Advertisement

Hepatic Failure

  • Mario RuedaEmail author
  • Pamela A. Lipsett
Chapter
  • 1.4k Downloads

Abstract

The progression of liver disease can cause several physiologic derangements that may precipitate hepatic failure and require admission to an intensive care unit. The underlying pathology may be acute, acute-on chronic, or chronic in nature. Liver failure may manifest with a variety of clinical signs and symptoms that need prompt attention. The compromised synthetic and metabolic activity of the failing liver affects all organ systems, from neurologic to integumentary. Supportive care and specific therapies should be instituted in order to improve outcome and minimize time of recovery.

In this chapter we will discuss the definition, clinical manifestations, workup, and management of acute and chronic liver failure and the general principles of treatment of these patients. Management of liver failure secondary to certain common etiologies will also be presented. Finally, liver transplantation and alternative therapies will also be discussed.

Keywords

Acute liver failure Chronic liver failure Hepatopulmonary syndrome Hepatic encephalopathy Acetaminophen toxicity Amatoxin intoxication Wilson’s disease Viral hepatitis Ischemic hepatitis Ascites Spontaneous bacterial peritonitis Variceal bleed Hepatorenal syndrome Liver transplantation 

Acute Liver Failure

Definition, Epidemiology, and Causes

Acute liver failure (ALF) refers to the rapid deterioration of liver function that is seen in previously healthy patients. Its defining characteristics include the development of coagulopathy, with an international normalized ratio (INR) >1.5, as well as alteration of mental status (encephalopathy). It occurs in individuals without preexisting cirrhosis and with an illness of no more than 26 weeks duration.

There are some minor differences that are associated with duration of symptoms, and therefore ALF can be further subdivided into hyperacute (less than 7 days), acute (7–21 days), or subacute (more than 21 days and less than 26 weeks). Hyperacute and acute liver failures are more commonly associated with cerebral edema, while patients with subacute failure can present with ascites, portal hypertension-related bleeding, and renal failure.

Approximately 2,300 patients experience ALF in the United States [1]. Half of these cases are associated with drug toxicity, most of them related to acetaminophen. Viral hepatitis accounts for one fifth of the cases, the remaining being different metabolic and vascular disorders (Table 18.1) [2].
Table 18.1

Causes of acute liver failure

Medications

Acetaminophen (paracetamol)

Tetracycline

Troglitazone

Isoniazid

Aspirin

Toxins

Amanita mushrooms

Lepiota helveola

Infectious

Hepatitis A

Hepatitis B

Hepatitis C (very uncommon)

Cytomegalovirus

Epstein-Barr virus

Metabolic

Acute fatty liver of pregnancy

Wilson’s disease

Reye’s syndrome

Vascular

Budd-Chiari syndrome

Portal vein thrombosis

Veno-occlusive disease

Ischemic hepatitis

Parenchyma replacement or loss

Breast cancer

Melanoma

Small cell lung cancer

Hepatectomy

Necrosis

Clinical Manifestations

The rapid compromise of hepatic physiologic function results in clinical features that can affect several organ systems and can be variable in their presence and intensity.

Neurologic System

Nonspecific complaints such as fatigue, malaise, lethargy, nausea, vomiting, headache, and anorexia are frequently present in patients with liver failure. As a defining characteristic, patients with ALF present with various degrees of encephalopathy, ranging from slight confusion to coma. In order to characterize the severity of the impairment, several grading scales have been described [3]. Most commonly used is the West-Haven criteria (Table 18.2) [4]. For moderate to severe cases of encephalopathy, the Glasgow Coma Scale can also be used.
Table 18.2

West-Haven criteria for grading hepatic encephalopathy

Grade I

Trivial lack of awareness

Euphoria or anxiety

Shortened attention span

Impaired performance of addition

Grade II

Lethargy or apathy

Minimal disorientation for time or place

Subtle personality change

Inappropriate behavior

Impaired performance of subtraction

Grade III

Somnolence to semistupor but responsive to verbal stimuli

Confusion

Gross disorientation

Grade IV

Coma (unresponsive to verbal or noxious stimuli)

The mechanism by which these changes occur has not been fully identified; however, there are some generally accepted theories that revolve around impaired detoxification of substances normally cleared by the liver.
  • Ammonia

    The metabolism of nitrogen-containing compounds in the gastrointestinal system results in the production of ammonia. In its normal state, the liver converts this neurotoxic product into glutamine and urea. Impaired liver function results in elevated blood ammonia. Astrocytes contain the enzyme glutamine synthetase in their endoplasmic reticulum as a means of handling excessive ammonia. Accumulation of glutamine within the astrocytes results in cell swelling which leads to a series of events that result in a neuroinhibitory state [5].

  • False Neurotransmitters

    The failing liver results in the production of false neurotransmitters. These molecules may interfere with normal brain functioning and have a net inhibitory effect [6].

  • Amino Acid Imbalance

    Patients with hepatic failure have decreased plasma levels of the branched-chain amino acids (BCAA) valine, leucine, and isoleucine while experiencing increased levels of aromatic amino acids (AAA) phenylalanine, tryptophan, and tyrosine. This is thought to be related to increased muscle catabolism and therefore increased BCAA metabolism as well as decreased breakdown of AAA by the compromised liver. The end result is an imbalance that leads to an increased influx of AAA in the brain which has an inhibitory effect in the nervous system [7].

  • GABA receptor

    Thought to be mediated by inflammatory cells, neurosteroids are produced by myelinated glial cells. This results in positive modulation of GABA receptors that in turn enhance the inhibitory tone [8].

Besides the astrocyte swelling that is seen with the accumulation of glutamine explained above, overall neurologic dysfunction results in loss of autoregulation of intracranial pressure as well as reduced cerebral blood flow. The result of these changes may result in further neurologic derangement and compromise [9].

Besides hepatic encephalopathy, patients with ALF can also present with cerebral edema. There is an overlap with the clinical features that are seen with encephalopathy and include nausea, vomiting, headache, and agitation. In advanced cases which can progress to brain herniation, hypertension, bradycardia, changes in pupillary exam or reflexes, as well as respiratory depression can be seen [10].

Respiratory System

Patients with ALF may present with nonspecific respiratory symptoms including dyspnea on exertion, orthopnea, anxiety, and air hunger. The affecting processes involved are very broad and can range from a simple pleural effusion to acute respiratory distress syndrome (ARDS) [11]. The spectrum of respiratory pathology that is seen can be grouped in to two major categories: infectious and noninfectious (Table 18.3).
Table 18.3

Respiratory complications seen in acute liver failure

Infectious

Upper respiratory infections

Pneumonia

Noninfectious

Pulmonary edema

Pleural effusion

Pneumothorax

Hepatopulmonary syndrome

Acute respiratory distress syndrome

Acute lung injury

Depressed central respiratory drive

Pulmonary edema can be of cardiogenic or noncardiogenic etiology. The prevalence of pulmonary edema appears to be higher in those patients with cerebral edema, suggesting the accumulation of osmotic substances within the lung parenchyma and outside the vasculature [12]. Molecular imbalance and injury to endothelial cells, accompanied by a decrease in oncotic pressure, may play a role in the development of this disease.

Hepatopulmonary syndrome can be seen in both ALF and chronic liver failure. It is thought to arise from microscopic shunting from arteriovenous dilations that occur in the pulmonary vasculature [13]. The precise mechanism is unknown; however, it is thought that the elevated levels of nitric oxide seen in patients with liver failure may mediate the abnormal vasodilation that occurs in the pulmonary parenchyma. The result is an overperfusion with maintenance of ventilation; a VQ mismatch occurs that ultimately leads to hypoxemia [14].

Cardiovascular and Hematologic System

As part of the pathophysiology associated with ALF, there is low systemic vascular resistance and a hyperdynamic circulation with elevated cardiac output. The pathophysiology is multifactorial but vasoactive substances are thought to mediate the process [15]. While the underlying pathophysiology may differ, hemodynamic variables appear very similar to those seen in sepsis and septic shock.

In the failing liver, there is an increase in splanchnic blood pooling that is associated with the increased resistance of flow through the liver. This results in increased shear stress in the splanchnic circulation that causes upregulation of endothelial nitric oxide synthase (eNOS) and ultimately nitric oxide (NO) production [15, 16]. There is further systemic vasodilation causing a low effective circulating volume and relative hypotension despite an overall elevated intravascular volume. The systemic baroreceptors are unloaded and there is a compensatory increase in cardiac output as well as activation of the renin-angiotensin-aldosterone system (RAAS) that may ultimately affect the renal system (Fig. 18.1) [15].
Fig. 18.1

Physiologic changes that occur in patients with liver failure

Patients with ALF usually present with varying degrees of coagulopathy. As the liver fails, there is decrease in the synthesis of factors involved in both coagulation and anticoagulation, specifically fibrinogen, prothrombin, protein C, protein S, and factors V, VII, VIII, IX, X, and XI. The end result is an increased in prothrombin and activated partial thromboplastin times as well as elevation of INR [17].

Overt bleeding is not typically seen, as there is a decrease in both coagulation and anticoagulation factors. However, mucosal bleeding from the oropharynx or the gastrointestinal mucosa can be frequently seen. This is compounded by the underlying platelet dysfunction that can occur in patients with liver failure.

Gastrointestinal and Endocrine Systems

Right upper quadrant pain, gastrointestinal bleeding, ascites, nausea, and vomiting can be seen in patients with ALF. These symptoms are nonspecific and can be multifactorial.

Patients with acute viral or autoimmune hepatitis may experience liver parenchyma inflammation as part of the normal response to infection. This leads to an increase in the overall volume of the liver. The liver capsule may be unable to accommodate acute volume changes, and stretching of it results in activation of pain receptors and right upper quadrant pain. Discomfort in this area can also be related to direct trauma causing bleeding.

Abdominal distention may be associated with ascites. The neurohumoral alterations are seen with ALF leading to excessive sodium retention and ultimately plasma volume expansion. This, combined with a decrease in the overall circulating proteins due to compromised liver function, leads to overflow of fluid into the peritoneal cavity [18]. Tense ascites can result in compromise of respiratory, renal, and cardiovascular function due to direct compression of the diaphragm and vasculature.

As part of its normal physiologic function, the liver is responsible for gluconeogenesis as well as glycogen storage. As liver function worsens, these two key metabolic functions are compromised. In up to 40 % of patients, hypoglycemia is seen and treatment is warranted [19].

Renal System and Electrolytes

Acute kidney injury can be present in 30–70 % of patients with ALF [20, 21]. The etiology can be variable: prerenal azotemia, drug toxicity, and acute tubular necrosis have all been implicated. Hepatorenal syndrome, especially type 1, has also been associated with the progression of this disease. Acute kidney injury can be divided into oliguric vs. anuric failure, with the latter making fluid management difficult in the critical care setting [15].

Accompanying this derangement we can also see electrolyte disturbances: hyperkalemia, hyperphosphatemia, hypophosphatemia, hypercalcemia, and hypomagnesaemia that can lead to secondary arrhythmias and mental status changes [22].

Lactic acidosis can be seen in patients with ALF. The accumulation of tissue lactate is multifactorial. The effective blood pressure is usually lower in those patients with liver failure. This causes a generalized tissue hypoxia that leads to the production of lactate. The compromised liver is unable to uptake and process the lactate, leading to its accumulation [23, 24, 25]. In addition, acute kidney injury can further contribute to the underlying acidosis due to failure of fixed acid clearance [22].

Infectious Disease

Kupffer cells can be found around the hepatic sinusoids. Because of their location, they are constantly exposed to gut bacteria and endotoxins. They play a key role in clearing these pathogens and in maintaining normal homeostasis. In patients with liver failure, their function is impaired, and there is an increased susceptibility to develop Gram-positive and Gram-negative bacterial infections as well as possible fungal and viral infections [26].

Hepatic encephalopathy has been linked to an increased incidence of infection [27]. Although the mechanism behind this has not been clearly elucidated, it is thought that CNS depression alters the immune system modulation. In ALF, there is also a change in the production as well as clearance of different cytokines in patients with liver failure and compromised neutrophil function. These problems will lead to decreased bacterial opsonization and clearance. These alterations ultimately contribute to the immunologic impairment [26, 27, 28].

Up to three quarters of patients with ALF will develop a bacterial infection. The organisms that are most commonly seen include Gram-negative-bacteria, Streptococcus, Staphylococcus, and Candida. They may develop a systemic inflammatory response syndrome (SIRS) that will be undistinguishable from noninfectious conditions including necrotic hepatocytes from the failing liver [29, 30, 31].

Other Systems

Jaundice and pruritus are common complaints of patients with ALF. Although not specific to liver failure, the presence of both symptoms should raise suspicion of compromised excretion of bilirubin by hepatocyte failure.

A normal by-product of the metabolism of heme, bilirubin is usually excreted in bile and urine. The liver is responsible for conjugating glucuronic acid with bilirubin in order to make a soluble compound. As a result, conjugated bilirubin passes into the colon and is eventually eliminated. In the failing liver, there is a severe compromise of the ability to metabolize and excrete bilirubin secondary to the undergoing cell necrosis. There is buildup of unconjugated bilirubin in the blood resulting in eventual deposition of these molecules in mucous membranes, skin, and conjunctiva, what is known as jaundice [32]. Because of the yellow color of the pigment, the physical appearance of the patient changes, directly correlating with bilirubin levels.

Besides bilirubin, there is also accumulation and deposition of bile acids in the skin. This has been associated with pruritus. Other mechanisms that may explain this symptom include the endogenous opioids theory which proposes that the liver failure patient has elevated opioid levels secondary to decrease clearance and metabolism. These molecules activate the mu opioid receptor which may produce pruritus [33, 34, 35].

Workup and Initial Management

As explained throughout this chapter, the management strategies for patients with ALF are different from those of patients that have chronic liver failure with an acute decompensation. It is imperative to determine what form of failure the patient is experiencing. For those with ALF, early recognition and transfer to a transplant center will improve outcomes and mortality.

On initial presentation, a patient’s mental status will be affected to different degrees; however it may deteriorate further. Getting a thorough history during the first encounter is therefore important as it can elucidate the possible cause of the acute failure.

The intensivist should review all medications that the patient ingested in the last 7 days. Specific questions about ingestion of acetaminophen should be asked. Dietary intake should also be explored, playing close attention to any exposure to mushrooms. Exact time of ingestion is key in order to determine treatment and further steps in management.

Social history should also be reviewed in detail. Recent travel to viral hepatitis endemic areas as well as contact with other patients that have required hospital visits should be evaluated. Focus on alcohol and drug use, sexual behaviors, and vaccination status can help determine the causative mechanism for the liver failure.

Past medical history plays a key role in determining if the patient has chronic liver disease or if they are experiencing an acute failure. A history of hepatitis, ascites, jaundice, asterixis, and gynecomastia and family history of a metabolic disorder favor chronic liver disease with an acute exacerbation. History of malignancy and lack of screening for colorectal cancer should also make the intensivist suspicious for metastatic malignancy. Physical exam may disclose important findings that can elicit cause. An effort to identify the clinical manifestations described previously should be done.

Laboratory values that should be routinely obtained are listed in Table 18.4.
Table 18.4

Laboratory exams that should be part of the initial evaluation of patients with acute liver failure

Infectious

White blood cell count

Hemoglobin and hematocrit

Platelet count

Hepatitis A IgM

Hepatitis B surface antigen

Hepatitis B surface antibody

Hepatitis B core antibody IgM

Hepatitis B e antigen

Hepatitis C antibody

Coagulopathy

Prothrombin time

Activated thromboplastin time

INR

Type and screen

Renal and metabolic

Serum electrolytes (Na, K, Cl, CO2, Mg, PO4, Ca)

Glucose

BUN and creatinine

AST

ALT

Alkaline phosphatase

Total bilirubin

Direct bilirubin

Albumin

Amylase

Lipase

Arterial blood gas

Serum lactate

Ammonia

Ceruloplasmin

Toxin

Acetaminophen level

Toxicology screen

Autoimmune

ANA

ASMA

Immunoglobulin levels

When testing for hepatitis B, it is important to evaluate for immunity (hepatitis B surface antibody), infectivity (hepatitis B e antigen), and the presence of an acute infection (hepatitis B core antibody IgM). Although hepatitis C can cause ALF, it is usually associated with chronic liver failure [36].

BUN and CO2 can usually be lower than reference values in patients with ALF. This is secondary to poor muscle mass as well as a respiratory alkalosis experienced by these patients. Presentation with concomitant renal failure will alter most serum electrolytes.

Elevation of liver enzymes can be indicative of acute hepatitis and ALF. However, values that are within reference range may be markers of poor prognosis as it may be reflective of decreased effective liver mass [26, 34].

Workup should be started on presentation, even if patient is going to be transferred to a liver center. Early identification of the etiology and early treatment can significantly improve outcome. It can also identify those patients that will need liver transplantation in order to treat their disorder.

If during the history and physical assessment a cause can be clearly identified, treatment should be started empirically. Waiting for laboratory values can be detrimental and result in further deterioration of the patient. Consultation with hepatology/gastroenterology, transplant surgery, and the intensivist should be done upon determination of liver failure of any cause.

Management

The development of ALF has very different etiologies as well as presentations. As such, the management may differ from patient to patient. Identification of the causative agent and treatment of it is important. However, supportive care in the intensive care unit is critical for ensuring a positive outcome.

Patients that have evidence of encephalopathy will require intensive care unit (ICU) admission and management while those with no neurologic derangement can be followed on a regular ward with close monitoring. Patients should have frequent checks of their coagulation parameters, arterial blood gases, complete blood counts, metabolic panels, serum aminotransferases, alkaline phosphatase, and bilirubin levels. Derangements warrant further investigation. Hemodynamic monitoring, precise fluid management, and monitoring for infections are all essential.

Encephalopathy, Cerebral Edema, and Intracranial Hypertension

The grade of hepatic encephalopathy guides the management and treatment of the neurologic system in ALF. This is because intracranial hypertension (ICH) and cerebral edema characterize the severity of patient presentation. Those with mild forms (grades I and II) very rarely develop these devastating complications while 25–35 % of patients with grade III and 65–75 % of those with grade IV present with ICH [11].

For those patients with grades I and II, frequent neurologic assessments should be performed to follow possible neurological progression. Maintaining the patient in a quiet environment helps minimize agitation. Sedation should be minimized; however, if needed minimal doses of short-acting benzodiazepines should be used [37]. For patients who present with or develop grade III and IV neurological symptoms, securing an airway should be the first treatment strategy followed by mechanical ventilation. For sedation, propofol should be used since there is evidence that it decreases cerebral blood flow and allows for frequent ongoing neurological assessment [38].

Intracranial pressure (ICP) monitoring devices are used in some ICUs in patients with ALF and grade III or grade IV encephalopathy [39]. The main reason for its use is the early identification of ICH and subsequent treatment. Also, not all patients present with Cushing’s trial of systemic hypertension, bradycardia, and irregular respirations. Several trials have shown that ICP monitoring can be performed safely and successfully be used to manage ICH [40, 41, 42]. However, no trial has demonstrated a survival benefit. Bleeding has been associated with the placement of monitors; however, recent literature reports that there is a decrease prevalence of this particular complication. The incidence of bleeding after placement of ICP monitor device has been less than 1 % [43].

CT scan of the brain should be considered in those patients with an acute mental status change and those with coagulopathy in order to rule out intracranial bleed. This imaging modality does not diagnose cerebral edema or ICH in all patients, and therefore, it is not needed in every case of encephalopathy. Patients at risk of encephalopathy should also have the head of their bed elevated at 30° [44], minimize ET suctioning, and minimize pain as these factors can lead to ICH [37].

For those patients with elevated ammonia levels (greater than 75 ug/dL) and ALF, administration of lactulose can lower the incidence of cerebral edema and decrease mortality [45]. Prior to prescribing this drug, the route of drug administration must be considered as the patient’s ability to tolerate PO intake may be compromised. Other compounds studied include L-ornithine L-aspartate but have failed to demonstrate any survival improvement [46].

Phenytoin has been proposed as a possible prophylactic measure to prevent cerebral edema. An initial study that involved evaluation of brain at autopsy showed that patients who were treated with prophylactic phenytoin had a decrease in cerebral edema [47]. Follow-up trials were unable to replicate these results and more importantly, there was no survival improvement when this agent was used prophylactically [48].

The administration of intravenous mannitol has been shown to transiently decrease cerebral edema and may be helpful in cases in which ICH is <60 mmHg [49]. A dose of 0.5–1 g/kg may be beneficial and it may be repeated if serum osmolality is below 320 mOsm/L. The use of hypertonic saline has also been suggested. There is a lower incidence of ICH in patients with ALF that are treated with hypertonic if it is used to achieve a serum sodium level between 145 and 155 mEq/L [50]. Use of hypertonic saline can be limited by renal failure. A newer treatment technique that has been proposed to prevent ICH is hypothermia. It is thought to mediate this benefit by preventing hyperemia [51]. Concerns regarding the use of hypothermia in the treatment of ALF include worsening coagulopathy and compromise of hepatocyte recovery [52].

Hyperventilation and use of corticosteroids have been proposed as a management option to reduce ICP. The former may achieve this goal via vasoconstriction. However, trials suggest that although there is a delay in the onset of cerebral herniation, there is no reduction in the incidence of cerebral edema and no survival benefit [53]. Hyperventilation should only be used after all other resources have failed.

Respiratory Management

While hypoxemia in patients with ALF arises from many causes, it is treated with supplemental oxygen. If the patient has grade III or IV hepatic encephalopathy, a definite airway should be established. During intubation, cis-atracurium is the agent of choice since it does not increase ICP [54].

Pleural effusions can be observed and may or may not be contributing to hypoxemia or other respiratory problems. The use of diuretics should be carefully considered as these patients are usually in a very delicate hemodynamic state. Overuse of diuretics can precipitate renal failure [34].

Hepatopulmonary syndrome (HPS) has been traditionally resistant to medical therapies [15]. Oxygen supplementation for hypoxemia is recommended. Transjugular intrahepatic portosystemic shunt (TIPS) has been reported to improve HPS; however, it is not currently recommended as its outcomes are variable [55, 56]. Liver transplantation is the only therapy that has been shown to improve oxygenation and decrease oxygen requirement [57]. The diagnosis of HPS should prompt immediate referral to a transplant center.

Cardiovascular and Hematologic Management

Decreases in blood pressure lead to compromised renal and brain perfusion. It is imperative to be attentive to blood pressure and heart rate values in order to ensure adequate hemodynamics and, most importantly, adequate perfusion. Patients with ALF should be resuscitated initially with crystalloid before considering vasoactive agents.

The generally accepted goal mean arterial pressure is 65 mmHg [58]. If after adequate volume resuscitation the patient is still hypotensive and not meeting blood pressure goals, vasopressors should be considered. Norepinephrine should be initiated and titrated to effect [59]. For resistant hypotension consideration to vasopressin should be given, although it should be used with caution as it has been associated with cerebral vasodilation and increased ICH [60, 61]. Terlipressin has also been suggested as adjuvant treatment but it is currently not available in the United States [60]. Other causes of hypotension resistant to vasopressor therapy should also be entertained including adrenal failure and severe acidosis.

During liver transplantation, ICH and hemodynamics improve immediately after hepatectomy, probably secondary to removal of vasoactive cytokines. Hepatectomy can improve these derangements for up to 48 h [62]. Hepatectomy is currently recommended only as a last resort and when a liver graft in the process of being delivered to the transplant institution [37].

Despite the derangements of coagulation laboratories in patients with ALF, their coagulation status remains in equilibrium and overall hemostasis. In the absence of bleeding, no correction of laboratory parameters should be performed [63]. Transfusion should be discouraged because treatment with FFP may precipitate pulmonary problems including hypoxia, and transfusion also prevents the use of INR as a marker of hepatocyte recovery [37].

If an invasive procedure is planned or if there is evidence of significant bleeding, correction of coagulopathy should be done. FFP can be used for this purpose; however, careful volume management should also be achieved. The use of plasmapheresis and recombinant activated factor VII (rFVIIa) can help in the correction of coagulopathy. rFVIIa has been proposed as it effectively corrects derangements without volume overload [64]. However, administration does carry the risk of myocardial infarction and portal vein thrombosis [65]. ALF has also been associated with vitamin K deficiency and it should be administered routinely in these patients [66].

Thrombocytopenia has also been reported in patients with ALF. Platelets should not be administered in the absence of bleeding. If the patient has platelet counts that are greater than 10,000/mm3, no prophylactic transfusion should be given [67]. If an invasive procedure is planned, platelets between 50,000/mm3 and 70,000/mm3 have been proposed, and in those bleeding, the intensivist should consider transfusion if platelets drop below 50,000/mm3 [67, 68].

Gastrointestinal and Endocrine Management

Bleeding from intestinal mucosa is rare but has been reported in patients with ALF. Histamine-2 receptor blockers have been used in critically ill patients as prophylaxis of gastrointestinal (GI) bleeding with great success [69]. Also, proton pump inhibitors (PPI) have contributed to the reduced incidence of upper GI bleeding in patients with liver dysfunction [70]. It is therefore recommended that ALF patients are started on prophylaxis while in the ICU.

Nutrition can be compromised in patients with ALF; therefore, enteral feedings should be started early unless there are contraindications. There is no evidence that using branched-chain amino acid formulas has benefits over other enteral tube feeds [71]. Protein supplementation should not be restricted but rather limited to 60 g per day in most patients. If gastrointestinal feeding is contraindicated, parenteral nutrition may be considered. There is also evidence that the risk of GI bleeding is reduced in patients that are on enteral feeding [72].

Hypoglycemia should be actively treated in patients with ALF. The intensivist should consider adding dextrose to crystalloids in the form of D5. If hypoglycemia is severe, central replacement with D20 concentration should be used. Frequent glucose checks should be performed in order to assess the response to glucose administration. Improvement and eventually weaning can be achieved in those patients that experience hepatocyte recovery.

Right upper quadrant pain can be treated with narcotics. Judicious doses should be used as metabolism of medications can be compromised with the failing liver [37]. The management of ascites will be discussed with chronic liver failure.

Renal Management

Close urine output monitoring is paramount in patients with ALF. Hemodynamic changes and alterations in the cardiovascular system make the kidneys susceptible to injury. Insertion of a urinary catheter should be performed upon determination of hepatic failure.

Besides serum electrolytes, measurement of urinary sodium and creatinine is necessary. High or normal urine sodium may indicate the presence of acute tubular necrosis, while a low urine sodium may indicate prerenal azotemia or hepatorenal syndrome. Several electrolyte derangements may occur and correction should be attempted. Accumulation of lactate may result from tissue hypoxia and combined with renal failure may cause life-threatening acidosis.

Renal replacement therapy may be necessary in these patients. When indicated, continuous dialysis should be used as studies have shown that it provides cardiovascular as well as intracranial pressure stability when compared to intermittent dialysis [73].

Infectious

The development of an infection in a patient with ALF has been associated with worsening encephalopathy and cerebral edema. Also, the presence of bacterial or fungal infections may compromise any attempts at performing a liver transplantation. Because of the impact that it has, prophylactic antimicrobials have been proposed as a prevention strategy for these patients [74].

Prophylactic antibiotics have been used and shown to decrease the incidence of infections in patients with ALF. In a prospective control trial by Rolando N et al., patients with fulminant liver failure were randomized to receive either selective parenteral and enteral antimicrobials vs. no treatment until clinically indicated. 104 patients were included in this study. Thirty-four percent of those patients randomized to receive prophylactic antibiotics developed an infection compared to 61 % of those that were treated when clinically indicated (p < 0.005). However, this did not translate into a survival benefit [75]. It is currently recommended that if no prophylactic antibiotics are used, periodic sputum, urine, and blood cultures are performed to determine if there are bacterial infections [37].

The use of antifungals has also been studied [76]. It is routine practice of the authors to use prophylactic enteric fluconazole in patients that are expected to be in the ICU for more than 3 days, given that there is a decrease in fungal infections in high-risk critically ill surgical patients [77].

It is paramount to perform an infectious workup to any patient with liver failure that develops a change in mental status as it may be a change precipitated by infection.

Specific Management

Acetaminophen Toxicity

The most common cause of ALF in the United States is acetaminophen (paracetamol) toxicity [78]. Over-the-counter availability and the fact that it can be found in combination with other medications make it the cause of voluntary or involuntary overdoses that compromise liver function and may result in fulminant liver failure.

Acetaminophen is usually taken orally and absorbed via the gastrointestinal system. Its half-life is usually 2–4 h with one exception being extended release preparations in which it is increased to more than 4 h. Total doses should not exceed 4 g per day. Ingesting doses less than 7.5 g per day is unlikely to result in acute toxicity; however, it can vary depending on underlying liver function [79].

The metabolism of acetaminophen is performed in the liver. Most of the compound, approximately 90 %, is conjugated with sulfate or glucuronide and excreted in the urine. Five percent of the remaining medication is excreted unchanged in the urine. The remaining acetaminophen is subject to metabolism by the cytochrome P450 pathway. It is converted into N-acetyl-p-benzoquinoneimine (NAPQI), a highly reactive and toxic compound that is immediately conjugated with hepatic glutathione and excreted in the urine.

When glutathione levels drop below 20 % physiologic levels, NAPQI forms covalent bonds via cysteine groups with hepatic molecules and proteins, leading to irreversible hepatocyte damage. A decrease in glutathione levels, enhanced cytochrome P450 activity secondary to medication use, acetaminophen overdose, or decreased liver function from chronic disease make patients more susceptible to developing toxicity.

The clinical presentation of acetaminophen toxicity can be divided into four different stages (Table 18.5).
Table 18.5

Clinical stages of acetaminophen toxicity

Stage

Onset

Symptoms

Laboratory values

Stage I

0–24 h

Nausea, vomiting, malaise

Elevated acetaminophen levels

Stage II

24–72 h

RUQ pain, nausea, vomiting

Elevated AST, ALT, ALP, total bilirubin, lactate, and creatinine

Stage III

72–96 h

Encephalopathy, jaundice

Elevated AST, ALT, ALP, total bilirubin, PT, INR, PTT, lactate, and creatinine

Hypoglycemia

Stage IV

5 days

Improvement in confusion, resolution of GI symptoms

Normalization of above values

Stage I includes a series of nonspecific GI symptoms that start shortly after ingestion. No liver abnormality can be seen. During stage II, there is usually transaminitis with a high AST/ALT ratio. Stage III is characterized by the clinical evidence of liver failure and, in some patients, renal failure. Mortality is higher at this stage. Those patients that survive this stage progress to stage IV in which there is normalization of most of their lab derangements.

Because patients may not show symptoms up to 24 h after ingestion, it is very important to obtain a detailed history. Standard workup should be initiated as discussed previously. Contacting poison control will help coordinate efforts to treat and eventually transfer patient to a liver center [37].

In order to determine the severity of the poisoning, a serum acetaminophen concentration (4 h post ingestion or later) should be plotted against time on the modified Rumack-Matthew nomogram (Fig. 18.2) [80, 81]. Patients with acetaminophen levels below the treatment line can be discharged home after psychiatric and social evaluation. All other patients should be admitted to the intensive care unit [82].
Fig. 18.2

Modified Rumack-Matthew nomogram. The X axis represents the number of hours after ingestion of acetaminophen and the Y axis the concentration of the medication in the blood. Levels are measured at least 4 h after ingestion. The solid line represents concentrations that are toxic. The dotted line represents a 25 % reduction in the toxic levels and it accounts for possible errors in acetaminophen assays. If the level is above the dotted line, NAC therapy should be started. If below, the patient can be safely discharged after medical evaluation (Data from Rumack and Matthew [80] and Rumack [81])

For those patients that ingested a single dose of acetaminophen of more than 7.5 g less than 4 h prior to presentation, administration of activated charcoal should be considered. Review of several small studies demonstrated that activated charcoal was the best available option to reduce absorption [83, 84, 85]. Also, there is a decreased risk of developing liver injury if charcoal is given prior to other forms of treatment [85]. If patient has an unstable airway, charcoal should not be administered until the airway is controlled.

The antidote of choice for acetaminophen toxicity is N-acetylcysteine (NAC). The exact mechanism of action is unclear; however, it appears to restore glutathione levels [86, 87]. Indications for administration include a serum acetaminophen level above the treatment line, ingestion of more than 7.5 g, serum acetaminophen level >10 mcg/mL if time of ingestion is unknown, evidence of liver injury, and a history of acetaminophen ingestion regardless of time of ingestion [86, 87, 88].

Oral and IV administration of NAC have been studied and both appear effective [86]. The main factor determining the mode of treatment should be the mental status of the patient. If the patient is confused or has evidence of encephalopathy, oral administration should be avoided. If the oral protocol is used, a loading dose of 140 mg/kg should be given followed by 17 doses of 70 mg/kg given every 4 h. If IV NAC is used, a loading dose of 150 mg/kg is given over 1 h. A second dose of 50 mg/kg is then given over 4 h and finally a third dose of 100 mg/kg is given over 16 h.

An alternative to NAC is hemodialysis. This method effectively removes acetaminophen [89]. However, because of the effectiveness of NAC, it should be reserved for cases in which the antidote is not available.

Acetaminophen toxicity is best managed in a multidisciplinary setting with assistance from hepatology and surgery teams.

Amatoxin Intoxication

Ingestion of poisonous mushrooms can lead to lethal emergencies including ALF. Amanita phalloides, Amanita bisporigera, Amanita verna, and other mushroom species may cause ALF. These mushrooms do not express repulsive smells or tastes, and they can be found throughout midsummer in moist oak forests.

Alpha-amanitin is the amatoxin responsible for liver failure. After gastrointestinal absorption, enterohepatic circulation is responsible for transportation into the liver, where via active transport it concentrates in hepatocytes. The toxin will bind to RNA polymerase and inhibit protein synthesis, ultimately leading to apoptosis [90].

The clinical presentation of patients that ingest amatoxin includes an initial asymptomatic period of a few hours. This is followed by gastrointestinal symptoms that include abdominal pain, nausea, vomiting, and diarrhea that can be bloody. Liver enzymes will be elevated and will continue to increase. One to two days after ingestion, the second phase of the presentation begins with an apparent recovery with continuing elevation of AST and ALT. In severe poisonings, coagulopathy and possible DIC and renal failure may ensue. The last phase includes ALF and typically starts 3 days after ingestion. Hypoglycemia and multi-organ failure can be seen.

Workup of a patient with suspected amanita ingestion should proceed as indicated earlier in this chapter. Detection of amatoxin can be performed in urine samples using enzyme-linked immunoassay (ELISA); this test is not readily available in all institutions and awaiting results should not preclude supportive treatment [91].

Supportive treatment should be started immediately after presentation. In addition, an effort to minimize toxin absorption should be attempted. Activated charcoal can bind amatoxin, and if given in repeated doses, it can reduce mortality significantly by increasing elimination via gastrointestinal tract [37].

Medications that can inhibit uptake of this toxin have also been described. These include penicillin G and silymarin. The former is given as a continuous infusion and has been show to decrease mortality [92, 93]. The latter is a more potent inhibitor and is available in IV and PO formats. Silymarin has been shown to minimize damage to hepatocytes [92, 94, 95].

NAC has also been used in the treatment of amatoxin intoxication. Mortality appears to improve with implementation of protocols very similar to those of acetaminophen toxicity [92, 96].

Wilson’s Disease

Wilson’s disease poses a different presentation from frank ALF. It normally occurs in the background of chronic liver disease that has been unrecognized. Treatment varies when presentation of this disease is acute, and this will be the focus of this section.

A genetically recessive disease, it is estimated that 2–3 % of ALF cases are related to Wilson’s disease [97]. The majority of copper that is ingested is transported into the liver where it is incorporated into enzymes and copper-binding proteins (ceruloplasmin). Excess copper is combined with apometallothionein and excreted into bile. In Wilson’s disease, the incorporation into ceruloplasmin is compromised and copper is accumulated in the liver. As the disease progresses, other organs are affected. Besides parkinsonian movements and tremors, Kayser-Fleischer rings, psychiatric alterations, and renal problems, Wilson’s disease will present with liver disease: cirrhosis, chronic failure without cirrhosis, and acute liver failure.

Laboratory workup should include serum ceruloplasmin, which is usually low, as well as serum copper level (above 200 mcg/dL) [97]. In patients with evidence of ALF, low transaminases, low alkaline phosphatase, hypokalemia, glycosuria, hypophosphatemia, and renal tubular acidosis, the diagnosis of Wilson’s disease should be considered.

In patients with acute failure, the aim should be to remove copper. Hemodialysis and peritoneal dialysis can successfully achieve this goal [98]. Albumin dialysis and the molecular absorbent recirculating system (MARS) device have also been used with promising results [99, 100]. Penicillamine, zinc, and other medications used for treatment of Wilson’s disease do not play a role in ALF.

Viral Hepatitis

The development of ALF from viral hepatitis may occur after acute infection; Ostapowicz et al. estimated that the etiology of 12 % of those patients that were diagnosed with ALF was viral hepatitis [101]. Most of the clinical deteriorations that are seen in patients with this etiology of disease are related to chronic liver infection. ALF is more common with hepatitis B but it can also present in patients with hepatitis A, C, and E [34].

Presentation of viral hepatitis is described in four phases. Phase 1 is characterized by lack of symptoms but changes in laboratory studies that may be suggestive of viral hepatitis. Phase 2 marks the development of symptoms that include nausea, vomiting, abdominal pain, arthralgias, and possible fevers. The next phase includes clinical characteristics of ALF including right upper quadrant pain, becoming icteric, and possible coagulopathy. The last phase, 4, leads to the normalization of laboratory values and resolution of symptoms.

Diagnosis of viral hepatitis relies on serum laboratories. Acute hepatitis A is diagnosed by the presence of IgM antibody against the hepatitis A virus. Presence of IgG implies previous infection and resolution.

Hepatitis B has several important antigens and antibodies. Hepatitis B surface antigen (HBsAg) is usually found in patients with acute infection. A second antigen, associated with infectivity, is hepatitis B e antigen. The first antibody that can be detected in patients acutely infected and that indicates acute presentation of disease is IgM anti-HBcAg. Resolution of acute infection and recovery results in IgG antibodies against this antigen. Finally, anti-HBsAg appears in the serum several months after infection, indicating resolution. They will also be found in patients with hepatitis B vaccine.

IgG anti-hepatitis C virus has been used to diagnose exposure to this viral infection. It can usually be found in the serum several months after an acute infection and contrary to anti-HBsAg, it does not confer immunity to Hepatitis C. Use of ELISA and RIBA testing for diagnosis has fallen out of favor. HCV RNA PCR assays were developed in order to detect the presence of the virus. It has been successful in not only establishing the diagnosis but also the presence of an acute infection.

Treatment of acute hepatitis A is limited to supportive care as there are no medications that improve outcome. Hepatitis B treatment usually follows the same principles as most antiviral therapy is directed toward treatment of chronic disease. However, recent studies have suggested that acute hepatitis B may benefit from administration of lamivudine [102]. Finally, acute hepatitis C has been treated with IFN therapy with resolution of HCV RNA after several months of treatment [103].

Ischemic Hepatitis

Low perfusion pressure to the liver may result in clinical manifestations of ALF known as ischemic or hypoxic hepatitis. It is an uncommon cause of liver failure, with a prevalence of 1 per 1,000 hospital admissions [104]. This can be a direct consequence of global hypoperfusion, hemodynamic instability, direct vascular occlusion during surgical procedures, hepatic artery disease (occlusion, dissection, thrombosis) in patients with portal vein thrombosis, or hepatic sickle cell crisis [105]. Hepatocytes in zone 3 become ischemic and eventually necrotic leading to liver insufficiency.

Prognosis of ischemic hepatitis is poor. Raurich et al. described an in-hospital mortality of 61.5 % in all patients that were diagnosed with this disease process. In those patients with concomitant septic shock and those that experienced cardiac arrest, mortality rates were higher, at 83.3 % and 77.7 %, respectively. Risk factors for mortality included an elevated INR, need for renal replacement therapy, and diagnosis of septic shock. Non-survivors were more likely to be on vasopressors and to require mechanical ventilation [106].

Patients with hepatitis secondary to shock present with several symptoms related to their hemodynamic instability including altered mental status, respiratory distress, severe hypotension, and renal failure. Patients with a history of cardiac compromise may present with nausea, vomiting, right upper quadrant pain, and malaise. Up to 14 % of patients with septic shock will also have ischemic hepatitis, presenting with fevers and severe hypotension [106].

Laboratory examination reveals elevated aminotransferase levels, usually above 1,000 IU/L. The ratio of serum alanine aminotransferase to LDH less than 1.5 suggests ischemic hepatitis [107]. If hypoperfusion is chronic in nature, synthetic function may be preserved and coagulation studies may be normal; however, in acute cases, there is severe derangements that continue to progress with time. If ischemic hepatitis is suspected, a right upper quadrant ultrasound with Doppler should be immediately performed as it may reveal the etiology of the insufficiency.

There is no specific treatment for ischemic hepatitis. Management is centered around restoring cardiac output and reestablishing hepatic perfusion. Appropriate resuscitation is necessary. Excessive fluid administration may lead to vascular congestion which can in turn compromise perfusion of hepatocytes and aggravate the presentation. Judicious use of diuretics should be exercised as diuresis may exacerbate hypoperfusion and therefore liver failure. Intensivists should rule out ischemic hepatitis in any patient that presents with septic shock and has elevated aminotransferases [106]. Prompt recognition of hypoperfusion state may lead to early intervention and possible better outcomes.

Chronic Liver Disease

Definition, Epidemiology, and Causes

Continuous hepatic injury that persists for more than 6 months is considered chronic liver disease (CLD). The liver parenchyma suffers continuous inflammation and potential destruction. The hepatic insult does not only result in damage but also in attempts of repair. Ultimately this leads to a broad spectrum of clinical manifestations including fibrosis, cirrhosis, and hepatocellular carcinoma. These changes are accompanied by alterations in serum liver function tests and can include physical exam finding suggestive of physiologic alterations.

In the United States, the most common causes of cirrhosis leading to liver transplantation are alcoholic liver disease, chronic viral hepatitis, and nonalcoholic liver disease (Table 18.6) [108]. This last etiology has increased significantly in incidence. Most patients are generally asymptomatic until decompensation occurs, making the calculation of prevalence difficult. Approximately 49,500 deaths in 2010 where associated with CLD [109].
Table 18.6

Causes of chronic liver disease

Infectious

Chronic hepatitis B

Chronic hepatitis C

Brucellosis

Syphilis

Echinococcosis

Schistosomiasis

Drugs and toxins

Alcohol

Amiodarone

Isoniazid

Methotrexate

Metabolic (acquired and genetic)

Nonalcoholic fatty liver disease (NAFLD)

Hemochromatosis

Wilson’s disease

α1-Antitrypsin deficiency

Vascular

Right heart failure

Veno-occlusive disease

Hereditary hemorrhagic telangiectasia

Other

Primary biliary cirrhosis

Primary sclerosing cholangitis

Autoimmune hepatitis

Clinical Manifestations

Patients with CLD may present with compensated or uncompensated hepatic failure. The former may be asymptomatic prior to evaluation, but patients usually report nonspecific symptoms such as weight change, fatigue, and lack of appetite. Those patients with an acute decompensation may show signs of active bleeding, confusion, and skin changes. Because of the broad spectrum of the disease, presentation will vary between different patients. Due to similar underlying pathophysiology, symptoms and findings may be similar to those described previously during the acute liver failure presentation.

Nervous System

Patients with CLD may present with varying degrees of hepatic encephalopathy. Classification and underlying pathophysiology are similar to those described previously in the ALF section. An acute exacerbation with an underlying chronic liver dysfunction can cause rapid progression from confusion to coma.

Respiratory System

Shortness of breath, dyspnea, and other nonspecific respiratory symptoms may also be reported. As with acute dysfunction, the etiology may be of infectious, metabolic, or of cardiac etiology. Hepatopulmonary syndrome can also play a role in underlying hypoxemia [15]. The mechanisms that lead to the respiratory derangements in CLD are similar to those described in acute liver compromise.

Cardiovascular and Hematologic System

Figure 18.1 explains the molecular mechanism behind the underlying decreased effective perfusion pressure seen in patients with liver failure. As a result, patients will have a lower than baseline blood pressure, with some of them transitioning from hypertensive to normotensive.

The cardiac output in patients with liver disease is usually high; however it is important to understand that myocardial cells are actually depressed from exposure to the changes in cytokines and other molecules. There is a slightly elevated heart rate that compensates for the depression and overall results in increase cardiac output, in a normal-sized man, often in the range of 10–12 L/min [15].

Patients with CLD may present with anemia, leukopenia, thrombocytopenia, and coagulopathy [110]. The pathophysiology behind anemia is multifactorial, and it may include episodes of gastrointestinal bleeding associated with portal hypertension and coagulopathy. There may also be nutritional deficiencies such as folate deficiency that can lead to compromised production of red cells and vitamin K deficiency that can lead to decreased production of coagulation factors [17]. Aplastic anemia, hypersplenism, and hemolysis may contribute to the anemia experienced by patients with chronic failure [111].

Thrombocytopenia is associated with portal hypertension: an enlarged spleen can sequester the majority of the circulating platelet mass and lead to a decrease platelet count. It has also been described that patients with liver disease have decreased levels of thrombopoietin that will also lead to thrombocytopenia [112].

Gastrointestinal and Endocrine Systems

Patients experiencing CLD can present with abdominal distention and pain, anorexia, nausea, and vomiting. Physical exam may also show ascites, hypogonadism, hypersplenism, and evidence of gastrointestinal (GI) bleeding such as hematemesis, hematochezia, and melena. GI bleeding can be the result of mucosal injury and thrombocytopenia or a more severe and life-threatening event such as variceal hemorrhage. An umbilical hernia may be seen when ascites becomes prominent.

For those patients with CLD, there are significant changes in the hemodynamics of the portal vein. The hepatic microcirculation, sinusoids, undergoes constriction secondary to architectural changes that compromise the lumen of these systems. Furthermore, there is active contraction of myofibroblasts and active smooth muscle secondary to cytokine changes (increased levels of intrahepatic ET-1) that cause even more restriction in the radius of these sinusoids [113, 114]. These changes lead to an increase in portal pressure.

A second factor that impacts the pressure of the portal vein is the increased in blood flow in the portal vein. As shown in Fig. 18.1, there is a splanchnic arteriolar vasodilation that leads to increase venous outflow and, therefore, increased flow that results in further increases of portal pressure and eventually portal hypertension (PHT) [15].

The elevated blood pressure and flow are partially relieved by decompressing the inflow into the portal vein into systemic collaterals. The esophageal submucosal veins are a preferred method of decompression and may result in esophageal varices. As flow increases so does the vessel radius [115]. This ultimately leads to an increase in wall tension that may end up in rupture and variceal bleeding [114, 116].

Ascites is also closely related to PHT. In fact, patients without evidence of PHT do not develop ascites even in the presence of cirrhosis. The threshold for formation of ascites appears to be 12 mmHg at the level of the portal vein [117]. As a response to this increase in pressure, there is splanchnic vasodilation leading to a decrease in effective arterial blood volume that is mediated by several molecules including nitric oxide (NO). There is subsequently an activation of the renin-angiotensin-aldosterone system that increases renal sodium retention and plasma expansion that ultimately leads to accumulation of fluid in the peritoneal cavity [118]. The low levels of circulating protein secondary to liver compromise may also favor the formation of ascites.

On physical exam, we can find evidence of PHT by placing a stethoscope over the epigastrium. If there are collateral connections between the portal system and the umbilical vein, a murmur can be auscultated. This finding is known as Cruveilhier-Baumgarten murmur.

Dizziness, diaphoresis, and overall malaise may be reflective of underlying hypoglycemia. Patients with CLD undergoing an acute exacerbation may see decreased levels of circulating glucose with corresponding changes in neurologic exam.

Male and female patients with CLD can report abnormalities related to infertility, impotence, and in the case of women chronic anovulation. Physical exam may show evidence of testicular atrophy in men, while ultrasound and other imaging may show atrophic ovaries and uterus. There are several possible mechanisms that explain these findings. The increased levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) observed in some patients suggest the primary dysfunction of the testicles or ovaries. An alternative mechanism suggests suppression of the hypothalamic-pituitary function. The dysfunction may be secondary to decreased clearance of estrogen, testosterone, prolactin, and other substances [119, 120].

Male patients with CLD may complain of loss of male pattern pubic hair, chest and axillary hair loss, and gynecomastia. This finding is thought to be related to an overall increase in estradiol: the adrenal glands produce and increase quantities of androstenedione that undergoes aromatization into estrone and eventually to estradiol [120].

Renal System

Similar to patients with ALF, patients with CLD can present with renal pathology. These may manifest as decreased urine output, arrhythmias, generalized body edema, and overall malaise. Most of the changes are associated with the underlying liver dysfunction.

In hospitalized patients with CLD, it is estimated that approximately 10 % of them will develop hepatorenal syndrome (HRS). The pathophysiology of HRS follows the development of PHT. As explained in Fig. 18.1, there is dilation of the splanchnic circulation, leading to a decrease in perfusion pressure. The response is cardiac compensation as well as activation of the renin-angiotensin-aldosterone system. There is also vasoconstriction mediated by the sympathetic nervous system. These changes ultimately lead to low renal perfusion and a significant decrease of the glomerular filtration rate [16].

Electrolyte abnormalities can accompany the changes that are seen on the renal system. Hyperkalemia, hyperphosphatemia, and hyponatremia can be detected in serum electrolytes. Symptoms may be variable and depend not only on severity of derangement but acuity. Dizziness, weakness, and palpitations may be reflections of these abnormalities.

Infectious Disease

CLD leads to acquired immune deficiency and makes these patients prone to developing infections. The mechanism by which the immune response is compromised includes the deficiency of serum complement [121] as well as the compromised activity and function of phagocytes such as macrophages, PMNs, and Kupffer cells [122, 123]. Certainly, the presence of fevers should make the intensivist suspicious for an infectious process and further investigation is warranted in order to determine additional symptoms that may guide further treatment. However, patients who present with decompensated liver failure may have an infection causing the decompensation. Thus, suspicion for the presence of infection should be high, and the threshold for obtaining cultures is low in any patient with liver failure who is acutely ill.

Abdominal pain that worsens and fevers should raise the suspicion for spontaneous bacterial peritonitis (SBP) in those patients with evidence of ascites. Up to 30 % of these patients may develop SBP [124]. Patients with cirrhosis have an increased intestinal permeability as well as altered intestinal motility. This may lead to the bacterial overgrowth and infection of ascites [125]. The most common organism seen is Escherichia coli; however, other organisms have also been described [126]. Typically SBP is monomicrobial and a polymicrobial infection should prompt consideration of a perforated viscous.

Other Systems

Similar to ALF, skin and urine color can change in patients with CLD. The increase in bilirubin secondary to compromised liver function leads to the accumulation in the skin leading to jaundice as well as dark appearance of urine. These changes are usually undetectable if the serum bilirubin is less than 2 mg/dL.

Another change that can be appreciated in the skin of patients with CLD includes palmar erythema. It is thought to be the consequence of altered sex hormone metabolism which may lead to capillary vasodilation [127].

Careful examination of the skin can also reveal vascular lesions characterized by the presence of a central arteriole with surrounding smaller vessels. These are called spider angiomata and their appearance is related to an increase in estradiol levels. The number as well as size of these lesions is related to the severity of liver disease although they are not specific for it [128].

As an additional route to decompress the portal vein during PHT, the umbilical vein may open leading to shunting into abdominal wall veins. These vessels engorge significantly making them very easy to identify during physical exam. This finding is known as caput medusa.

Workup and Initial Management

Initial workup and management of patients with CLD should begin with a thorough history. Onset of symptoms and identification of disease progression helps determine the pathophysiologic manifestations of the disease. Previous medical diagnosis including viral hepatitis should be assessed. A thorough review of all medications that the patient takes can help identify potential additional mechanisms of liver injury. Hospitalizations and transfusions should be reviewed.

Social history including exposure to high-risk behaviors such as intravenous drug use and alcohol abuse should be performed. Family history of liver disease and personal history of malignancy (including oncologic treatment and surveillance studies) also play a key role in the development of disease and should be explored.

A complete physical exam should be performed and an attempt to determine if any of the clinical manifestation discussed previously are present. The exam should include neurologic, rectal, and skin exam. Assessment of vital signs in order to identify possible hypotension, hypoxemia, as well as end-organ perfusion should be performed.

There is no serologic test that can diagnose CLD accurately. Laboratory abnormalities that are identified could be related to ALF or another etiology with some degree of liver dysfunction. Besides serologic tests, evaluation of the degree of liver fibrosis and additional characteristics of CLD can be investigated with radiologic studies.

The initial serologic studies that are performed as well as initial management are similar to those described in Table 18.4 in the ALF section. In addition, studies from ascitic fluid should also be performed when it is desired to identify etiology of fluid and possibility of infection. After paracentesis with removal of 50 mL of ascites in a sterile fashion, the intensivist should send the fluid for cell count, cytology, albumin, total protein, triglycerides, amylase, adenosine deaminase, as well as culture [129]. This should be accompanied by a serum albumin in order to calculate the serum-ascites albumin gradient (SAAG). This is done by subtracting the albumin in the ascitic fluid from the serum value. Based on such studies, the etiology of ascites can be determined (Table 18.7).
Table 18.7

Ascitic fluid studies and etiology of disease

Chylous ascites

Triglycerides

Peritoneal tuberculosis

Adenosine deaminase

Pancreatic ascites

Amylase and protein

Spontaneous bacterial peritonitis

Cell count

Culture

Malignant ascites

Cytology

SAAG >1.1 g/dL

Portal hypertension

SAAG <1.1 g/dL

Nephrotic syndrome

Tuberculosis

Pancreatic ascites

Malignancy

Imaging studies that are routinely used include ultrasonography (US), CT scan, and magnetic resonance imaging (MRI). US can help identify morphologic changes such as nodularity. With Doppler US, patterns of flow as well as possible occlusions can be identified. CT and MRI are able to identify nodularity and changes in volume of liver mass (hypertrophy or atrophy) as well as assess the portal vasculature [130]. Evaluation of collateral circulation, varices, and tumors can also be performed. Since US does not use contrast, this can be very helpful in those patients with renal compromise [131, 132].

If after a thorough workup, the diagnosis of CLD cannot safely be established, liver biopsy should be considered. Identifying changes consistent with CLD may be very beneficial as it may prevent delays in therapy and potential worsening of the patient [133, 134, 135]. Surgery and interventional radiology teams should be involved in order to determine the safest and least invasive method that can render a diagnosis.

Suspicious findings for CLD should prompt consultation with hepatology/gastroenterology and transplant surgery in order to determine if the patient will benefit from additional therapies and workup including possible transplantation.

Evidence of encephalopathy, compromised ventilation, hypotension, hypoperfusion, active bleeding, sepsis, and SBP should prompt admission to the ICU. Consideration of additional hemodynamic monitors such as an arterial line and central access may be considered in every patient. A Foley catheter should be placed in all patients with hemodynamic instability or with poor renal function but avoided in those with anuria to prevent a urinary tract infection.

It is also helpful to classify the severity of liver disease. The Child-Turcotte Pugh (CTP) classification divides patients into three groups based on serum labs and clinical presentation. It can help in determining possible surgical treatments or additional therapies [136, 137]. This specific scoring system is presented in Table 18.8.
Table 18.8

Child-Turcotte-Pugh (CTP) classification

Measurement

Points

1

2

3

Albumin (g/dL)

>3.5

2.8–3.5

<2.8

Bilirubin (mg/dL)

1–2

2–3

>3

Ascites

Absent

Slight

Moderate

Encephalopathy grade

None

1 and 2

3 and 4

PT

1–4

4–6

>6

or

INR

<1.7

1.7–2.3

>2.3

Another classification system that is used for the allocation of organs in the Unites States is the model for end-stage liver disease (MELD). It consists of a formula that will assign a score to a patient and that accurately predicts mortality within 3 months. The formula is based on three laboratory values (bilirubin, INR, and creatinine) and it is modified by etiology. The formula is shown below [138]:
$$ \begin{array}{c}\mathrm{MELD}=3.78 \times \ln \left(\mathrm{serum}\kern0.5em \mathrm{bilirubin}\ \left(\frac{\mathrm{mg}}{\mathrm{dL}}\right)\right)+11.2 \times \ln \left(\mathrm{I}\mathrm{N}\mathrm{R}\right)+9.57\\ {} \times \ln \left(\mathrm{serum}\kern0.5em \mathrm{creatinine}\ \left(\frac{\mathrm{mg}}{\mathrm{dL}}\right)\right)+6.43 \times \mathrm{etiology}\end{array} $$

If the disease process is alcohol, 1 is assigned to etiology. If the liver failure is secondary to a cholestatic process, 0 is assigned instead. Several factors can modify the calculated MELD score for allocation purposes, and these include dialysis and the presence of hepatocellular carcinoma.

The CTP and MELD system have been compared in several studies in order to determine which provides a better answer to prognosis for patients. Although some studies show superiorities of MELD, others show no difference and good predictions with both systems [139, 140, 141, 142]. A systematic review, suggested that the MELD was better for predicting 3-month mortality but otherwise the systems were similar [143]. Because of its use with United Network for Organ Sharing (UNOS) lists for allocation of organs, MELD has become more popular.

Management

Encephalopathy

Hepatic encephalopathy (HE) is a diagnosis of exclusion, and therefore, an effort to identify other etiologies of altered mental status should be performed. It is also necessary to determine the precipitating event leading to the neurologic derangement which includes bleeding, renal failure, electrolyte abnormalities, changes in diet, and changes in medication [144].

Treatment principles are similar to those described in the ALF section. They should be based on supportive care, attempts to correct precipitating factors, minimizing GI nitrogen intake, and establishment of therapy.

Admission to an ICU is important as patients with HE need constant neurologic assessments for progression or resolution. For grade III and grade IV HE, establishment of definite airway should be the first step in management. Laboratory studies are key in order to identify possible precipitating events.

A decrease in nitrogen production as well as nitrogen delivery should be attempted with medication. The most common therapy used is lactulose, which reduces the absorption of ammonia. Twenty-five milliliter should be given twice a day and should be titrated to achieve two soft bowel movements [145].

Rifaximin has also been used as an add-on therapy to lactulose. It is an antibiotic with activity against Gram-positive and Gram-negative aerobes and anaerobes. The usual dose is 400 mg three times a day. Trials have shown benefit in the treatment of HE when rifaximin is used in addition to lactulose [146]. Another antibiotic that has been use is neomycin. This alternative treatment has been used for the treatment of overt hepatic encephalopathy [147]. However, because it has been associated with complications such as ototoxicity and nephrotoxicity, neomycin is used less commonly today [145].

An assessment of nitrogen intake by assessing a patient’s diet is also very important. If a patient’s HE is unresponsive to the therapies described above, oral branched-chain amino acids (BCAA) should be considered in an attempt to reduce the hepatically metabolized nitrogen load. A recent meta-analysis showed that BCAA-enriched formulations may be beneficial in some patients with HE and CLD [71]. The daily protein intake should be 1.2–1.5 g/kg/day as severe restriction may be detrimental in the catabolic state of CLD [145].

Ascites

The first step in management of a patient with CLD and ascites should be sodium restriction to no more than 2,000 mg per day [129]. This should also be accompanied by oral spironolactone and possibly furosemide in order to perform natriuresis while maintaining normokalemia. Spironolactone inhibits sodium reabsorption in the distal tubule and collecting ducts but it can lead to gynecomastia and hyperkalemia. Furosemide is a loop diuretic and inhibits the luminal Na-K-2Cl symporter causing natriuresis and also hypokalemia when used alone. Combination therapy has been used more effectively in achieving sustained results. If the serum sodium is less than 125 mmol/L, fluid restriction to no more than 1.2 L per day should also be done [148].

For those patients that are not responsive to diuretic therapy, serial paracenteses can be performed in order to relieve symptoms [149]. In carefully selected patients, transjugular intrahepatic portosystemic shunt (TIPS) should be considered. Trials have demonstrated that there is better control of ascites and overall survival with this procedure; however, there is worsening hepatic encephalopathy [150]. Referral to a transplant center should be done for patients with refractory ascites.

Tense ascites with respiratory compromise and abdominal discomfort can also be the initial presentation of patients with CLD. Prior to sodium restriction, paracentesis should be performed. For large volume (>5 L) removal, albumin replacement should be done [151]. Replacement of 6–8 g of albumin per L of fluid removed has been shown to improve survival [129].

Replacement after paracentesis has remained a controversial topic. In one study performed by Gines et al., patients with tense ascites were randomized to receive albumin or no replacement. Those that did not receive albumin had more changes in serum electrolytes, plasma renin, and creatinine but had no survival advantage [152]. There has been no study up to date demonstrating decreased survival in patients without replacement when compared to albumin [153].

In a meta-analysis by Bernardi et al., 1,225 patients from 17 trials were analyzed. Albumin was shown to be superior to other plasma expanders, with an infusion between 5 and 10 g of albumin per liter removed [154].

Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aspirin, and nonsteroidal anti-inflammatory agents should be avoided in patients with CLD and ascites: prostaglandin inhibition can severely affect renal hemodynamics as well as natriuresis.

It is important to evaluate patients with ascites for ventral and umbilical hernias. For those patients with ascites, hernia repair should only be attempted after medical treatment of ascites. For those with refractory ascites, repair should be deferred until after liver transplantation. If the patient has an incarcerated or strangulated hernia, emergency repair is warranted, but special attention to the ascites postoperatively must be made.

Spontaneous Bacterial Peritonitis

The diagnosis of spontaneous bacterial peritonitis (SBP) is established with studies sent from ascitic fluid revealing one of the following three findings:
  1. 1.

    Leukocyte count of more than 500 per mm3

     
  2. 2.

    Polymorphonuclear count of more than 250 per mm3

     
  3. 3.

    Positive bacterial culture

     

The causative organism is usually a Gram-negative enteric bacteria; if more than one organism is identified, secondary peritonitis should be considered. Escherichia coli and Klebsiella are responsible for more than 50 % of the cases [155]. Therapy is tailored based on the most likely causative agent.

If the patient has not been on empiric antibiotics prior to presentation, an intravenous third-generation cephalosporin should be started, preferably cefotaxime 2 g every 8 h. If the patient has been exposed prior to this medication, coverage should be based on hospital antibiogram [129]. Therapy should be started if there is a high suspicion for infection while cultures are pending.

The recurrence rate of SBP can be as high as 70 % and therefore prophylaxis is advocated. Long-term antibiotic therapy, norfloxacin 400 mg daily, is recommended [156]. Trimethoprim/sulfamethoxazole can be used as a second-line agent for those patients with sensitivities [129].

Variceal Hemorrhage

The presence of esophageal varices in patients with CLD warrants prophylactic therapy. The most effective medication has been propranolol that inhibits stimulation of the beta-2 venodilator receptors seen in varices. It should be started at low doses, 5 mg orally twice a day, and titrated to reduction of pulse rate by 25 %. If patients cannot take propranolol, isosorbide mononitrate can be used. If the patient is unable to tolerate medical therapy, esophagogastroduodenoscopy (EGD) and variceal banding should be performed [157].

Three principles govern the management of an acute variceal bleed: stabilization and resuscitation, identification and treatment of bleeding, and prevention of recurrence. If a patient presents with evidence of GI bleeding, immediate type and cross should be performed, and if needed, transfusion of untyped and uncrossed blood should begin. Waiting for laboratory values to show anemia may worsen the overall clinical condition of the patient.

Upper GI bleeding in a patient with presumed CLD prompts urgent endoscopy to identify possible bleeding esophageal or gastric varices. If during endoscopy, no varices are seen, repeat evaluation should be done in 3 years. If varices are identified but not bleeding, follow-up endoscopy should be done after 1 year. If active bleeding is encountered and it appears to involve esophageal varices, an attempt at controlling the bleeding varices should be done. Banding followed by sclerotherapy are the two most common methods of achieving control. If after appropriate attempts bleeding does not stop, a Sengstaken-Blakemore tube should be inserted. TIPS and surgical shunts should be considered if all previous methods fail. TIPS has shown improved outcomes [129]; however, it is associated with HE [157]. Surgical shunts carry a high morbidity and should be considered a last resort.

CLD patients with GI bleeding are at risk of developing bacterial infections. Some advocate the use of ceftriaxone for 7 days while patients are GI bleeding [158, 159]. If the patient stabilizes and tolerates oral intake, changing to norfloxacin is reasonable.

Hepatorenal Syndrome

The diagnostic criteria for hepatorenal syndrome (HRS) are shown in Table 18.9.
Table 18.9

Criteria for diagnosis of hepatorenal syndrome

Major criteria

Chronic or acute liver disease with advanced hepatic failure and portal hypertension

Low glomerular filtration rate

 Serum creatinine >1.5 mg/dL

 or

 24 h creatinine clearance <40 mL/min

Absence of shock, ongoing bacterial infection, and current or recent treatment with nephrotoxic drugs

Absence of GI fluid losses

Absence of renal fluid losses in response to diuretic therapy

No sustained improvement in renal function after diuretic withdrawal and expansion of plasma volume with 1.5 L of plasma expander

Proteinuria <500 mg/day

No obstructive uropathy, parenchymal renal disease, microhematuria

Minor criteria

Urine volume <500 mL/day

Urine sodium <10 mEq/L

Urine osmolality greater than plasma osmolality

Urine RBCs <50/high-power field

Serum sodium concentration <130 mEq/L

HRS is a diagnosis of exclusion and it is important to rule out other etiologies including prerenal azotemia, intrinsic renal disease, and post renal failure. In order to diagnose HRS, all major criteria in Table 18.9 must be met. Minor criteria are not required; however, they provide supportive evidence that the pathophysiology is consistent with HRS. Identification of precipitating event is also instrumental in the management of HRS as additional therapy can be instituted.

When performing large volume (>5 L) paracentesis, it is recommended to replace volume with albumin (see ascites section above) as this procedure may lead to HRS. Evaluation for possible SBP as well as workup for GI bleeding should be considered as they are well-established risk factors for the development of this syndrome.

There are two manifestations of HRS: type I and type II. The former shows a rapid decline in renal function with either an initial creatinine of greater than 2.5 mg/dL or a 50 % reduction in the creatinine clearance. Type II usually leads to moderate renal failure that progresses slowly and is manifested as diuretic-resistant ascites [160].

Liver transplantation is the preferred treatment for patients with HRS. Any patient with evidence of this syndrome should be referred to a liver transplantation center in order to be listed for transplantation [161]. Bridging with pharmacotherapy is necessary in most patients as there is rapid decompensation, especially in those with type I HRS.

The basic principle behind the management of HRS is reversal of renal vasoconstriction and splanchnic vasodilation. Dopamine, fenoldopam, and prostaglandins have been used in an attempt to cause direct renal vasodilation [15]. Results of several trials have not favored any of these agents as none have improved outcome [160, 161, 162].

Splanchnic vasoconstriction, in an attempt to reduce portal blood flow and decrease pressure, has been attempted with vasopressin, ornipressin, terlipressin, norepinephrine, and midodrine [15]. Ornipressin, with some promising results, resulted in an increase rate of ischemic events [163]. Terlipressin in combination with albumin has shown the most promising results, with improvements in renal function although its use has not been approved in the United States [164]. Norepinephrine and vasopressin have been used with improvement of renal function and successful bridging to transplantation [60].

Hemodialysis may be required in the treatment of these patients, especially those with type 1 disease. Those patients that are hospitalized in an ICU should receive continuous dialysis rather than intermittent as it minimizes changes of abrupt hemodynamic changes and further compromise of these frail patients [73].

Liver Transplantation

Patients with ALF and CLD may benefit from liver transplantation. This therapeutic option should be considered when medical therapy has failed and when there is progression of disease. Referral to transplant center should occur once the patient has experienced ascites, variceal hemorrhage, HRS, and HE. Consultation with hepatology and transplant surgery teams ensures early consideration for transplantation. Table 18.10 presents poor prognostic factors from the King’s College Criteria that may suggest that the need for transplantation is increased.
Table 18.10

King’s College criteria that suggests poor prognosis

Non-acetaminophen

INR greater than 6.5 or

Three of the following five criteria:

 Patient age of less than 11 or greater than 40

 Serum bilirubin of greater than 300 μmol per liter

 Time from onset of jaundice to the development of coma of greater than 7 days

 INR greater than 3.5

 Drug toxicity, regardless of etiology of ALF

Acetaminophen

Arterial pH <7.3

INR greater than 6.5

Creatinine greater than 300 μmol per liter

Encephalopathy (grade III or IV)

Prior to transplantation, a thorough evaluation is performed on patients regardless of etiology. This includes assessment of cardiac function, possible occult malignancy, identification of infection, contraindications to chronic steroid therapy, and appropriate social support.

The rapidly progressive nature of ALF designates that these patients are currently listed as Status 1 by the United Network for Organ Sharing (UNOS) [165]. Approximately 40 % of patients with ALF will undergo liver transplantation, 25 % of them will improve with supportive care, and 35 % will not survive their presentation; of those that have a liver transplant performed, the 3-year survival is approximately 75 % [165]. Patients with failure secondary to viral hepatitis usually have better outcomes than those with drug reactions or metabolic causes. Also, patients with ALF have worst outcomes when compared with patients with CLD.

The 1-year survival for patients with CLD that undergo liver transplantation is 90 % [166]. Timing is not standard and is usually dependent on severity of MELD. Living donors have been used secondary to decrease in organ availability and it has been successful. This therapy has not been studied in patients with ALF.

Other Therapies

Liver replacement therapies (LRT), also known as liver dialysis, have been studied and used as a bridging therapy to transplant [167, 168, 169, 170]. Several methods have been developed and they can be grouped into artificial and bioartificial devices. Regardless of the mode of action, they attempt to clear toxins that are free and protein bound, as well as to regenerate or replace proteins that are affected by the liver failure process.

Among the artificial methods, the most studied is the molecular adsorbent recirculation system (MARS). It effectively clears several toxic compounds and causes a dramatic improvement in serum laboratories and in some symptoms such as pruritus [171]. Unfortunately, this has not translated into clinical benefits [172].

Biologic methods include devices with porcine hepatocytes and with human hepatoblastoma cells [167, 171, 172, 173]. Their theoretical advantage is the production of proteins and compounds produced by a normal liver as well as detoxification functions. As opposed to artificial systems, technology is not readily available. The results from different trials have been promising, showing improvement in survival to transplantation and normalization of serum laboratories [167].

An alternative to liver transplantation is hepatocyte transplantation. This consists of injecting human hepatocytes into the portal vein with an attempt to restore hepatic function [174]. It has been principally used to correct errors of metabolism, and trials have shown improvement in encephalopathy and ammonia and serum laboratories in patients with ALF that undergo this therapy [175]. More trials are needed in order to establish the role of this treatment option.

References

  1. 1.
    Khashab M, Tector AJ, Kwo PY. Epidemiology of acute liver failure. Curr Gastroenterol Rep. 2007;9:66–73.Google Scholar
  2. 2.
    Bowen DG, Shackel NA, McCaughan GW. East meets west: acute liver failure in the global village. J Gastroenterol Hepatol. 2000;15:467–9. November 1999.Google Scholar
  3. 3.
    Parsons-Smith BG, Summerskill WH, Dawson AM, Sherlock S. The electroencephalograph in liver disease. Lancet. 1957;273:867–71.Google Scholar
  4. 4.
    Blei AT, Córdoba J. Hepatic encephalopathy. Am J Gastroenterol. 2001;96:1968–76.Google Scholar
  5. 5.
    Shawcross DL, Balata S, Olde Damink SWM, Hayes PC, Wardlaw J, Marshall I, et al. Low myo-inositol and high glutamine levels in brain are associated with neuropsychological deterioration after induced hyperammonemia. Am J Physiol Gastrointest Liver Physiol. 2004;287:G503–9.Google Scholar
  6. 6.
    Ytrebø LM, Sen S, Rose C, Ten Have GAM, Davies NA, Hodges S, et al. Interorgan ammonia, glutamate, and glutamine trafficking in pigs with acute liver failure. Am J Physiol Gastrointest Liver Physiol. 2006;291:G373–81.Google Scholar
  7. 7.
    Tajiri K, Shimizu Y. Branched-chain amino acids in liver diseases. World J Gastroenterol [Internet]. 2013;19:7620–9. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3837260&tool=pmcentrez&rendertype=abstract.Google Scholar
  8. 8.
    Ahboucha S, Coyne L, Hirakawa R, Butterworth RF, Halliwell RF. An interaction between benzodiazepines and neuroactive steroids at GABA A receptors in cultured hippocampal neurons. Neurochem Int. 2006;48:703–7.Google Scholar
  9. 9.
    Strauss G, Hansen BA, Kirkegaard P, Rasmussen A, Hjortrup A, Larsen FS. Liver function, cerebral blood flow autoregulation, and hepatic encephalopathy in fulminant hepatic failure. Hepatology. 1997;25:837–9.Google Scholar
  10. 10.
    Eroglu Y, Byrne WJ. Hepatic Encephalopathy. Emerg Med Clin N Am. 2009;27:401–14.Google Scholar
  11. 11.
    Munoz SJ. Difficult management problems in fulminant hepatic failure. Semin Liver Dis. 1993;13:395–413.Google Scholar
  12. 12.
    Trewby PN, Warren R, Contini S, Crosbie WA, Wilkinson SP, Laws JW, et al. Incidence and pathophysiology of pulmonary edema in fulminant hepatic failure. Gastroenterology. 1978;74:859–65.Google Scholar
  13. 13.
    Fritz JS, Fallon MB, Kawut SM. Pulmonary vascular complications of liver disease. Am J Respir Crit Care Med. 2013;187:133–43.PubMedCentralPubMedGoogle Scholar
  14. 14.
    Rolla G. Hepatopulmonary syndrome: role of nitric oxide and clinical aspects. Dig Liver Dis. 2004;36:303–8.Google Scholar
  15. 15.
    Wadei HM, Mai ML, Ahsan N, Gonwa TA. Hepatorenal syndrome: pathophysiology and management. Clin J Am Soc Nephrol CJASN. 2006;1:1066–79.Google Scholar
  16. 16.
    Cárdenas A. Hepatorenal syndrome: a dreaded complication of end-stage liver disease. Am J Gastroenterol. 2005;100:460–7.Google Scholar
  17. 17.
    Pluta A, Gutkowski K, Hartleb M. Coagulopathy in liver diseases. Adv Med Sci. 2010;55:16–21.Google Scholar
  18. 18.
    Cardenas A, Arroyo V. Mechanisms of water and sodium retention in cirrhosis and the pathogenesis of ascites. Best Pr Res Clin Endorcinol Metab. 2003;17(4):607.Google Scholar
  19. 19.
    Gill RQ, Sterling RK. Acute liver failure. J Clin Gastroenterol. 2001;33:191–8.Google Scholar
  20. 20.
    Caraceni P, Van Thiel DH. Acute liver failure. Lancet [Internet]. 1995;345:163–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21252557, http://www.sciencedirect.com/science/article/pii/S014067369590171X.Google Scholar
  21. 21.
    Tujios SR, Hynan LS, Vazquez M a, Larson AM, Seremba E, Sanders CM, et al. Risk factors and outcomes of acute kidney injury in patients with acute liver failure. Clin Gastroenterol Hepatol [Internet]. 2014;1–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25019700.
  22. 22.
    Moreau R, Lebrec D. Diagnosis and treatment of acute renal failure in patients with cirrhosis. Best Pract Res Clin Gastroenterol. 2007;21:111–23.Google Scholar
  23. 23.
    Vernon C, LeTourneau JL. Lactic acidosis: recognition, kinetics, and associated prognosis. Crit Care Clin. 2010;26:255–83.Google Scholar
  24. 24.
    Stacpoole PW. Lactic acidosis. Endocrinol Metab Clin North Am [Internet]. 1993;22:221–45. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8325284.Google Scholar
  25. 25.
    Marko P, Gabrielli A, Caruso LJ, Mizock BA, Franklin C. Too much lactate or too little liver? J Clin Anesth. 2004;16:389–95.Google Scholar
  26. 26.
    Bernal W, Auzinger G, Sizer E, Wendon J. Intensive care management of acute liver failure. Semin Liver Dis. 2008;28:188–200.Google Scholar
  27. 27.
    Wasmuth HE, Kunz D, Yagmur E, Timmer-Stranghöner A, Vidacek D, Siewert E, et al. Patients with acute on chronic liver failure display “sepsis-like” immune paralysis. J Hepatol. 2005;42:195–201.Google Scholar
  28. 28.
    Bode C, Kugler V, Bode JC. Endotoxemia in patients with alcoholic and non-alcoholic cirrhosis and in subjects with no evidence of chronic liver disease following acute alcohol excess. J Hepatol. 1987;4:8–14.Google Scholar
  29. 29.
    Karvellas CJ, Cavazos J, Battenhouse H, Durkalski V, Balko J, Sanders C, et al. Effects of antimicrobial prophylaxis and blood stream infections in patients with acute liver failure: a retrospective cohort study. Clin Gastroenterol Hepatol [Internet]. 2014; Available from: http://www.ncbi.nlm.nih.gov/pubmed/24674942.
  30. 30.
    Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R. The systemic inflammatory response syndrome in acute liver failure. Hepatology. 2000;32:734–9.PubMedGoogle Scholar
  31. 31.
    Vaquero J, Polson J, Chung C, Helenowski I, Schiodt FV, Reisch J, et al. Infection and the progression of hepatic encephalopathy in acute liver failure. Gastroenterology. 2003;125:755–64.PubMedGoogle Scholar
  32. 32.
    Pashankar D, Schreiber RA. Jaundice in older children and adolescents. Pediatr Rev. 2001;22(7):219–26.PubMedGoogle Scholar
  33. 33.
    Bergasa NV. Update on the treatment of the pruritus of cholestasis. Clin Liver Dis. 2008;12:219–34.PubMedGoogle Scholar
  34. 34.
    Bernal W, Auzinger G, Dhawan A, Wendon J. Acute liver failure. Lancet. 2010;376:190–201.PubMedGoogle Scholar
  35. 35.
    Bergasa NV. Medical palliation of the jaundiced patient with pruritus. Gastroenterol Clin N Am. 2006;35:113–23.Google Scholar
  36. 36.
    Maheshwari A, Ray S, Thuluvath PJ. Acute hepatitis C. Lancet. 2008;372:321–32.Google Scholar
  37. 37.
    Lee WM, Larson AM, Stravitz RT. AASLD position paper : the management of acute liver failure : update 2011. Hepatology [Internet]. 2011;1–22. Available from: http://aasld.org/practiceguidelines/Documents/AcuteLiverFailureUpdate2011.pdf.
  38. 38.
    Wijkicks EFM, Nyberg SL. Propofol to control intracranial pressure in fulminant hepatic failure. Transpl Proc. 2002;34:1220–2.Google Scholar
  39. 39.
    Hay JE, McGuire B, Ostapowicz G, Lee WM. Management of fulminant hepatic failure in the USA: results from a survey of 14 liver transplant programs. Gastroenterology. 2001;120:542A.Google Scholar
  40. 40.
    Keays RT, Alexander GJ, Williams R. The safety and value of extradural intracranial pressure monitors in fulminant hepatic failure. J Hepatol. 1993;18:205–9.PubMedGoogle Scholar
  41. 41.
    McCashland TM, Shaw BW, Tape E. The American experience with transplantation for acute liver failure. Semin Liver Dis. 1996;16:427–33.PubMedGoogle Scholar
  42. 42.
    Blei AT, Olafsson S, Therrien G, Butterworth RF. Ammonia-induced brain edema and intracranial hypertension in rats after portacaval anastomosis. Hepatology [Internet]. 1994;19:1437–44. Available from: <Go to ISI>://A1994NP54700018\http://onlinelibrary.wiley.com/store/10.1002/hep.1840190619/asset/1840190619_ftp.pdf?v=1&t=h69623wx&s=028ff0c956d8d45d735bce8c146e7b7aaa86a967.Google Scholar
  43. 43.
    Blei AT, Olafsson S, Webster S, Levy R. Complications of intracranial pressure monitoring in fulminant hepatic failure. Lancet. 1993;341:157–8.PubMedGoogle Scholar
  44. 44.
    Durward QJ, Amacher AL, Del Maestro RF, Sibbald WJ. Cerebral and cardiovascular responses to changes in head elevation in patients with intracranial hypertension. J Neurosurg. 1983;59:938–44.PubMedGoogle Scholar
  45. 45.
    Alba L, Hay JE, Angulo P, Lee WM. Lactulose therapy in acute liver failure. J Hepatol. 2002;36:33A.Google Scholar
  46. 46.
    Acharya SK, Bhatia V, Sreenivas V, Khanal S, Panda SK. Efficacy of L-ornithine L-aspartate in acute liver failure: a double-blind, randomized. Placebo-controlled study. Gastroenterology. 2009;136:2159–68.PubMedGoogle Scholar
  47. 47.
    Ellis AJ, Wendon JA, Williams R. Subclinical seizure activity and prophylactic phenytoin infusion in acute liver failure: a controlled clinical trial. Hepatology (Baltimore, Md). 2000;32:536–41.Google Scholar
  48. 48.
    Bhatia V, Batra Y, Acharya SK. Prophylactic phenytoin does not improve cerebral edema or survival in acute liver failure – a controlled clinical trial. J Hepatol. 2004;41:89–96.PubMedGoogle Scholar
  49. 49.
    Nath F, Galbraith S. The effect of mannitol on cerebral white matter water content. J Neurosurg. 1986;65:41–3.PubMedGoogle Scholar
  50. 50.
    Murphy N, Auzinger G, Bernel W, Wendon J. The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure. Hepatology (Baltimore, Md). 2004;39:464–70.Google Scholar
  51. 51.
    Jalan R, Olde Damink SWM, Deutz NEP, Davies NA, Garden OJ, Madhavan KK, et al. Moderate hypothermia prevents cerebral hyperemia and increase in intracranial pressure in patients undergoing liver transplantation for acute liver failure. Transplantation. 2003;75:2034–9.PubMedGoogle Scholar
  52. 52.
    Jalan R, Olde Damink SWMM, Deutz NEPP, Hayes PC, Lee A. Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension. Gastroenterology. 2004;127:1338–46.PubMedGoogle Scholar
  53. 53.
    Rakela J, Mosley JW, Edwards VM, Govindarajan S, Alpert E. A double-blinded, randomized trial of hydrocortisone in acute hepatic failure. The Acute Hepatic Failure Study Group. Dig Dis Sci. 1991;36:1223–8.PubMedGoogle Scholar
  54. 54.
    Bion JF, Bowden MI, Chow B, Honisberger L, Weatherley BC. Atracurium infusions in patients with fulminant hepatic failure awaiting liver transplantation. Intensive Care Med. 1993;19:S94–8.PubMedGoogle Scholar
  55. 55.
    Martinez-Palli G, Drake BB, Garcia-Pagan JC, Barbera JA, Arguedas MR, Rodriguez-Roisin R, et al. Effect of transjugular intrahepatic portosystemic shunt on pulmonary gas exchange in patients with portal hypertension and hepatopulmonary syndrome. World J Gastroenterol. 2005;11:6858–62.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Selim KM, Akriviadis EA, Zuckerman E, Chen D, Reynolds TB. Transjugular intrahepatic portosystemic shunt: a successful treatment for hepatopulmonary syndrome. Am J Gastroenter. 1998;93:455–8.PubMedGoogle Scholar
  57. 57.
    Gupta S, Castel H, Rao RV, Picard M, Lilly L, Faughnan ME, et al. Improved survival after liver transplantation in patients with hepatopulmonary syndrome. Am J Transplant. 2010;10:354–63.PubMedGoogle Scholar
  58. 58.
    Patton H, Misel M, Gish RG. Acute liver failure in adults: an evidence-based management protocol for clinicians. Gastroenterol Hepatol (N Y). 2012;8:161–212.Google Scholar
  59. 59.
    Stravitz RT, Kramer DJ. Management of acute liver failure. Nat Rev Gastroenterol Hepatol. 2009;6:542–53.PubMedGoogle Scholar
  60. 60.
    Eefsen M, Dethloff T, Frederiksen HJ, Hauerberg J, Hansen BA, Larsen FS. Comparison of terlipressin and noradrenalin on cerebral perfusion, intracranial pressure and cerebral extracellular concentrations of lactate and pyruvate in patients with acute liver failure in need of inotropic support. J Hepatol. 2007;47:381–6.PubMedGoogle Scholar
  61. 61.
    Shawcross DL, Davies NA, Mookerjee RP, Hayes PC, Williams R, Lee A, et al. Worsening of cerebral hyperemia by the administration of terlipressin in acute liver failure with severe encephalopathy. Hepatology. 2004;39:471–5.PubMedGoogle Scholar
  62. 62.
    Guirl MJ, Weinstein JS, Goldstein RM, Levy MF, Klintmalm GB. Two-stage total hepatectomy and liver transplantation for acute deterioration of chronic liver disease: a new bridge to transplantation. Liver Transpl. 2004;10:564–70.PubMedGoogle Scholar
  63. 63.
    Stravitz RT, Lisman T, Luketic VA, Sterling RK, Puri P, Fuchs M, et al. Minimal effects of acute liver injury/acute liver failure on hemostasis as assessed by thromboelastography. J Hepatol. 2012;56:129–36.PubMedGoogle Scholar
  64. 64.
    Shami VM, Caldwell SH, Hespenheide EE, Arseneau KO, Bickston SJ, Macik BG. Recombinant activated factor VII for coagulopathy in fulminant hepatic failure compared with conventional therapy. Liver Transpl. 2003;9:138–43.PubMedGoogle Scholar
  65. 65.
    Pavese P, Bonadona A, Beaubien J, Labrecque P, Pernod G, Letoublon C, et al. FVIIa corrects the coagulopathy of fulminant hepatic failure but may be associated with thrombosis: a report of four cases. Can J Anaesth = J Can Anesth. 2005;52:26–9.Google Scholar
  66. 66.
    Pereira SP, Rowbotham D, Fitt S, Shearer MJ, Wendon J, Williams R. Pharmacokinetics and efficacy of oral versus intravenous mixed-micellar phylloquinone (vitamin K1) in severe acute liver disease. J Hepatol. 2005;42:365–70.PubMedGoogle Scholar
  67. 67.
    Woolf SH, Sox HC. The expert panel on preventive services: continuing the work of the USPSTF. Am J Prev Med. 1991;7:326–30.PubMedGoogle Scholar
  68. 68.
    Munoz SJ, Stravitz RT, Gabriel DA. Coagulopathy of acute liver failure. Clin Liver Dis. 2009;13:95–107.PubMedGoogle Scholar
  69. 69.
    Pemberton LB, Schaefer N, Goehring L, Gaddis M, Arrighi DA. Oral ranitidine as prophylaxis for gastric stress ulcers in intensive care unit patients: serum concentrations and cost comparisons. Crit Care Med. 1993;21:339–42.PubMedGoogle Scholar
  70. 70.
    Alhazzani W, Alenezi F, Jaeschke RZ, Moayyedi P, Cook DJ. Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis. Crit Care Med. 2013;41:693–705.PubMedGoogle Scholar
  71. 71.
    Naylor CD, O’Rourke K, Detsky AS, Baker JP. Parenteral nutrition with branched-chain amino acids in hepatic encephalopathy. A meta-analysis. Gastroenterology. 1989;97:1033–42.Google Scholar
  72. 72.
    Raff T, Germann G, Hartmann B. The value of early enteral nutrition in the prophylaxis of stress ulceration in the severely burned patient. Burns. 1997;23:313–8.Google Scholar
  73. 73.
    Davenport A, Will EJ, Davidson AM. Improved cardiovascular stability during continuous modes of renal replacement therapy in critically ill patients with acute hepatic and renal failure. Crit Care Med. 1993;21:328–38.Google Scholar
  74. 74.
    Rolando N, Harvey F, Brahm J, Philpott-Howard J, Alexander G, Gimson A, et al. Prospective study of bacterial infection in acute liver failure: an analysis of fifty patients. Hepatology. 1990;11:49–53.Google Scholar
  75. 75.
    Rolando N, Gimson A, Wade J, Philpott-Howard J, Casewell M, Williams R. Prospective controlled trial of selective parenteral and enteral antimicrobial regimen in fulminant liver failure. Hepatology. 1993;17:196–201.Google Scholar
  76. 76.
    Rolando N, Harvey F, Brahm J, Philpott-Howard, Alexander G, Casewell M, et al. Fungal infection: a common, unrecognised complication of acute liver failure. J Hepatol. 1991;12:1–9.Google Scholar
  77. 77.
    Pelz RK, Hendrix CW, Swoboda SM, Diener-West M, Merz WG, Hammond J, et al. Double-blind placebo-controlled trial of fluconazole to prevent candidal infections in critically ill surgical patients. Ann Surg. 2001;233:542–8.PubMedCentralPubMedGoogle Scholar
  78. 78.
    Watson WA, Litovitz Toby L, Rodgers Jr GC, Klein-Schwartz W, Reid N, Youniss J, et al. 2004 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 2005;23:589–666.Google Scholar
  79. 79.
    Lewis RK, Paloucek FP. Assessment and treatment of acetaminophen overdose. Clin Pharm. 1991;10:765–74.Google Scholar
  80. 80.
    Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics. 1975;55:871.Google Scholar
  81. 81.
    Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol. 2002;40:3–20.Google Scholar
  82. 82.
    Hodgman MJ, Garrard AR. A review of acetaminophen poisoning. Crit Care Clin. 2012;28:499–516.Google Scholar
  83. 83.
    Rose SR, Gorman RL, Oderda GM, Klein-Schwartz W, Watson WA. Simulated acetaminophen overdose: pharmacokinetics and effectiveness of activated charcoal. Ann Emerg Med. 1991;20:1064–8.Google Scholar
  84. 84.
    Spiller HA, Sawyer TS. Impact of activated charcoal after acute acetaminophen overdoses treated with N-acetylcysteine. J Emerg Med. 2007;33:141–4.Google Scholar
  85. 85.
    Spiller HA, Krenzelok EP, Grande GA, Safir EF, Diamond JJ. A prospective evaluation of the effect of activated charcoal before oral N-acetylcysteine in acetaminophen overdose. Ann Emerg Med. 1994;23:519–23.Google Scholar
  86. 86.
    Kanter MZ. Comparison of oral and i.v. acetylcysteine in the treatment of acetaminophen poisoning. Am J Health Syst Pharm. 2006;63:1821–7.Google Scholar
  87. 87.
    Prescott LF, Park J, Ballantyne A, Adriaenssens P, Proudfoot AT. Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine. Lancet. 1977;2:432–4.Google Scholar
  88. 88.
    Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med. 2008;359:285–92.PubMedCentralPubMedGoogle Scholar
  89. 89.
    Wu ML, Tsai WJ, Deng JF, Yang CC. Hemodialysis as adjunctive therapy for severe acetaminophen poisoning: a case report. Zhonghua Yi Xue Za Zhi. 1999;62:907–13.Google Scholar
  90. 90.
    Wieland T, Faulstich H. Amatoxins, phallotoxins, phallolysin, and antamanide: the biologically active components of poisonous Amanita mushrooms. CRC Crit Rev Biochem. 1978;5:185–260.Google Scholar
  91. 91.
    Parant F, Peltier L, Lardet G, Pulce C, Descotes J, Moulsma M. Phalloidin syndrome: role of Elisa-based assay for the detection of alpha- and gamma-amanitins in urine. Preliminary results. Acta Clin Belg Suppl. 2006;61:11–7.Google Scholar
  92. 92.
    Enjalbert F, Rapior S, Nouguier-Soulé J, Guillon S, Amouroux N, Cabot C. Treatment of amatoxin poisoning: 20-year retrospective analysis. J Toxicol Clin Toxicol. 2002;40:715–57.Google Scholar
  93. 93.
    Chen WC, Kassi M, Saeed U, Frenette CT. A rare case of amatoxin poisoning in the state of Texas. Case Rep Gastroenterol. 2012;6:350–7.PubMedCentralPubMedGoogle Scholar
  94. 94.
    Saller R, Meier R, Brignoli R. The use of silymarin in the treatment of liver diseases. Drugs. 2001;61:2035–63.Google Scholar
  95. 95.
    Parés A, Planas R, Torres M, Caballería J, Viver JM, Acero D, et al. Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial. J Hepatol. 1998;28:615–21.Google Scholar
  96. 96.
    Poucheret P, Fons F, Doré JC, Michelot D, Rapior S. Amatoxin poisoning treatment decision-making: pharmaco-therapeutic clinical strategy assessment using multidimensional multivariate statistic analysis. Toxicon. 2010;55:1338–45.Google Scholar
  97. 97.
    Roberts EA, Schilsky ML. AASLD practice guidelines: Wilson disease. Hepatology. 2003;37:1475–92.Google Scholar
  98. 98.
    Hamlyn AN, Gollan JL, Douglas AP, Sherlock S. Fulminant Wilson’s disease with haemolysis and renal failure: copper studies and assessment of dialysis regimens. Br Med J. 1977;10:660–3.Google Scholar
  99. 99.
    Stange J, Mitzner SR, Risler T, Erley CM, Lauchart W, Goehl H, et al. Molecular adsorbent recycling system (MARS): clinical results of a new membrane-based blood purification system for bioartificial liver support. Artif Organs. 1999;23:319–30.Google Scholar
  100. 100.
    Kreymann B, Seige M, Schweigart U, Kopp KF, Classen M. Albumin dialysis: effective removal of copper in a patient with fulminant Wilson disease and successful bridging to liver transplantation: a new possibility for the elimination of protein-bound toxins. J Hepatol. 1999;31:1080–5.Google Scholar
  101. 101.
    Ostapowicz G, Fontana RJ, Schiødt FV, Larson A, Davern TJ, Han SHB, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med. 2002;137:947–54.Google Scholar
  102. 102.
    Schmilovitz-Weiss H, Ben-Ari Z, Sikuler E, Zuckerman E, Sbeit W, Ackerman Z, et al. Lamivudine treatment for acute severe hepatitis B: a pilot study. Liver Int. 2004;24:547–51.Google Scholar
  103. 103.
    Jaeckel E, Cornberg M, Wedemeyer H, Santantonio T, Mayer J, Zankel M, et al. Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med. 2001;345:1452–7.Google Scholar
  104. 104.
    Henrion J. Hypoxic hepatitis. Liver Int [Internet]. 2012;32(7):1039–52. [cited 2015 May 13]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22098491.Google Scholar
  105. 105.
    Ebert EC. Hypoxic liver injury. Mayo Clin Proc. 2006;81:1232–6.Google Scholar
  106. 106.
    Raurich JM, Llompart-Pou JA, Ferreruela M, Colomar A, Molina M, Royo C, et al. Hypoxic hepatitis in critically ill patients: incidence, etiology and risk factors for mortality. J Anesth. 2011;25:50–6.Google Scholar
  107. 107.
    Cassidy WM, Reynolds TB. Serum lactic dehydrogenase in the differential diagnosis of acute hepatocellular injury. J Clin Gastroenterol. 1994;19:118–21.Google Scholar
  108. 108.
    Wong RJ, Aguilar M, Cheung R, Perumpail RB, Harrison SA, Younossi ZM, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology. 2015;148(3):547–55.Google Scholar
  109. 109.
    US Burden of Disease Collaborators. The state of US health, 1990–2010: burden of diseases, injuries, and risk factors. JAMA. 2013;310:591–608.PubMedCentralPubMedGoogle Scholar
  110. 110.
    Qamar AA, Grace ND, Groszmann RJ, Garcia-Tsao G, Bosch J, Burroughs AK, et al. Incidence, prevalence, and clinical significance of abnormal hematologic indices in compensated cirrhosis. Clin Gastroenterol Hepatol. 2009;7:689–95.PubMedCentralPubMedGoogle Scholar
  111. 111.
    McCormick PA, Murphy KM. Splenomegaly, hypersplenism and coagulation abnormalities in liver disease. Best Pract Res Clin Gastroenterol. 2000;14:1009–31.Google Scholar
  112. 112.
    Schiodt FV, Balko J, Schilsky M, Harrison ME, Thornton A, Lee WM. Thrombopoietin in acute liver failure. Hepatology. 2003;37:558–61.Google Scholar
  113. 113.
    Gupta TK, Toruner M, Chung MK, Groszmann RK. Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats. Hepatology. 1998;28(4):926–31.Google Scholar
  114. 114.
    Obara K. Hemodynamic mechanism of esophageal varices. Dig Endosc. 2006;18(1):6–9.Google Scholar
  115. 115.
    Maruyama H, Yokosuka O. Pathophysiology of portal hypertension and esophageal varices. Int J Hepatol. 2012;2012:895787.PubMedCentralPubMedGoogle Scholar
  116. 116.
    Sanyal AJ, Bosch J, Blei A, Arroyo V. Portal hypertension and its complications. Gastroenterology. 2008;134:1715–28.Google Scholar
  117. 117.
    Morali GA, Sniderman KW, Deitel KM, Tobe S, Witt-Sullivan H, Simon M, et al. Is sinusoidal portal hypertension a necessary factor for the development of hepatic ascites? J Hepatol. 1992;16(1):249.Google Scholar
  118. 118.
    Arroyo V, Badalamenti S, Gines P. Pathogenesis of ascites in cirrhosis. Minerva Med. 1987;78:645–50.Google Scholar
  119. 119.
    Cundy TF, Butler J, Pope RM, Saggar-Malik AK, Wheeler MJ, Williams R. Amenorrhoea in women with non-alcoholic chronic liver disease. Gut. 1991;32:202–6.PubMedCentralPubMedGoogle Scholar
  120. 120.
    Van Thiel DH, Gavaler JS, Spero JA, Egler KM, Wright C, Sanghvi AT, et al. Patterns of hypothalamic-pituitary-gonadal dysfunction in men with liver disease due to differing etiologies. Hepatology. 1981;1:39–46.Google Scholar
  121. 121.
    Runyon BA. Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis. Gastroenterology. 1986;91:1343–6.Google Scholar
  122. 122.
    Bilzer M, Roggel F, Gerbes AL. Role of Kupffer cells in host defense and liver disease. Liver Int. 2006;26:1175–86.Google Scholar
  123. 123.
    Kolios G, Valatas V, Kouroumalis E. Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol [Internet]. 2006;12:7413–20. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17167827.Google Scholar
  124. 124.
    Parsi MA, Atreja A, Zein NN. Spontaneous bacterial peritonitis: Recent data on incidence and treatment. Cleve Clin J Med. 2004;71:569–76.Google Scholar
  125. 125.
    Scarpellini E, Valenza V, Gabrielli M, Lauritano EC, Perotti G, Merra G, et al. Intestinal permeability in cirrhotic patients with and without spontaneous bacterial peritonitis: is the ring closed? Am J Gastroenterol. 2010;105:323–7.Google Scholar
  126. 126.
    Căruntu FA, Benea L. Spontaneous bacterial peritonitis: pathogenesis, diagnosis, treatment. J Gastrointestin Liver Dis. 2006;15:51–6.Google Scholar
  127. 127.
    Serrao R, Zirwas M, English JC. Palmar erythema. Am J Clin Dermatol. 2007;8:347–56.Google Scholar
  128. 128.
    Coetzee T. Clinical anatomy of the umbilicus. S Afr Med J. 1980;57:463–6.Google Scholar
  129. 129.
    Runyon BA. AASLD practice guideline management of adult patients with ascites due to cirrhosis: update 2012. Hepatology. 2013;57:1651–3.Google Scholar
  130. 130.
    Kim YK, Park G, Kim CS, Han YM. CT and MRI findings of cirrhosis-related benign nodules with ischaemia or infarction after variceal bleeding. Clin Radiol. 2010;65:801–8.Google Scholar
  131. 131.
    Kono Y, Mattrey RF. Ultrasound of the liver. Radiol Clin N Am. 2005;43:815–26.PubMedGoogle Scholar
  132. 132.
    Quaia E. The real capabilities of contrast-enhanced ultrasound in the characterization of solid focal liver lesions. Eur Radiol. 2011;21:457–62.PubMedGoogle Scholar
  133. 133.
    Carey E, Carey WD. Noninvasive tests for liver disease, fibrosis, and cirrhosis: is liver biopsy obsolete? Cleve Clin J Med. 2010;77:519–27.PubMedGoogle Scholar
  134. 134.
    Abdi W, Millan JC, Mezey E. Sampling variability on percutaneous liver biopsy. Arch Intern Med. 1979;139:667–9.PubMedGoogle Scholar
  135. 135.
    Ratziu V, Charlotte F, Heurtier A, Gombert S, Giral P, Bruckert E, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128:1898–906.PubMedGoogle Scholar
  136. 136.
    Margarit C, Escartín A, Castells L, Vargas V, Allende E, Bilbao I. Resection for hepatocellular carcinoma is a good option in Child-Turcotte-Pugh class a patients with cirrhosis who are eligible for liver transplantation. Liver Transplant. 2005;11:1242–51.Google Scholar
  137. 137.
    Park JK, Lee SH, Yoon WJ, Lee JK, Park SC, Park BJ, et al. Evaluation of hernia repair operation in Child-Turcotte-Pugh class C cirrhosis and refractory ascites. J Gastroenterol Hepatol. 2007;22:377–82.PubMedGoogle Scholar
  138. 138.
    Kamath PS, Kim WR. The model for end-stage liver disease (MELD). Hepatology. 2007;45:797–805.PubMedGoogle Scholar
  139. 139.
    Papatheodoridis GV, Cholongitas E, Dimitriadou E, Touloumi G, Sevastianos V, Archimandritis AJ. MELD vs Child-Pugh and creatinine-modified Child-Pugh score for predicting survival in patients with decompensated cirrhosis. World J Gastroenterol. 2005;11:3099–104.PubMedCentralPubMedGoogle Scholar
  140. 140.
    Salerno F, Merli M, Cazzaniga M, Valeriano V, Rossi P, Lovaria A, et al. MELD score is better than Child-Pugh score in predicting 3-month survival of patients undergoing transjugular intrahepatic portosystemic shunt. J Hepatol. 2002;36:494–500.PubMedGoogle Scholar
  141. 141.
    Boursier J, Cesbron E, Tropet A-L, Pilette C. Comparison and improvement of MELD and Child-Pugh score accuracies for the prediction of 6-month mortality in cirrhotic patients. J Clin Gastroenterol. 2009;43:580–5.PubMedGoogle Scholar
  142. 142.
    Schepke M, Roth F, Fimmers R, Brensing KA, Sudhop T, Schild HH, et al. Comparison of MELD, Child-Pugh, and Emory model for the prediction of survival in patients undergoing transjugular intrahepatic portosystemic shunting. Am J Gastroenterol. 2003;98:1167–74.PubMedGoogle Scholar
  143. 143.
    Cholongitas E, Papatheodoridis GV, Vangeli M, Terreni N, Patch D, Burroughs AK. Systematic review: The model for end-stage liver disease – should it replace Child-Pugh’s classification for assessing prognosis in cirrhosis? Aliment Pharmacol Ther. 2005;22:1079–89.Google Scholar
  144. 144.
    Bismuth M, Funakoshi N, Cadranel J-F, Blanc P. Hepatic encephalopathy: from pathophysiology to therapeutic management. Eur J Gastroenterol Hepatol. 2011;23:8–22.PubMedGoogle Scholar
  145. 145.
    Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD, et al. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by AASLD and EASL. J Hepatol. 2014;60(2):715–35.Google Scholar
  146. 146.
    Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010;362:1071–81.PubMedGoogle Scholar
  147. 147.
    Hawkins RA, Jessy J, Mans AM, Chedid A, DeJoseph MR. Neomycin reduces the intestinal production of ammonia from glutamine. Adv Exp Med Biol. 1994;368:125–34.PubMedGoogle Scholar
  148. 148.
    Stanley MM, Ochi S, Lee KK, Nemchausky BA, Greenlee HB, Allen JI, et al. Peritoneovenous shunting as compared with medical treatment in patients with alcoholic cirrhosis and massive ascites. N Engl J Med. 1989;321:1632–8.PubMedGoogle Scholar
  149. 149.
    Ginés P, Arroyo V, Quintero E, Planas R, Bory F, Cabrera J, et al. Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites. Results of a randomized study. Gastroenterology. 1987;93:234–41.PubMedGoogle Scholar
  150. 150.
    Salerno F, Merli M, Riggio O, Cazzaniga M, Valeriano V, Pozzi M, et al. Randomized controlled study of TIPS versus paracentesis plus albumin in cirrhosis with severe ascites. Hepatology. 2004;40:629–35.PubMedGoogle Scholar
  151. 151.
    Liumbruno GM, Bennardello F, Lattanzio A, Piccoli P, Rossettias G. Recommendations for the use of albumin and immunoglobulins. Blood Transfus. 2009;7(3):216–34. [Cited 3 May 2015] Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2719274&tool=pmcentrez&rendertype=abstract.PubMedCentralPubMedGoogle Scholar
  152. 152.
    Gines P, Tito L, Arroyo V, Planas R, Panes J, Viver J, et al. Randomized study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology. 1988;94:1493–502.PubMedGoogle Scholar
  153. 153.
    Ginès A, Fernández-Esparrach G, Monescillo A, Vila C, Domènech E, Abecasis R, et al. Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis. Gastroenterology. 1996;111:1002–10.PubMedGoogle Scholar
  154. 154.
    Bernardi M, Caraceni P, Navickis RJ, Wilkes MM. Albumin infusion in patients undergoing large-volume paracentesis: a meta-analysis of randomized trials. Hepatology. 2012;55:1172–81.PubMedGoogle Scholar
  155. 155.
    Garcia-Tsao G. Spontaneous bacterial peritonitis. Gastroenterol Clin North Am. 1992;21:257–75.PubMedGoogle Scholar
  156. 156.
    Ginés P, Rimola A, Planas R, Vargas V, Marco F, Almela M, et al. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology (Baltimore, Md). 1990;12:716–24.Google Scholar
  157. 157.
    García-Pagán JC, Morillas R, Bañares R, Albillos A, Villanueva C, Vila C, et al. Propranolol plus placebo versus propranolol plus isosorbide-5-mononitrate in the prevention of a first variceal bleed: a double-blind RCT. Hepatology. 2003;37:1260–6.PubMedGoogle Scholar
  158. 158.
    Carbonell N, Pauwels A, Serfaty L, Fourdan O, Lévy VG, Poupon R. Improved survival after variceal bleeding in patients with cirrhosis over the past two decades. Hepatology. 2004;40:652–9.PubMedGoogle Scholar
  159. 159.
    Bernard B, Grangé JD, Khac EN, Amiot X, Opolon P, Poynard T. Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis. Hepatology. 1999;29:1655–61.PubMedGoogle Scholar
  160. 160.
    Arroyo V, Gines P, Gerbes AL. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology. 1996;23:164–76.Google Scholar
  161. 161.
    Ginès P, Guevara M, Arroyo V, Rodés J. Hepatorenal syndrome. Lancet. 2003;362:1819–27.Google Scholar
  162. 162.
    Ginès A, Salmerón JM, Ginès P, Arroyo V, Jiménez W, Rivera F, et al. Oral misoprostol or intravenous prostaglandin E2 do not improve renal function in patients with cirrhosis and ascites with hyponatremia or renal failure. J Hepatol. 1993;17:220–6.PubMedGoogle Scholar
  163. 163.
    Guevara M, Gines P, Fernandez-Esparrach G, Sort P, Salmeron JM, Jimenez W, et al. Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion. Hepatology. 1998;27:35–41.Google Scholar
  164. 164.
    Krag A, Møller S, Henriksen JH, Holstein-Rathlou NH, Larsen FS, Bendtsen F. Terlipressin improves renal function in patients with cirrhosis and ascites without hepatorenal syndrome. Hepatology. 2007;46:1863–71.PubMedGoogle Scholar
  165. 165.
    Schiodt FV, Atillasoy E, Shakil AO, Schiff ER, Caldwell C, Kowdley KV, et al. Etiology and outcome for 295 patients with acute liver failure in the United States. Liver Transpl Surg. 1999;5:29–34.PubMedGoogle Scholar
  166. 166.
    Busuttil RW, Farmer DG, Yersiz H, Hiatt JR, McDiarmid SV, Goldstein LI, et al. Analysis of long-term outcomes of 3200 liver transplantations over two decades: a single-center experience. Ann Surg. 2005;241:905–16; discussion 916–918.PubMedCentralPubMedGoogle Scholar
  167. 167.
    Demetriou AA, Brown RSJ, Busuttil RW, Fair J, McGuire BM, Rosenthal P, et al. Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure. [Internet]. Ann Surg. 2004;660–70. Available from: http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=med4&NEWS=N&AN=15082970.PubMedCentralPubMedGoogle Scholar
  168. 168.
    Şentürk E, Esen F, Özcan PE, Rifai K, Pinarbaşi B, Çakar N, et al. The treatment of acute liver failure with fractionated plasma separation and adsorption system: experience in 85 applications. J Clin Apher. 2010;25:195–201.PubMedGoogle Scholar
  169. 169.
    Sauer IM, Goetz M, Steffen I, Walter G, Kehr DC, Schwartlander R, et al. In vitro comparison of the Molecular Adsorbent Recirculation System (MARS) and Single-pass Albumin Dialysis (SPAD). Hepatology. 2004;39:1408–14.PubMedGoogle Scholar
  170. 170.
    Mitzner SR. Extracorporeal liver support-albumin dialysis with the molecular adsorbent recirculating system (MARS). Ann Hepatol. 2011;10:S21–8.PubMedGoogle Scholar
  171. 171.
    Parés A, Herrera M, Avilés J, Sanz M, Mas A. Treatment of resistant pruritus from cholestasis with albumin dialysis: combined analysis of patients from three centers. J Hepatol. 2010;53:307–12.PubMedGoogle Scholar
  172. 172.
    Bañares R, Nevens F, Larsen FS, Jalan R, Albillos A, Dollinger M, et al. Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial. Hepatology. 2013;3:1153–62.Google Scholar
  173. 173.
    Ellis AJ, Hughes RD, Wendon JA, Dunne J, Langley PG, Kelly JH, et al. Pilot-controlled trial of the extracorporeal liver assist device in acute liver failure. Hepatology. 1996;24:1446–51.PubMedGoogle Scholar
  174. 174.
    Chowdhury JR. Foreword: prospects of liver cell transplantation and liver-directed gene therapy. Semin Liver Dis. 1999;19:1–6.PubMedGoogle Scholar
  175. 175.
    Fox IJ, Chowdhury JR, Kaufman SS, Goertzen TC, Chowdhury NR, Warkentin PI, et al. Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. N Engl J Med. 1998;338:1422–6.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Open Access This chapter is licensed under the terms of the Creative Commons Attribution-NonCommercial 2.5 International License (http://creativecommons.org/licenses/by-nc/2.5/), which permits any noncommercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

Authors and Affiliations

  1. 1.Department of SurgeryJohns Hopkins HospitalBaltimoreUSA

Personalised recommendations