tissue c-Met mRNA expression and marked elevation of plasma TGF- 1 levels. We carried out an experiment to determine whether a limited number of isolated hepatocytes transplanted ectopically (spleen) would prolong animal survival and improve and trigger regeneration in the native liver.

Enterocyte Transplantation

The specific activity of the bilirubin UDPGT in rat small intestine has been shown to be only 10 of the activity of the enzyme in the liver. Based on that observation, it would be expected that the enzyme activity in isolated enterocytes would be less than that seen in isolated hepatocytes. This may explain in part why in a significant number of animals we saw no appreciable increase in bile bilirubin conjugates following enterocyte transplantation. In addition, no other major liver-specific functions have been described in isolated enterocytes. It is thus unlikely that these cells will have any direct utility in the treatment of acute liver failure.

Steven D Colquhoun Caroline A Connelly

Reversible derangement of thought and behavior which accompany liver disease.1 Although there may be significant overlap in symptoms and etiology, both liver disease and hepatic encephalopathy can exist in either acute or chronic forms. Although chronic hepatic encephalopathy is more prevalent, the neurologic changes accompanying acute liver failure are more dramatic and may develop rapidly. Clinically, the management of these two entities can be quite distinct. Fulminant hepatic failure (FHF) is a true medical emergency and the onset of encephalopathy is both a defining symptom and a major prognostic indi-cator.2 Without appropriate and timely intervention, the underlying neuropathology of this condition can lead directly to the patient's death. In the past decade, survival of FHF patients improved significantly due, in part, to enhanced ability to manage the cerebral manifestations of the disease.2 This section will focus on the prevailing theories regarding the pathophysiology of...

Hepatic Encephalopathy and Cerebral Edema

Neuroinhibitory processes may also contribute to the development of hepatic encephalopathy. The levels of the inhibitory neurotransmitter g-aminobutyric acid (GABA), and its postsynaptic GABA receptor, increased in a rabbit model of liver failure 19 however, results were inconclusive in patients.20-22 Autopsy studies have demonstrated the presence of diazepam and desmethyldiazepam in brain tissue, indicating the existence of natural benzodiazepines.23 Limited trials using flumazenil, a pure benzodiazepine antagonist, suggest that hepatic encephalopathy can be transiently reversed or ameliorated.24,25 This may allow one to test the neurologic integrity of the comatose patient. However, lack of consistent response and risk of seizure induction as a consequence of flumazenil preclude the routine use of this medication. The pathogenesis of encephalopathy may not be purely a benzodiaz-epine response, since the postsynaptic GABA receptor is closely linked to the benzodiazepine and...

OGrady Classification

The above definitions have attempted to clarify the relationship between prognosis and time of onset of encephalopathy. However, after a detailed review of their FHF patients, O'Grady et al proposed a new terminology (Table 2.1).8 Hyperacute liver failure was defined as the development of encephalopathy within 7 days of the appearance of jaundice. These patients had a fair prognosis with a survival rate of 36 , despite a 69 incidence of cerebral edema. Etiology in this group included all cases of paracetamol overdose and many hepatitis A and B virus infections. Patients with acute liver failure developed encephalopathy 8-28 days after the onset of liver dysfunction. Even though the incidence of cerebral edema (56 ) was similar to that seen in hyperacute liver failure, the survival rate was only 7 . Indeterminate etiology accounted for 46 of these cases. Subacute hepatic failure occurred when encephalopathy developed 5-12 weeks after the onset of jaundice. Although the incidence of...

Brief Historical Perspective

And Addison (1836) were the first to describe fatty liver changes, and Kiernan (1833), Carswell and Hallmann differentiated cirrhosis of the liver from hepatic tumors.12-16 Alcoholic cirrhosis was first described by English clinicians in the eighteenth century after the gin plague but it was Matthew Baillie (1793) who, in his book Morbid Anatomy, described the association between cirrhosis (common tubercle of the liver) with consumption of alcohol.17,18 The term cirrhosis is derived from the Greek word kirrhos, meaning orange-colored. La nnec, (1819) in his book De L'auscultation M diate, proposed the term cirrhosis to describe chronic diffuse fibrosis of the liver in alcoholics after noticing the yellowish color of granular deposits in the liver.19 Bamberger (1864), and earlier Freichs (1861), differentiated the morphologic course of cirrhosis into two stages an inflammatory stage, followed by the development of shrinking, nodular scar tissue.20 Cirrhosis, as the clinical-pathologic...

Critical Clinical Care Issues

The LSU represents a tertiary referral site for patients with severe forms of liver failure. Compulsive attention to detail is the hallmark of care in this setting it has to start before a patient arrives at the Unit. Most patients are transferred to the LSU from other facilities. It is important to establish whether patients require airway protection, sedation and treatment of cerebral edema during transport. A line of communication needs to be established with referring physicians to ensure that all diagnostic material, including copies of films as well as histologic slides and records of diagnostic and therapeutic interventions are forwarded to the LSU. This avoids delays in diagnosis and duplication of tests. In addition, it allows more accurate assessment of disease progression. The key clinical issue is a determination of whether a patient suffers from acute exacerbation of an underlying chronic liver disease, a subfulminant form of liver failure or fulminant hepatic failure...

Walid S Arnaout David Reybould

With the introduction of orthotopic liver transplantation (OLT) as a treatment of choice for irreversible severe acute liver failure, overall patient survival has improved from less than 20 to greater than 50 .1-9 A recent report described actuarial one year survival of 92 for FHF and 100 for subfulminant hepatic failure (SFHF).10 As the experience with OLT for FHF increased, it became apparent that appropriate, and optimal, patient selection is essential for a successful outcome. Patients with FHF should be considered for OLT prior to development of irreversible brain injury or multisystem organ failure and sepsis. Patient selection should be based on a clear understanding of the natural history of the disease as well as the underlying etiology and chances of spontaneous recovery without liver transplantation. One of the most difficult aspects in the management of these patients is lack of reliable prognostic indicators or criteria predicting outcome. This means that a small number...

Late Onset Hepatic Failure LOHF

The above definitions did not take into account patients with prolonged illness prior to the onset of encephalopathy. Various terms have been used to describe this disease entity, including subacute or subchronic atrophy of the liver, subacute hepatitis, subacute (fatal) hepatitis and subacute hepatic necrosis. More recently, the term LOHF has been introduced by Gimson to describe patients who develop encephalopathy 2-6 months after the onset of liver dysfunction (Table 2.1).7 Generally, in contrast to patients with FHF, patients with LOHF have an older median age (45 years vs. 30 years), increased incidence of NANBH (compared to hepatitis A or B), increased severe cholestasis and ascites and decreased incidence of cerebral edema. Elevated immunoglobulin G levels and anti-smooth muscle and anti-nuclear antibodies suggest a possible overlap between LOHF and chronic active hepatitis. LOHF mortality is high (81 ) and survivors often develop chronic liver disease and post-necrotic...

Drug Induced Hepatotoxicity

Patients with nonacetaminophen drug-induced FHF have a poorer prognosis.68 Severe liver failure has been reported in patients taking isoniazid.85 Increased risk of toxicity occurs in those who chronically ingest alcohol.86 Patients who ingest isoniazid with the enzyme inducer rifampin, have an increased risk of developing FHF. The interval between drug administration and onset of liver disease is shorter with rifampin.87,88 Psychotropic drugs such as the monoamine oxidase inhibitors and tricyclic antidepressants have been reported to cause FHF, particularly when used in conjunction with hepatic enzyme inducers.89,90 Nonsteroidal anti-inflammatory drugs (NSAIDs) can be hepatotoxic and several cases of FHF have been reported in patients using piroxicam, pirprofen, ibuprofen and indometha-cin.91-94 The mechanism of hepatocellular injury induced by these drugs is thought to be idiosyncratic rather than intrinsic toxicity.95 Halothane-induced FHF occurs within 2 weeks of general anesthesia...

Transplant Evaluation

Patients with FHF are admitted to a surgical intensive care unit for management, as discussed in a previous section of the monograph. In addition to aggressive ICU care, transplant surgeons and hepatologists have to assess the patient's overall condition, attempt to determine the underlying etiology of the disease, predict the chances of spontaneous recovery and complete an emergency evaluation for liver transplantation. At our center, the King's College criteria are used as a guideline to predict outcome without liver transplantation. In addition, we follow the general trend in the severity of encephalopathy and elevation of ICP, the degree of coagulopathy, metabolic acidosis and renal failure. Once the initial assessment is made, an emergency evaluation for liver transplantation is completed, usually within 12-24 hours. This evaluation is similar to evaluation of patients with chronic liver disease, with a few exceptions. Patients with FHF usually are not known to have underlying...

Transplantation of Fetal Rat Hepatocytes

In contrast to adult hepatocytes, fetal hepatocytes (FH) are thought to be less immuno-genic and relatively more resistant to cryopreservation and ischemic injuries. These qualities could enhance transplanted cell engraftment. Nonetheless, only a few attempts have been made to transplant fetal liver tissue cells in rats with liver failure and heritable disorders of liver metabolism.30-32 Although some studies provided evidence of transplanted cell function, several issues regarding transplantation of fetal hepatocytes have not been addressed. For example, there appears to be confusion as to whether cell isolates enriched with committed hepatocyte progenitors can be obtained without resorting to use of complex, low yield methods such as immunological panning and fluorescence-activated cell sorting. In addition, intraportal injection of fetal hepatocytes has not been critically examined, even though the liver may provide a potentially immunologically privileged site and a unique...

Cerebral Blood Flow

Primary alterations in cerebral blood flow (CBF) have been postulated to play a role in the genesis of cerebral edema and elevation of intracranial pressure (ICP). The determinants of ICP are described by the Monroe-Kellie doctrine Within the fixed space of the cranium, an increase in any of the three compartments of brain, cerebrospinal fluid (CSF), or blood will cause an increase in pressure. Under normal conditions, CBF is under autoregulatory control meaning that blood flow remains relatively constant over a wide range of mean arterial pressure (MAP). Whether CBF changes are primary or secondary to cerebral edema is not clear. Cerebral blood flow studies in both animals and humans have provided conflicting information.14 In experimental studies of acute liver failure in rats, it has been shown that a linear decrease in cerebral blood flow precedes a rise in ICP.11 This has been presumed to occur via auto-regulatory changes responding to diminished metabolic activity.11 It has also...


Glutamine is an important organic osmolyte appearing to strongly participate in the generation of cerebral edema. In the neuroglia, glutamine is formed when ammonia binds to glutamate in a reaction catalyzed by glutamine synthetase. In acute liver failure, the presence of excessive ammonia drives this reaction toward accumulation of glutamine.5 In the absence of compensatory changes, fluid shifts into glial cells and contributes to tissue edema. Indeed, cerebral edema and elevated ICP occur in other conditions of hyperammonemia such as Reye's syndrome and ornithine decarboxylase deficiency. In animal models, ammonia infusion alone can result in elevated ICP, and the inhibition of glutamine synthetase can provide protection from ammonia in both in vivo and in vitro models. Glutamine levels are increased in animal models of acute liver failure, in humans examined by MRI spectroscopy and in autopsy studies.18,19 Interestingly, glutamine is also elevated in the brains of patients with...


In addition to being a critical substrate necessary for the synthesis of glutamine, glutamate is also an important excitatory neurotransmitter in the central nervous system.22 In acute liver failure, total brain glutamate content is reduced in both patients and animal models.7,23 At the same time, the glutamate required for excitatory synaptic transmission, found in the extracellular spaces of the brain, is actually increased.24-26 Excess glutamate in the extracellular space apparently results from impaired transport of glutamate from the extracellular to intracellular space and correlates well with blood ammonia concentrations.24 Consistent with this theory, the GLAST and GLT-1 transporter proteins responsible for moving glutamate across the membrane into the cells, and the mRNA encoding for these proteins, are both decreased in comatose rats with acute liver failure.27 Elevation of ammonia in the brain (1-3 mM) appears to signal the downregulation of these glutamate transporter...

Nitric Oxide

Excess production of nitric oxide (NO) and oxidants derived from NO, such as peroxynitrite, may be involved in the pathogenesis of hepatic encephalopathy (Fig. 3.2). Nitric oxide and its metabolites may play a role in many of the systemic manifestations of acute liver failure, including those which are neurologic.29 The metabolic products of NO have been shown to be elevated in the plasma of patients with acute liver failure.29 Nitric oxide (NO) affects large regions by rapidly diffusing from one neuron to another to act directly on intracellular components. Because NO is permeable to membranes, it cannot be stored or concentrated by cells. Rather, NO activity is regulated through its synthesis by the enzyme nitric oxide synthase (NOS). NOS expression correlates locally with NO activity. Endothelial constitutive NOS (ecNOS) and nitrotyrosine, a metabolic endproduct indicative of excess nitric oxide production, are both regionally increased in the brains of portocaval-shunted rats...


Brain edema in acute liver failure is due in large part to swelling of the star-shaped neuroglial astrocytes surrounding neurons and supporting their function.1,32 Astrocytes are critically important for the maintenance of the extracellular microenvironment necessary to support the function of neurons. Initially described simply as neural glue, the role of glia has expanded as it has become clear that these cells participate in the uptake and release of neurotransmitters, ions and neuromodulators which profoundly impact the efficacy of signal transmission in the brain. Astrocytes, rather than neurons, appear to be the major site of morphologic change in hepatic encephalopathy.

NaK Pump

In animal models of acute liver failure, alterations in the neuronal active transport of sodium and potassium have also been observed. Circulating toxins or conditions of ischemia may inhibit Na+K+ ATPase. The subsequent accumulation of intracellular sodium could contribute to edema formation, giving rise to a cycle of ischemia and edema that may accelerate pathologic conditions.36 A number of animal models and clinical observations support the idea that an element of ischemia may be associated with abnormal sodium ion transport. Once again, whether such observations represent primary or secondary pathologic changes remains to be determined.

Seizure Activity

It has been observed that some patients with acute liver failure may develop seizure activity which may markedly affect both cerebral blood flow and brain oxygen utilization.1,29 Such activity may go unrecognized in the setting of mechanical ventilation, sedation and pharmacologic paralysis. It has been suggested that unrecognized seizure activity could contribute to the formation of cerebral edema.50 Although it is certainly important to recognize and treat seizure activity, as a mechanism for edema formation this has been met with skepticism. Most neurologists can cite examples of patients with unrecognized and untreated status epilepticus who did not develop cerebral edema.


Acute hepatic encephalopathy is a disorder representing the nexus of the two most complex organs of the body, and is clearly an integral aspect of acute liver failure. Its presence defines FHF and its progression reflects its prognosis. For the scientist, the pathophysiology of this syndrome is a fascinating and active area of research, bridging numerous independent disciplines in new and creative ways. For the clinician, acute hepatic encephalopathy represents a challenging aspect of the FHF syndrome, both from a diagnostic as well as a therapeutic perspective.

Total Hepatectomy

Patients' status after total hepatectomy.20,21 However, these reports do not include any information about ICP evolution. The use of total hepatectomy in FHF is controversial and needs to be studied in the experimental laboratory. In an anhepatic pig model developed in our laboratory, animals became comatose without a concomitant increase in ICP, whereas animals with ischemic liver failure developed coma and ICP elevation this suggests that the necrotic liver may be responsible for the elevated ICP in FHF. In our retrospective study of 14 patients with FHF who were transplanted and had subdural ICP monitors, the mean ICP was lower during the anhepatic phase of the OLT than during the preclamp, reperfusion and postoperative phases (Fig. 4.1). As indicated above, in our institution, total hepatectomy was performed in two FHF patients with refractory ICP elevation. In the first case, the anhepatic phase lasted 14 hours and during this time the patient was kept in moderate hypothermia and...

The Challenge

In the setting of severe, irreversible liver necrosis resulting in acute liver failure, it is easy to understand that patients will not recover until the diseased liver is removed and replaced with a healthy organ. Thus, in this group of patients, the role of extracorporeal liver support and other therapeutic modalities is to buy time until a new liver becomes available. There will also be patients who suffer from severe, but potentially reversible, liver injury whose livers can recover and regenerate. In these patients, liver support therapy can potentially serve as the definitive treatment. The challenge in the management of severe acute liver failure is to develop a therapeutic regimen for a disease in which we are faced with several major limitations 5. Small numbers of patients with severe acute liver failure are seen at a single institution, making standardized data collection and development of management protocols difficult


Acetaminophen toxicity is a common cause of acute liver failure.1,11 Intensive care management in dedicated liver units, combined with OLT, has resulted in a significant improvement in overall survival.11 Nevertheless, patients who fulfill the KCH criteria still face dismal prognosis if OLT is not performed in a timely manner. Classically, management of these patients includes listing for urgent OLT if no contraindications are present and conservative measures aimed at controlling brain edema (hyperventilation, mannitol, barbiturates, etc.) until a liver graft is procured.1,6,7 However, this approach has yielded disappointing results primarily for two reasons

Surgical Technique

Veno Venous Bypass Liver Transplant

Moritz was the first to report successful use of HLT in a 19-year-old woman with non-A, non-B, non-C hepatitis with FHF and stage IV hepatic encephalopathy the patient recovered fully. He and his associates chose the heterotopic position, citing an adverse effect of manipulation of the necrotic liver on ICP, causing severe hemodynamic instability. Despite the use of a reduced size donor liver, which was placed in the right paravertebral gutter, abdominal wound closure required a silastic mesh. The surgeons reported that native liver biopsy at 6 months showed cirrhosis however, subsequent evaluation at 22 months revealed normal native liver histology and absent hepatocytes with diffuse fibrovascular (granulation) tissue in the graft. Imaging studies revealed a shrunken graft with no hepato-cyte function and a native liver of normal size and function. Immunosuppression was withdrawn and the graft allowed to undergo atrophy. At 44 months following HLT, the patient continued to have...

Advances in Device and Cellular Engineering

A number of new technologies have been developed and refined during the past several decades which set the stage for a significant advance in transplantation as a major means for treating human disease. These technologies include the identification and isolation of specific cells and cell products which play a major role in disease (hormones, growth factors, immune products, cellular toxins),30 cell engineering enabling the production of living cells which produce these specific bioactive compounds, and advances in bioreactor design for in vitro maintenance and propagation of these cells.31 A particular case of encapsulation involves immunoisolation of mammalian cells. Examples include the bioartificial pancreas, enzyme systems32 and enzyme replacement therapy,33 encapsulated hepatocytes for the treatment of severe liver failure,2 the bioartificial kidney,14 high-density cell growth for immunotherapy,5 controlled delivery of medicinal substances and other bioactive agents,34...

Unusual Species of Infecting Bacteria

However, the appearance of Yersinia enterocolitica in a dozen cases of SBP demonstrates that this organism, which was first known for its capacity to induce mucosal colonic ulcerations (20,21), was found to have an even more unusual aspect. It showed great predilection for patients with cirrhosis, especially those with hemochromatosis or other ironic disorders (22,23). This association with the metabolism of iron, on which Yersinial organisms are dependent, renders Yersinial infections a unique species. In addition, this species has a unique aspect, i.e., its capacity to cross react with Brucella organisms to give a positive Widal agglutination test (24). The finding of a positive Widal serologic test has led to the diagnosis of Yersinial infections.

SBP in Acute Liver Disease

SBP has almost always been reported in patients with cirrhosis, i.e., in patients with chronic long-standing liver disease. It was reported in acute liver disease as early as 1982 and occasionally since (74). Recently, Chu and coworkers reported that SBP is very common in severe acute hepatitis in Taiwan (75). SBP was observed in 26 of 82 consecutive patients with acute, viral hepatitis (32 ). Why was SBP so common in this group of patients Usually SBP occurs in patients with cirrhosis and severe portal hypertension with well-developed portal-systemic shunting. The SBP was monobacterial as in the cirrhotic type, and the infecting bacteria were largely aerobic, gram-negative rods. Were these Taiwanese patients different in some fundamental way Indeed, they were The hepatitis in these patients was very severe. Prothrombin times were > 5 sec prolonged in > 90 of them. In fact, they were so prolonged that it was too dangerous to perform liver biopsies in these patients, and so the...

Aids And Tuberculosis

Although uncommon in the United States and other developed nations, TBP is a frequent cause of ascites in developing countries (1,9,16,22,25), and is a common complication in patients with cirrhosis (1,23,19). It is an especially frequent complication of chronic, ambulatory, peritoneal dialysis (CAPD) (33). This specific syndrome will be discussed in greater detail in this chapter.

Clinical Pathogenesis of Spontaneous Bacterial Peritonitis

Patients with decompensated cirrhosis occasionally develop spontaneous peritonitis and bacteremia caused by enteric bacteria. This syndrome is characterized by the abrupt onset of fever, chills, abdominal pain and tenderness, hypoactive bowel sounds, hypotension, and hepatic coma. The diagnosis can be made by the demonstration of turbid ascitic fluid containing increased numbers of polymorphonuclear leukocytes and bacteria and confirmed by the isolation of the enteric organisms from the blood and ascitic fluid.

What Factors Predispose To The Initial Bacteremia That Precipitates Peritonitis In Ascitic Cirrhotic Patients

There are several factors, which by their great frequency in our series, must be considered to be potential predisposing causes. The role of diarrhea in the production of spontaneous peritonitis, for example, is not clear. Diarrhea, which occurs commonly in cirrhosis (2), may only be coincidentally associated with the peritonitis. It is possible that some of the various causes of diarrhea may be injurious to the mucosa and may permit the escape of intestinal bacteria from the lumen. Diarrhea itself may in some way alter host-bacterial relationships. Diarrhea of diverse etiologies may cause alteration in both the types of bacteria and in the physical distribution of flora in the intestinal tract. Even in acute, experimentally-induced diarrhea in normal subjects coliform organisms may appear as high as the small intestine, where they are not usually present, and may be replaced by enterobacteria as the dominant organisms of the stools (15). Such alterations alone or in combination with...

Chronic Liver Disease

Liver diseases impose a heavy burden and affect approximately 17 of the population. Cirrhosis, the end result of long-term liver damage, has long been an important cause of death in the UK and showed a large increase in death rates over the past 20 years.1 Cirrhosis is a progressive liver disease and is marked by the gradual destruction of liver tissue over a period of time. Several liver diseases fall under this category, including fibrosis of the liver, and hepatitis B and C viral infections. At the cir-rhotic stage, liver disease is considered irreversible and the only alternative is orthotopic liver transplantation. While orthotopic liver transplantation cures chronic liver disease and a variety of metabolic and genetic deficiency disorders, the increasing shortage of donor organs restricts liver transplantation. The number of patients waiting for orthotopic liver transplantation is far greater than the organ supply, and there is obviously a demand for new strategies to supplement...

Overview Of The Induction Of Bt In Experimental Animals

BT has been induced in a variety of ways. To assess them in a rational manner we have classified them according to the major means of induction. These specific substances, injuries, disorders, and procedures are listed in Table 7.1. These methods range from acute injury to the liver caused by D-galactosamine to chronic liver disease induced by carbon tetrachloride or by biliary obstruction, which are attempts to simulate the two most common types of cirrhosis. Closely related are attempts to induce portal hypertension, which is the underlying abnormality of SBP. Some of these techniques are induced by direct interventions such as portal vein clamping or by major hepatic resection, the consequences of which are increments in portal venous pressure and impairment of liver function. Not surprisingly, some of these translocations are mediated by infections such as bacteremia (fungal, lactobacillary), by substances produced during infections (endotoxin, interleukins), or by attempts to...

Human Disorders That Induce Bt

In both patients and rats, Wang and coworkers have demonstrated prompt, severe BT after major hepatic resections in which the severity of the BT was related to the amount of liver tissue resected (45,46). However, the largest hepatic resections (approximately 90 ) induced liver failure with increased serum bilirubin concentrations and a doubling or tripling of aminotransferase activity, as well as positive cultures of enteric organisms in the blood, MLN, liver, spleen, and kidneys. A severe decrease in arterial blood pressure was also noted. Because shock and acute liver failure are both associated with BT, it is not clear whether the hepatic resections per se or their consequences, e.g., the increase in portal venous pressure, were responsible for the infectious problems.

Multiple Organ Failure Syndrome

In a recent article Runyon et al. studied the effect of SID with norfloxacin on BT and SBP in a rat model of cirrhosis, ascites, and SBP (113). Norfloxacin was administered to half the rats in drinking water at night in a dose of 5 mg per kg per day. The appearance of ascites was associated with weight loss, choluria, diarrhea, and lethargy. Death was induced in preterminal rats by methoxyflurane inhalation and ketamine injections. Abdominal paracentesis was performed for ascitic fluid (AF) cell counts and culture of feces and a biopsy of the liver for histologic examination was taken. SBP was defined as a positive AF culture and > 250 neutrophilic leukocytes per mm3, whereas bacterascites (BA) was defined as a positive AF culture and < 250 neutrophilic leukocytes per mm3. Both were considered to represent SBP. Virtually all 45 rats, 25 of which were receiving norfloxacin and 20 of which were untreated control animals, developed cirrhosis. Ninety-five percent had developed ascites...

James T Mayes J Michael Henderson

Figure 24-1 A, Survival probabilities in patients with ascites. B, Survival probabilities after spontaneous bacterial peritonitis. (A and B, modified from Gines, P., Quintero, E, Arroyo, V., et al. Compensated cirrhosis Natural history and prognostic factors. Hepatology, 7 122-128, 1987 and D 'Amico, G., Morabito, A., Pagliaro, L., et al. Survival and prognostic indicators in compensated and decompensated cirrhosis. Dig. Dis. Sci., 31 468-475, 1986.)

David R Fischer Timothy A Pritts Josef E Fischer

The patient with obstructive jaundice was previously thought to be basically a normal person whose bilirubin is not being excreted because of obstruction to the flow of the bile. The inclusion of both cirrhosis and preoperative preparation for biliary surgery in this chapter is a recognition that the patient with obstructive jaundice is not physiologically normal but shares many of the physiologic deficits of patients with cirrhosis, deficits that are potentially dangerous at the time of surgery. Furthermore, the jaundiced patient with cholestasis secondary to sepsis is a patient with an impaired liver. However, because of the sufficient differences between these conditions, they are discussed in separate portions of the chapter.

Warren R Maley Andrew S Klein

The information thus garnered has been applied in the clinical setting with increasing success. The general medical and perioperative care of patients with compromised hepatic function and portal hypertension has advanced considerably. Pharmacologic manipulations aimed at reducing splanchnic blood flow or hepatic vascular resistance have proved useful in the prophylaxis and amelioration of acute hemorrhage. Endoscopic methods have been devised for the treatment of active variceal bleeding and for the prevention of recurrent episodes of variceal rupture. Invasive radiologic procedures have provided, in addition to detailed anatomic and hemodynamic data, a therapeutic modality for certain hemorrhagic complications of portal hypertension. New surgical procedures have been devised, and older operations have been revised. Finally, liver transplantation has evolved from an experimental procedure to the treatment of choice for selected patients with portal hypertension and end-stage liver...

Medical Management Of Acute Variceal Hemorrhage

The patient with cirrhosis and bleeding esophageal varices suffers from a debilitating disease with many remote manifestations. These patients often die of hepatic failure, renal failure, or sepsis rather than exsanguination. Accordingly, supportive care is critical to survival. The first order of priority is fluid resuscitation, initially with crystalloid and then, as soon as possible, with packed red blood cells and fresh frozen plasma. The combination of thrombocytopenia (from hypersplenism) and severe hemorrhage may warrant the administration of platelet infusions. Care should be taken to avoid the infusion of too much salt-containing fluid because of avid sodium retention and resultant ascites, edema, and dilutional hyponatremia. The restoration of blood volume should be monitored by hourly urine output through a Foley catheter and by measurement of central venous pressure.

Calcium in Prevention of BT

Total parenteral nutrition is fraught with hepatic hazards including cholestasis, cholelethiasis, hepatic fibrosis, biliary cirrhosis and, ultimately, hepatic failure. It is surprising that TPN solutions when administered both enterally and parenterally may promote BT (56,57), and sometimes these effects may be related both directly or inversely to the duration of administration of the diet.

Clinical Manifestations

Matic abnormalities of serum transaminases (alanine aminotransferase and aspartate aminotrans-ferase) are most commonly observed. In the setting of chronic GVHD, alkaline phosphatase and bilirubin may also be elevated. However, bilirubin elevation is variable and does not correlate with clinical outcome. Patients with chronic liver dysfunction frequently report constitutional complaints such as pruritus, fatigue and weight loss. In contrast, hepatic veno-occlusive disease is characterized by the acute onset of jaundice, upper quadrant pain on the right side, hepatomegaly, ascites, liver dysfunction and thrombocytopenia. The clinical course of VOD varies from mild and reversible to life-threatening, with progressive hepatic failure. The impact of acute VOD on long-term hepatic function has not been established. Chronic progressive hepatic fibrosis associated with cirrhosis may cause portal hypertension and resulting sequelae, such as hypersplenism and variceal bleeding. If cirrhosis...

Bone Marrow Transplant

And represents a major cause of transplant-related morbidity and mortality 95 .Approximately 80 of individuals with chronic GVHD have liver involvement 10, 96 . Drug toxicity from immunosuppres-sive agents, antibiotics, antifungal and antiviral drugs, sedatives, antiemetics and antipyretics may exacerbate chronic GVHD 22 . Chronic infections, most commonly hepatitis-C, may also accelerate the course of liver injury. Severe chronic liver disease with cirrhosis represents an important late complication of hematopoietic stem cell transplantation that, in most cases,is due to chronic hepatitis-C (Fig. 12.6) 16, 19, 20 . Reports documenting deaths from cirrhosis and hepatic failure suggest that chronic liver disease may predispose to early mortality in long-term survivors treated with allogeneic bone marrow transplantation 11, 16, 19 .

Transfusion Acquired Chronic Hepatitis

Screening was implemented in 1971 in the United States. Hepatitis-C screening by the first generation enzyme immunoassay (EIA) was initiated in 1990 a more sensitive, second generation EIA became available in 1992. Hence, transfusion-acquired viral hepatitis should be considered in long-term survivors presenting with chronic hepatic dysfunction who received transfusions before donor screening was available. Hepatitis-B is characterized by a more aggressive acute clinical course and a lower rate of chronic infection (< 10 ). In contrast, acute infection with hepatitis-C is often mild or asymptomatic, but the rate of chronic infection is high (approximately 80 ). Regardless of the etiology, survivors with chronic hepatitis experience significant morbidity and mortality related to cirrhosis, end-stage liver disease and hepatocellular carcinoma 15, 17, 18, 97-100 . Co-infection with hepatitis-B and -C appears to accelerate the progression of liver disease, as does the immunosuppression...

Darrell A Campbell Jr

Budd-Chiari syndrome (BCS) is an unusual disorder produced by occlusion of the hepatic veins, with resultant abdominal pain, hepatomegaly, and ascites. Until recent years, BCS was seen as a discrete entity, no treatment options were available, and mortality was high. Investigators now appreciate that BCS represents a heterogeneous mix of patients who differ in terms of the disorder's cause, the degree of involvement of the hepatic veins, the rapidity with which thrombosis has occurred, the prior development of effective decompressive collateral vessels, and the degree of fibrosis or even cirrhosis that has developed. These variables and the rapid pace at which new therapeutic options have evolved present the clinician with a challenge to perform a detailed evaluation and to tailor a therapeutic plan that takes advantage of all the information available. Figure 28-1 presents a flow chart for evaluation of these patients. Formulation of a reasonable plan of treatment must take into...

Bile Duct Resection Alone

This operation is rarely indicated nowadays and only when the primary tumour is located exactly in the middle of the common hepatic duct with no invasion or spread, without portal or arterial involvement. It is also an option for high-risk patients who cannot tolerate hepatic resection due to the presence of cirrhosis or severe co-morbidities. It is considered a minimally invasive, less radical surgical treatment. After completion of lymph node dissection of hepatic pedicle and division of distal bile duct at the supraduodenal level, right and left Glisson pedicles are more exteriorized thanks to posterior access at the hilum that allows en-bloc resection of Glisson sheath and intrahepatic biliary ducts. Particular attention must be paid to dissect biliary confluence from portal vascular plane and right hepatic artery that runs behind biliary bifurcation. Whenever the right and left hepatic ducts are exposed, they are divided upon positioning a stay suture. The section of the left...

Iievolution Of Prognosis In Recent Decades

This improvement in the prognosis of the SBP was attributed to several factors (a) the recognition in the 1970s and early 1980s of SBP as a frequent and life-threatening complication of ascitic cirrhosis that led to the use of systematic paracentesis not only when suspecting SBP, but also whenever the overall condition of a cirrhotic patient with ascites deteriorates, as occurs with the appearance of hepatic encephalopathy, fever, or gastrointestinal bleeding (b) the lowering of the threshold in polymorphonuclear (PMN) count for the diagnosis of SBP from 500 to 250 cells mm3 (8,9), which allows the treatment of patients in an earlier, less severe stage of the infection with the resultant improvement in the survival rate and (c) the progress in antibiotic treatment, with the usage of very effective, well-tolerated, non-nephrotoxic antibiotic agents, such as third-generation cephalosporins (15,16), the combination of amoxicillin and clavulanic acid, or oral quinolones, such as...

Diagnostic Procedures

An open liver biopsy is usually performed through a limited right subcostal incision. The incision should be placed over the inferior edge of the liver, but it should be no less than 3 cm from the costal margin to allow for adequate wound closure. Failure to identify the edge of the liver properly by percussion or palpation may result in an inability to expose the inferior hepatic surface of an enlarged liver (incision placed too high) or difficulty in accessing a small, shrunken, cirrhotic liver (incision too low). If the incision is placed properly, a fascial opening of 4 to 6 cm will be sufficient. The liver is examined both visually and by gentle palpation, with care taken not to disturb any well-vascularized mesenteric-systemic collateral vessels that may be present. The disruption of these friable vessels, or a seemingly innocent tear in the hepatic capsule, may transform this limited biopsy procedure rapidly into a major abdominal operation. The liver is inspected for gross...

Epidemiologic Strength

For example, an observational study that examines the relationship between the use of an anti-diabetic drug and liver failure may also focus on the relationship between exposure duration and the incidence of acute liver failure. This would require a relative risk (with corresponding confidence interval and p-value) for each dose-duration category. In addition, one could measure the proportion of patients, who have elevated liver enzymes. This collection of evaluations improves the quality of the assessment of the true nature of the exposure-disease relationship. However, each requires an additional analysis.

Gi Stem Cell Plasticity

2001), bone marrow stem cells differentiate into cardiomyocytes, endothelial cells, and smooth muscle cells. Functional capability of the transdifferentiated cells in repair and regeneration of diseased tissue is demonstrated in fumarylacetoacetate hydrolase (FAH)-deficient mice, which resemble type 1 tyrosinemia in humans and are rescued from liver failure by transplantation of purified hematopoietic stem cells (HSCs) that differentiate into morphologically normal hepatocytes and express the FAH enzyme (Lagasse et al., 2000).

Hepatopancreatoduodenectomy HPD

In presence of longitudinal tumour spread from the hepatic duct to the intrapan-creatic bile duct or massive lymph-node metastases along the bile duct and behind the pancreatic head, HPD has been proposed to achieve surgical radical-ity. If massive lymph node infiltration occurred, HPD is not indicated due to the poor prognostic significance of lymph node invasion. In the first reported experiences, mortality and morbidity rates of HPD were very high because of postoperative liver failure and leakage of pancreatojejunostomy 8 . For this reason a two-stage operation in which reconstruction of the pancreatic duct is deferred to a second stage was proposed. This technique, associated with preoperative biliary drainage and PVE, has reduced complications and mortality significantly. Miyagawa 9 reported a consecutive series of 12 patients without mortality.

Other Prognostic Factors

There are other variables associated with survival in cirrhotic patients with SBP. Age has been identified as one such prognostic factor in some studies (20,26). The existence of a recent upper gastrointestinal hemorrhage was shown to be a poor prognostic sign for survival in the study by Llovet et al. (18). Although gastrointestinal bleeding itself is a severe complication of cirrhosis, the detrimental effects of gastrointestinal bleeding on the immune response in cirrhosis could also account for its negative prognostic value in SBP. This observation is a further argument for using selective intestinal decontamination in cirrhotic patients with gastrointestinal hemorrhage. Finally, the existence of a hepatocarcinoma at the time of diagnosis of SBP has been found to be associated with a very poor prognosis (29).

Disorders of Later Infancy with Recurrent Metabolic Crises

Hyperammonemia is encountered in other disorders. Reye's syndrome can be differentiated by the elevated transaminase and high plasma lysine levels. Patients with liver failure usually have elevated plasma methionine and tyrosine levels, which are not observed in UCDs of various types. Patients with valproate toxicity have elevated valproylcarnitine levels and deficiency of free carnitine in studies with tandem mass spectrometry.

Liver Directed Cell Therapy for Inborn Errors of Metabolism

Several excellent animal models are available to establish the principles of liver cell therapy. These animal models include the Gunn rat model of Crigler-Najjar Syndrome type 1 (73), in which bilirubin-UDP-glucuronosyltransferase (UGT1A1) activity is deficient and unconjugated bilirubin accumulates producing neurotoxicity Nagase analbuminemic rats (NAR), which exhibit extremely low levels of serum albumin resulting from defective albumin mRNA processing the Watanabe heritable hyperlipidemic rabbit, which lack cell surface receptors for low-density lipoproteins and models familial hypercholesterolemia (74) the Long-Evans Cinnamon (LEC) rat, an animal model for Wilson's disease (75) the FAH mouse, which models hereditary tyrosinemia type-1 (13,21) and the mdr-2 knockout mice, which model progressive familial intrahepatic cholestasis (76). Mutant animals with diseases of the urea cycle, porphyria, lipidoses, and coagulation disorders are also available (77-80). Similarly, animal models...

Morbidity and Mortality

Liver failure 29 (27.6 ) Bilirubin level and cholangitis in the preoperative period are significantly associated with postoperative liver failure Fujii noticed that jaundice at admission was present in 71 of patients with postoperative liver failure and only in 25 of patients without postoperative liver failure 20 . Half of the patients with postoperative liver failure presented preoperative cholangitis, compared to 4 of patients without liver failure 20 . Postoperative liver failure is related to the volume of the remnant liver the failure rate is 16.7 in patients with resection of less than 50 of liver volume but it increases to 36.8 for resection of more than 50 21 . The extensive use of portal vein embolisation (PVE) can reduce the rate of this complication after major hepatic resection. In literature the reported rates of liver failure after major hepatectomy without PVE range from 0 to 30 , whereas with PVE they range from 0 to 5 5,9,11,16-19,22-23 . Another frequent...

Stress Proteins in Inflammatory Liver Disease

The liver is not only involved as a bystander organ in many systemic diseases, it is also, more than most other organs, the focus of many chronic inflammatory diseases. Hepatitis B virus infection is the most prevalent infectious disease in the world, and chronic hepatitis C appears to be similarly common worldwide, although with a different geographical distribution. Alcoholic hepatitis as the inflammatory lesion in many patients with alcoholic liver disease is thought to be largely immune mediated. Although systemic autoimmune diseases like lupus erythematosus rarely affect the liver, the liver itself is the target organ of autoimmune attack in autoimmune hepatitis (which in itself is probably a heterogeneous group of diseases), primary biliary cirrhosis, amd primary sclerosing cholangitis.

Transplantation with Adjuvant and Neoadjuvant Treatments

The protocol proposed by the University of Nebraska implies neoadjuvant treatment with Ir-192 biliary catheters brachytherapy for a total dose of 6000cGy associated with chemotherapy with continuous infusion of 5-FU (daily dose 300 mg m2). The treatment is continued until transplantation. In this initial experience only patients who were excluded from surgical resection due to the stage of the disease or presence of cirrhosis were included in this study. Six of the 17 recruited patients (35 ) were excluded from transplantation since the onset of complications or neoplasm progression while on the waiting list. The 11 patients who underwent transplantation showed a mortality rate of 27 and 3-year survival of 45 two patients (18 ) presented recurrence of disease during follow-up 12 . The second trial proposed by the Mayo Clinic includes patients who were unresectable due to the stage of the disease or concomitant cirrhosis, and is based on external and intraluminal radiation therapy...

Stem Cells and Liver Disease

Liver fibrosis and liver cancer are two very major causes of human morbidity and mortality, and both appear to have their foundations in stem cells. In the mouse liver, transplanted bone marrow cells can acquire the phenotype of quiescent stellate cells and after liver injury can become activated into aSMA-expressing cells.103 In human cirrhosis, by examining sex-mismatched allografts, Forbes etal. have shown that up to 40 of myofibroblasts are of bone

Mechanistic toxicogenomics

Ficacious dose of a compound and the dose at which the very first adverse events are detectable, was seen as the best possible way to progress the development of a NCE to a usable marketable drug. However, the pharmaceutical industry together with regulatory authorities around the world is now increasingly inclined to try to understand toxicity events 18 . Traditionally, this involved the development of a hypothesis that was tested and possibly verified by all available techniques and disciplines. Having molecular clues, rather than just morphological, physiological and clinical observations, is obviously valuable for the generation of a more accurate and a more focussed mechanistic hypothesis. There are now more published data of classical chemical-, and to a lesser extent, drug-induced adverse events 19 . One of the best-studied cases is certainly the effect of acetaminophen toxicity in either mouse or rat liver 20-24 . These studies rapidly provided new insights into molecular...

Preoperative Evaluation

The degree of hepatic reserve must be estimated, based on available tests of liver function including prothrombin time, albumin, bilirubin, liver enzymes, and the presence of ascites, varices, or encephalopathy. The Childs-Pugh classification is helpful, but can underestimate the degree of liver dysfunction. The vast majority of liver tumors in cirrhotic patients are not resectable due to parenchymal dysfunction. Alternate methods of tumor ablation must be considered in the majority of patients with cirrhosis and limited hepatic reserve.

P16INK4a induction with Ageing Telomere Independent

A particularly important question relates to the relationship of telomeres and p16INK4a. As discussed, some data suggest that sufficient telomere attrition occurs in human stem cells during normal ageing to activate an intrinsic DNA damage response with attendant compromise of stem cell replicative function. Humans who harbor short telomeres because of congenital deficiencies of the telomerase complex develop an age-related failure of bone marrow function and other self-renewing compartments (Mitchell et al. 1999, Vulliamy et al. 2001, Yamaguchi et al. 2005) (see also Du et al., this volume). Moreover, telomere shortening has been shown to precede the development in overt cirrhosis in patients with chronic hepatitis of various etiologies (Kitada et al. 1995, Miura et al. 1997, Urabe et al. 1996, Wiemann et al. 2002). Lastly, some studies have demonstrated a relationship between telomere length in peripheral blood lymphocytes (PBL) and the onset of certain diseases associated with...

Human Liver Stem Cells

Immunohistochemical analysis of diseased human liver tissue. Sections were immunostained using the biliary-specific marker HEA 125. Tissue was from end-stage livers removed at the time of orthotopic transplantation from patients with (A) a1-Anti-trypsin deficiency, (B) biliary atresia, and (C) primary biliary cirrhosis. Note the presence of aberrant ductular proliferative cells in each case (arrows) with differing morphological features. Fig. 1. Immunohistochemical analysis of diseased human liver tissue. Sections were immunostained using the biliary-specific marker HEA 125. Tissue was from end-stage livers removed at the time of orthotopic transplantation from patients with (A) a1-Anti-trypsin deficiency, (B) biliary atresia, and (C) primary biliary cirrhosis. Note the presence of aberrant ductular proliferative cells in each case (arrows) with differing morphological features. the liver, with the consequence of cholestasis and the secondary damage that ensues, leading to...

Cell Fusion Or Transdifferentiation

RT-PCR analysis of Notch receptor expression in liver-derived c-kit+ cells immediately following isolation. cDNA was prepared from purified cells immediately following immunoisolation using c-kit antibodies. PBC, primary biliary cirrhosis. Fig. 6. RT-PCR analysis of Notch receptor expression in liver-derived c-kit+ cells immediately following isolation. cDNA was prepared from purified cells immediately following immunoisolation using c-kit antibodies. PBC, primary biliary cirrhosis.

Molecular Mechanisms of Tumor Initiation in Response to Telomere Shortening

Most human cancers that evolve during ageing and at the end stage of chronic diseases are associated with high rates of chromosomal instability (CIN). A current concept in molecular oncology indicates that CIN induces genetic lesions that promote the step-wise progression of altered cells to transform into cancer cells (Michor et al. 2005). Since telomere shortening is associated with an increased cancer risk during ageing and chronic disease, it is conceivable that loss of telomere capping function contributes to the induction of chromosomal instability and cancer initiation (Fig. 11.2). In agreement with this assumption, telomere shortening in humans correlates with the evolution of CIN in chronic diseases associated with an increased cancer risk, e.g., ulcerative colitis and liver cirrhosis (O'Sullivan et al. 2002), as well as with the evolution of aneuploidy on the single-cell level in human hepato-cellular carcinoma (Plentz et al. 2005).

Sanjeev Gupta mbbs md facp frcp and Jae Jin Cho dvm phd

Transplantation of liver stem progenitor cells offers a new approach for treating genetic diseases or liver failure. Transplantation of mature liver cells or whole liver is limited by severe shortages of donor organs. Extensive studies indicate that optimal function of transplanted cells may require cell transplantation into the liver itself rather than into ectopic sites. Cells may be transplanted into the liver by intraportal or intrasplenic injection, which leads to the entry of transplanted cells in liver sinusoids, and eventually transplanted cells become incorporated in the liver parenchyma. During this process, transplanted cells disrupt sinusoidal endothelial cells to enter the liver plate and reestablish plasma membrane structures by joining with native liver cells. Some liver progenitor cells (LPCs) are less able to integrate and may remain within the vascular spaces. Approximately 1 to 2 of the normal liver can be repopulated in animals when a somewhat larger cell number is...

Function And Proliferation

In the rat liver, use of DNA-damaging agents has been helpful for inducing liver repopulation with transplanted cells. Obviously, such liver injury should be insidious without precipitating acute liver failure. Use of the pyrollizidine alkaloid retrorsine, which alkylates DNA and inhibits proliferation in native hepato-cytes, has been extraordinarily effective for liver repopulation in the DPPIV- rat (Laconi et al., 1998). It is noteworthy that retrorsine induces extensive polyploidy in the rat liver, which is also induced by two-thirds partial hepatectomy and the thyroid hormone triiodothyronine (T3) (Sigal et al., 1999 Torres et al., 1999). Polyploid hepatocytes exhibit DNA damage with evidence for the activation of cell-aging events, increased apoptosis, and decreased proliferation capacity in vitro, as well as in vivo after transplantation into DPPIV- rats (Sigal et al., 1999 Gorla et al., 2001). Therefore, it should not be surprising that the combination of either partial...

Transplantation Analysis Of Representative Types Of Liver Stem Cells

Transplantation of hepatic oval cells, which originally referred to poorly differentiated cholangiolar cells following carcinogenic induction (Farber, 1956), has been under investigation as a potentially useful progenitor cell type. Oval cells arise during liver regeneration induced by chemicals, such as carbon tetrachloride and D-galactosamine (GalN), as well as following acute liver failure in humans (Sell, 2001). As reviewed elsewhere, oval cells exhibit a variety of hepatocytic and biliary markers, including albumin, (-fetoprotein (AFP), glycogen, glucose-6-phosphatase, and hybrid isoenzymes. Various studies have shown that primary oval cells isolated from the normal rat liver, as well as the diseased liver of LEC rats with copper toxicosis, can differentiate into mature hepatocytes (Yasui et al., 1997 Hooth et al., 1998 Ott et al., 1999a Malouf et al., 2001). Similarly, isolation of oval celllike ductular cells from the pancreas of rats subjected to a regimen of copper depletion...

Animal Models Available For Assessing Therapeutic Potential Of Stem Cells

These models should be similarly effective in defining the potential of stem cell transplantation. If the goal is to correct genetically determined metabolic disorders, transplantation of normal hepatocytes will be required. Alternatively, one could modify autologous stem cells in vitro and transplant corrected cells (ex vivo gene therapy). Treatment of acquired disorders, such as chronic viral hepatitis, requires transplantation of hepatocytes resistant to hepatitis virus infection. By contrast, patients with acute liver failure could be treated with healthy cells from any source.

Past History of SBP

Patients who have recovered from the first episode of SBP constitute the group of cirrhotic patients with the greatest risk of developing SBP. The demonstration and characterization of SBP as a highly recurrent disorder was made by Tito et al. in 1988 (7). These authors analyzed the long-term course of 75 consecutive patients with cirrhosis who recovered from their initial episode of SBP. No patient was excluded from the analysis and no prophylactic measures were attempted to prevent recurrence. Half of the patients developed one or more episodes of SBP during a mean follow-up period of 10 months (range 0.1-56 months). SBP recurred once in 22 patients, twice in 10, and three times or more in six patients. The cumulative probability of SBP recurrence was 43 at 6 months, 69 at one year, and 74 at two years of follow-up (Fig. 12.1). In addition to the highlighting of this high recurrence rate, four additional important clinical observations were made. First, gram-negative bacteria of...

Gastrointestinal Bleeding

Gastrointestinal bleeding is a major risk factor that precedes the development of bacterial infections in cirrhosis approximately one-third of patients develop infections in close temporal relationship to an episode of bleeding (13-19). Bacterial infections show a bimodal distribution, with an early peak of incidence that corresponds to infections documented at admission or within the first 48 h after bleeding, and a second peak between 5 and 10 days after the index hemorrhage (18). Infections that develop in cirrhotic patients after gastrointestinal bleeding are particularly severe, the most common of which are SBP, bacteremia, and pneumonia. In the whole population of bleeding cirrhotic patients, the prevalence of SBP is relatively low, ranging from 7 to 15 in different studies. However, when only bleeding patients with ascites are considered the incidence of SBP is very high, ranging from 29 to 50 (Table 12.1). Several factors may account for this high incidence of bacterial...

Type of Surgical Resection

Surgical resection of cholangiocarcinoma is represented by anatomic hepatic resection. Advanced-stage neoplasms must often be treated by extended hepate-ctomy, with extension of the resection to the extrahepatic biliary tract, vascular hilar structures, vena cava and diaphragm. Usually, this type of neoplasm develops in a non-cirrhotic liver, which allows the surgeon to perform extended resection without the need of portal-vein embolisation. The mortality and morbidity rates in these cases vary from 3-9 and 30-40 , respectively 4,12-15 .

Cirrhotic Patients At High Risk Of The First Episode Of Spontaneous Bacterial Peritionitis

Cirrhotic patients who have had gastrointestinal hemorrhage constitute another high-risk group for developing bacterial infections, including SBP (28,29). This predisposition appears to be related to several other dysfunctions of acute hemorrhage in the already impaired antimicrobial mechanisms of cirrhotic patients, such as a depression of reticuloendothelial activity and an increase in intestinal permeability and bacterial translocation due to hypovolemia (30,31). An enhanced incidence of bacterial translocation to mesenteric lymph nodes after hemorrhagic shock has recently been observed in rats with cirrhosis and shock compared to shocked noncirrhotic rats and to nonshocked cirrhotic rats (32,33). These observations suggest that both cirrhosis and hypovolemia are independent factors that favor bacterial translocation. As a consequence of these disturbances, 20 of cirrhotic patients admitted with gastrointestinal hemorrhage are already infected at the time of admission to the...

Primary Longterm Prophylaxis Of Spontaneous Bacterial Peritonitis In Cirrhotic Outpatients

Runyon et al. (76) evaluated long-term primary prophylaxis of SBP with norfloxacin in rats with experimental cirrhosis. Treated rats showed a lower incidence of bacterial translocation and SBP than control rats, suggesting that Grang et al. (90) performed a multicentric, double-blind, placebo-con-trolled trial of primary prophylaxis of SBP in patients with cirrhosis and low ascitic fluid total protein levels (< 1.5 g dL). In this study, 54 patients were treated during six months with oral norfloxacin 400 mg daily and 53 patients received placebo. The incidence of the first episode of SBP during follow-up was significantly lower in the treated patients than in the placebo group (0 vs. 7.5 , respectively), but the incidence of other infections and mortality was similar in both groups. Only two patients exhibited nausea and hypersomnia, which are considered side effects attributable to norfloxacin. Recently, Novella et al. (91) carried out a randomized study to evaluate long-term...

Pros And Cons Of Antibiotic Prophylaxis Of Spontaneous Bacterial Peritonitis

Short-term prophylaxis does not reduce the length of hospitalization Norfloxacin prophylaxis increases intestinal bacterial overgrowth and bacterial translocation of gram-positive cocci and SBP caused by these bacteria in experimental cirrhosis Emergence of norfloxacin-resistant bacteria in stools and infections caused by these bacteria in patients on prophylaxis

Programming of Neohepatocytes and Neoislets

In view of the urgent need for autologous cell replacement strategies in the treatment of diabetes or liver diseases and for drug testing screening purposes, we focussed on the generation and functional evaluation of pancreatic islet and hepatocytes-like cells. We go on to show that these monocyte-derived neo-islets and neo-hepatocytes acquire highly specialized functions in vitro, otherwise only displayed by primary hepatocytes and islet cells, respectively. Moreover, we demonstrate that neoheps are able to repopulate critically resected liver organs and restore liver function in animals otherwise succumbing to acute liver failure.

Risk Based Healthcare Definition and Rationale

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 and adequate calcium intake, can modify risk. Longitudinal care addressing other late effects, such as infertility, musculoskeletal problems, cognitive dysfunction and psychosocial issues, may also improve survivors' health outcomes and quality of life.

Sbp As A Criterion For Indicating Liver Transplantation

In general terms, liver transplantation is indicated in patients fulfilling two major criteria (a) progressive, lethal, and otherwise unbeatable liver disease and (b) survival expectancy with conventional management clearly lower than that with liver transplantation (1-7). In this setting liver transplantation should be considered in every patient with SBP for the following reasons. First, SBP develops very frequently in cirrhotic patients with advanced liver disease (8-15). In a study that included a large series of consecutive, unselected patients with SBP, 76.5 of patients had Child-Pugh class C cirrhosis, 23 had class B, and 0.5 had class A (12). Therefore, most patients with SBP satisfy the criteria for liver transplantation of severe, advanced cirrhosis with limited life expectancy.

Hepatitis C Virus HCV

HCV is a single-stranded RNA virus which shows marked genetic heterogeneity and at least six major subtypes are known, of which Ib is thought to be the most likely to lead to chronic liver disease. Whilst it is associated with only about one-sixth of all cases of hepatocellular carcinoma world-wide, this proportion is higher and rising in some areas, notably Japan and, to a lesser extent, Spain, Italy and the Middle East (Idilman et al., 1998 Bosch et al., 1999 Colombo, 1999). The infection is usually acquired in adult life via transfusion of blood and blood products or by the use of contaminated instruments and syringes by intravenous drug abusers. Perinatal and sexual transmission are unimportant. The onset of malignancy is preceded by cirrhosis in 90 of cases. The course is long, 20-40 years from infection to tumour, and patients are affected in late middle to old age. Table 3 shows that HCV is definitely associated with hepatocellular carcinoma in case-control and follow-up...

Congenital Abnormalities and Metabolic Disorders

These include Alagille's syndrome, ataxia-telangiectasia, familial polyposis of the colon, hereditary haemorrhagic telangiectasia, familial cholestatic cirrhosis, neonatal hepatitis biliary atresia, neurofibromatosis and Soto syndrome. All of these are rare and some cases may have been pure chance associations (Anthony, 1994). Inborn errors of metabolism are not all rare and some carry a surprisingly high risk of hepatocellular carcinoma (European Association for the Study of the Liver, 1999). It is interesting that this tumour is the only malignancy that complicates these disorders regularly. Genetic haemo-chromatosis is an autosomal recessive iron storage disorder associated with two mutations in the HFE gene C282Y and H63D. The frequency in the general population is 0.51.0 in Northern Europe but lower elsewhere. The accumulation of iron leads to cirrhosis which then may be complicated by hepatocellular carcinoma, especially in males. The relative risk is about 100 over that of...

The Macroscopic Pathology of Hepatocellular Carcinoma

A frequently debated issue is multicentricity of hepa-tocellular carcinoma, namely the simultaneous development of separate primary tumours, usually in a cirrhotic liver. This undoubtedly occurs as evidenced by studies of differences in patterns of HBV DNA integration and in