Alcoholic Hepatitis

Alcoholic hepatitis is a common manifestation of alcohol abuse. Between 20% and 30% of heavy drinkers will present with it at some time. The clinical picture is variable from a relatively mild syndrome associated with loss of appetite, nausea, and vomiting with right upper quadrant pain to severe life-threatening liver decompensation, but the most obvious sign is the sudden onset of jaundice, and this can be the first indication of liver disease in a heavy drinker. Overall, following first presentation, 35% to 50% of patients will die within the first month of diagnosis.⁴ It usually presents following a bout of heavy drinking and often occurs on a background of cirrhosis. Patients frequently deteriorate after stopping alcohol. This may be due to the immunosuppressive effects of alcohol. In patients without cirrhosis abstinence and nutritional support can lead to a marked improvement in liver function over time.

Features suggestive of malnutrition such as muscle wasting and vitamin deficiency are seen commonly. In severe decompensation other intercurrent illnesses such as pneumonia or urinary tract infection or a gastrointestinal bleed are often present. Systemic inflammation may be the precipitant of decompensation in these patients.⁵

In alcoholic hepatitis liver enzymes are moderately raised with an aspartate aminotransferase (AST) rarely greater than 300 IU. The ratio of AST to alanine aminotransferase (ALT) is usually raised to greater than 2.⁶ A high white blood cell count and bilirubin are also typical. The liver is usually enlarged and fatty on ultrasound. Portal hypertension often complicates the clinical picture, presenting as worsening of ascites. Assessment of filling pressures can be difficult if ascites is tense. Further hemodynamic monitoring is recommended if there is any doubt regarding filling status or if cardiac output is thought to be compromised.

Strictly speaking, liver biopsy is required to make the diagnosis of alcoholic hepatitis and is often performed to assess the extent of fibrosis, although it is not required for acute management. Demonstrated under light microscopy, the Mallory’s hyaline and a neutrophil infiltration (the amount of which is a marker of severity and prognosis), necrosis of hepatocytes, collagen deposition, and fatty change establish the diagnosis.

The prognosis of patients with alcoholic hepatitis depends on the severity of the disease. Risk stratification is important, both in defining the indications for the use of specific pharmacologic agents aimed at the interruption of progression and in clinical research. Serum markers and liver histologic findings provide the best means for risk stratification, the presence of cirrhosis being a poor marker.⁷ In many cases, however, biopsy is precluded because of the risks of bleeding. Serum bilirubin, coagulation parameters, and creatinine have been shown to predict outcome and have been combined into several scoring systems; the discriminative function (DF); Child, Turcotte, Pugh (CTP); the Mayo end-stage liver disease (MELD) score; and the Glasgow Alcoholic Hepatitis (GAH) score have been used to evaluate outcome. Of these, the MELD score appears to offer the best prediction of mortality risk because of the inclusion of renal function (creatinine) as well as liver function; renal deterioration in this setting has a particularly poor prognosis.⁸ Standard critical care prognostic scores have also been used to assess the prognosis of patients with decompensated chronic liver disease of any cause. The sequential organ failure (SOFA) score has been shown to provide useful prognostic information.^1,9

In early disease, abstinence and good nutrition, including supplementation with B vitamins, is the mainstay of management. In severe disease, progression to hepatic encephalopathy and organ failure can be rapid. In addition to general supportive care, specific therapies have been used in an attempt to halt and reverse the hepatic inflammation and prevent the fall into multiple organ failure and ultimately death. Of these, and pentoxifylline have been the most extensively studied.¹⁰

Portal Hypertensive Bleeding

Portal hypertension is a significant complication of chronic liver disease leading to the formation of portosystemic collateral vessels. Of these vessels, the most significant clinically are those that occur in the wall of the stomach and esophagus. In patients with portal hypertension as a result of cirrhosis the development of gastrointestinal varices occurs in approximately 60% at the time of diagnosis.¹¹ The incidence of the first acute bleed in an unselected patient is relatively low at about 5% per year but it can be catastrophic when it occurs.¹² The mortality rate associated with the event has fallen over the past 20 years from approximately 30% to 50% to about 20% and control of the initial bleeding episode is achieved in about 90% of patients.¹³ Half of all fatalities occur in the first 5 days following an acute bleed and about half of them are due to uncontrolled bleeding and the rest are due to multiple organ failure. This pattern remains the same when mortality rate in the first 6 weeks following the first bleed is examined.¹³

Control of bleeding episodes is via direct endoscopic therapy, usually in the form of band ligation in the case of esophageal varices.¹⁴ Terlipressin, a synthetic analog of vasopressin, can be used as an adjunct to band ligation. Terlipressin induces splanchnic vasoconstriction and reduces portal pressure and has been shown to reduce mortality rate.¹⁵ There is some evidence that somatostatin may reduce the amount of blood transfused but the evidence is weak.¹⁶ Uncontrolled bleeding due to either failed endoscopic or pharmacologic therapy or when resources do not allow immediate endoscopic therapy may be managed with balloon tamponade of the stomach or esophageal varices. Primary control of esophageal varices is usually successful but balloons should not be inflated for more than 12 hours because of the risks of mucosal necrosis. Care should be exercised when inserting and inflating a Sensgtaken-Blakemore or Minnesota tube because perforation of the esophagus is usually fatal in this setting. Following control with the insertion of a balloon tamponade device, further endoscopic therapy, surgical shunting, or transjugular intrahepatic portosystemic stent shunts (TIPS) may be attempted. Of the shunt procedures used TIPS is the most commonly attempted, where technical skills are available. The procedure involves decompressing the portal circulation into the hepatic vein via a stent inserted percutaneously through the liver via the internal jugular vein. The procedure is a very successful salvage therapy for controlling bleeding but can induce certain complications, including (a) volume overload as a result of portal shunting into the right atrium, which can induce heart failure; (b) bypassing the portal circulation resulting in ischemic liver injury and, rarely, liver failure; and (c) worsening of encephalopathy grade (the most common complication) resulting in failure to wake from the procedure, the need for extended ventilation, and the risk of hospital-acquired infection. There have not yet been any controlled trials of TIPS as salvage therapy in this setting and it is unclear what role TIPS has in the management of acute bleeding varices as it may just result in prolongation of the dying process. Despite better prevention of rebleeding when compared to endoscopic therapy in patients with bleeding varices, a mortality benefit cannot be shown with TIPS.¹⁷ Recently, Garcia-Pagan and colleagues have shown that TIPS, not done as salvage therapy, but used as a primary form of therapy once the initial bleed has been controlled, results in a dramatic reduction in rebleeding rates and mortality rates.¹⁸ This study has huge resource implications and needs to be repeated.

Coagulation abnormalities are commonly present in patients with acutely bleeding varices, and abnormalities in clotting factors have been shown to be independent prognostic factors in patients with esophageal varices. Attempts to treat coagulation abnormalities with clotting components should be undertaken during an acute bleed to include fresh frozen plasma (FFP) and platelets targeted to correct abnormal partial thromboplastin time (PTT) and platelet count. Activated factor VII has also been investigated in this setting. The authors showed that in patients with worse cirrhosis, as defined by Child-Pugh grades B and C, recombinant activated factor VII (rFVIIa) increased the chances of controlling the bleeding, although a more recent study by the same group shows no difference between groups.¹⁹

Bleeding from varices is associated with infection. Between 35% and 60% of cirrhotic patients with bleeding varices have documented infection over the following 2 weeks.²⁰

The use of antibiotic prophylaxis has been shown to reduce the incidence of infection in this group of patients and to improve short-term mortality rate.20,21 It has been proposed that infection is the precipitant to an acute increase in portal pressure that may trigger bleeding.²²

Bacterial Peritonitis

Patients with chronic liver disease are at increased risk of infection. The immunosuppression associated with chronic liver disease is incompletely understood but relates to a range of factors including an impaired innate and adaptive immune response.23,24

In cirrhotic patients with ascites, decompensation to liver failure is often precipitated by infection. Bacterial peritonitis is a common and severe complication. It can be completely asymptomatic but can present with a range of symptoms and signs including local signs of peritonitis, abdominal pain, diarrhea, and signs of systemic inflammation such as fever, rigors, raised white blood cell count, hypotension, and tachycardia.²⁵

Bacterial peritonitis is often spontaneous, without any obvious source, although it can be secondary to other intra-abdominal disease. It is generally caused by aerobic gram-negative bacteria, although gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) should be suspected if there is treatment failure, especially if the patient has been taking prophylactic antibiotics.²⁶ In any patient with ascites and decompensation of liver disease, spontaneous bacterial peritonitis (SBP) should be suspected. Diagnosis is demonstrated by sampling of the ascitic fluid. An absolute leukocyte count in ascitic fluid of greater than 250/µL is diagnostic. Antibiotics should be started as soon as SBP is suspected, following blood culture and a diagnostic ascitic tap. Empiric broad-spectrum antibiotic coverage for gram-negative and MRSA organisms (depending on local prevalence) should be started until cultures are available.

Renal failure is a significant complication of SBP in patients with cirrhosis and is discussed later. The use of human albumin solution (HAS) in SBP has been shown to reduce the incidence of progression to renal failure and should be considered in this setting.²⁵

Outcome and Data on ICU Use in Decompensated Cirrhosis

Despite ICU care, the outcome in patients with decompensated cirrhosis is poor. In one study overall cumulative mortality rates were 36% in the critical care unit, 46% in the hospital, and 56% at 6-month follow-up.⁴⁷

In patients who require organ support within the critical care environment a number of observations can be made. Derangement of acute physiology at admission is a predictor of outcome, as it is for unselected patients admitted to the ICU.⁴⁸ In addition, the number of organs requiring support also is predictive of outcome, as it is in unselected patients.^47,49 If you compare the number of organs failing (defined as an organ-specific SOFA score greater than 3) there is an excess mortality rate associated with cirrhosis when compared to an unselected group (Fig. 75.2).⁵⁰ Patients with cirrhosis and three organ systems requiring support have a mortality rate in excess of 90% in some studies.⁴⁹ Severity of liver disease at admission has a significant bearing on outcome irrespective of indication for admission to the ICU.^49,51

Acetaminophen (Paracetamol)

Acetaminophen-induced liver failure is the cause of the vast majority of hyperacute liver failure. Acetaminophen poisoning is a common cause of presentation to acute and emergency departments in the United Kingdom and United States; however, the case progression to ALF following paracetamol ingestion is rare at just 0.6% of all presentations in the United Kingdom.⁶²

It was in the mid-1960s that the main mechanisms of paracetamol-induced liver injury were elucidated. The scheme outline by various groups revealed the production of electrophilic quinone imine (N-acetyl-p-benzoquinone imine, NAPQI), which covalently binds to hepatic proteins, was central to the resultant centrilobular necrosis seen following poisoning. The two major pathways for metabolism are the glucuronidation and sulfation of the phenolic group, with the metabolites produced excreted in the urine. In therapeutic doses approximately 80% of the drug is metabolized via these two pathways and 5% to 10% is excreted unchanged in the urine. The remainder is metabolized via the hepatic mixed function oxidase, cytochrome P-450, to produce NAPQI.

Following poisoning the half-life of acetaminophen is greatly prolonged because of the saturation of glucuronidation and sulfate conjugation. As a result, there is an increase in the quantity of NAPQI produced. NAPQI is extremely reactive in biologic systems and has a short half-life. Following poisoning, reaction of NAPQI occurs within the centrilobular portions of the liver and leads to necrosis in experimental models. It reacts with cellular constituents in a covalent and noncovalent manner. The exact mechanisms by which NAPQI induces cell death are incompletely understood but include the deactivation of critical cellular proteins, the induction of reactive oxygen species, and the activation of Kupffer cells.⁶³ The loss of regulatory protein function results in abnormal calcium homeostasis and resultant energy failure within the cell and mitochondria.⁶³ Other events such as noncovalent interaction with intracellular signaling and lipid peroxidation also contribute to the toxicity of this molecule. Following this primary toxic phase there is a secondary or extrinsic phase. This extrinsic phase is equated with the recruitment of immune cells to the liver. The liver is one of the major immune organs of the body. Up to 35% of the liver is made up of nonparenchymal cells, including endothelium, Kupffer cells, and resident lymphocytes. These cells, together with macrophages within the liver, perform a major role in immune regulation and in the filtering of antigens from the gut contents via the portal circulation. They are also implicated in the pathologic processes that occur following liver insult. Massive activation of immune cells in response to the intrinsic cellular damage induces the release of cytokines and chemokines both locally and into the systemic circulation.^64,65

The pathophysiologic consequences of severe liver injury result from a combination of factors, including the release of cytokines and other inflammatory molecules resulting from the necrosis of hepatocytes and activation of local and systemic immune cells, and from the loss of metabolic activity related to a critical reduction in liver cell mass. The relative contribution of these factors is not completely clear but is debated and has led to attempts at therapy including temporizing hepatectomy and nonbiologic liver assist devices.

The minimum dose that can induce hepatic damage appears to be about 125 mg/kg. This represents 15500-mg tablets in a 60-kg individual, although hepatic necrosis has been recorded at much lower doses, especially if associated with hepatic enzyme induction. Doses above 250 mg/kg (30500-mg tablets in a 60-kg individual) will often produce damage, and doses in excess of 350 mg/kg invariably produce significant damage.⁶⁶

The symptoms over the first 24 hours following a significant intake of paracetamol, irrespective of amount ingested, are usually nausea and vomiting. During the following 4 to 5 days, if liver failure ensues, there is a gradual worsening of the patient’s general condition. Those with significant overdose should be admitted to the hospital and monitored closely.

The antidote for acetaminophen poisoning is N-acetylcysteine (NAC). It provides complete protection against hepatotoxicity if given within 12 hours of nonstaggered ingestion.⁶⁷ Within 12 hours, if the time from ingestion is known with certainty and a plasma acetaminophen level is obtained, reference can be made to the nomogram to see if the potential for hepatotoxicity is present. The nomograms are unreliable if the time from ingestion is uncertain or if there was staggered ingestion over a period of time, as often occurs with therapeutic misadventure or repeated overdose. The use of alcohol often accompanies ingestion, making timing unreliable. Situations that alter normal cytochrome P-450 function such as drug induction, (chronic ethanol use, phenytoin, and isoniazid) again render the information unreliable.⁶⁸ The use of the nomogram as the only basis for the decision to withhold NAC therapy is to be discouraged because of the uncertainty associated with this timing and the catastrophic potential if NAC is erroneously withheld (Fig. 75.5).

The main effect of NAC is to increase hepatic glutathione production. This promotes the conjugation of NAPQI and its subsequent excretion. In addition, NAC may act as an antioxidant within and outside the liver. It is most effective if given within the first 8 hours following overdose but is still effective following this, although less so. There is some evidence that NAC is effective when administered to the patient up to 72 hours following poisoning, although the mechanism of action is unclear and probably relates to antioxidant effects rather than to any effect on acetaminophen metabolism.⁶⁹ The role of NAC in established ALF from any cause is more controversial despite widespread use, but recent data have lent support to its use certainly at lower coma grades. However, the mechanism of action is unclear.^70,71

Viral Hepatitis

Both epidemic and serum hepatitis were recognized well before the viral form was discovered. In the seminal work of Lucké and Mallory in 1946, they describe 196 patients who died of ALF following both epidemic hepatitis and serum hepatitis, related to the administration of blood products during World War II.⁵³

ALF following acute viral hepatitis is uncommon, with a reported incidence of 0.2% to 4% depending on the underlying cause.⁷² Liver failure following viral hepatitis tends to run an acute or hyperacute course with the onset of encephalopathy occurring within days or weeks of the first symptoms.⁷³

Hepatitis A is now rare in the United States and Western Europe but is still a common form of acute enterally transmitted hepatitis in the underdeveloped world where it is mainly a mild and self-limiting illness of children.73,74 Infection with hepatitis A carries the lowest risk of conversion to acute hepatic failure of all the hepatotropic viruses. In the West the incidence of ALF following hepatitis A appears to be higher than in the endemic areas. It occurs more commonly in adults and is more severe. Persistent infection with hepatitis A has also been reported⁷⁵ and even recurring following liver transplantation.⁷⁶ Diagnosis is made on the basis of IgM antibodies at the time of hospitalization although false-negative results can occur.⁷⁷

Hepatitis B may lead to ALF is several settings. It occurs most commonly following acute infection but can occur following an acute increase in viral replication following immunosuppressive therapy such as cancer chemotherapy or steroids as well as with coinfection with other viral agents such as delta virus. The host immune response is thought to be responsible for the severity of reaction to the virus, subsequent clearance, and the induction of ALF. This can be seen following the withdrawal of immunosuppressive therapy when there is a very active immune response to the increased viral load. In acute infection surface antigen (HBsAg) is often negative but IgM antibodies to the viral core (HBcAb) will usually be positive. Mutations to the precore stop codon or the core promotor region of the viral genome may be associated with a higher incidence of ALF.⁷⁸ These particular genes code for HBeAg, and lack of this antigen is associated with a more profound immune response. There have been reports of a very high incidence of ALF associated with outbreaks of acute hepatitis B in the setting of intravenous drug use and chronic hepatitis C infection.⁷⁹ Lamivudine antiviral therapy for acute HBV-induced hepatitis has been tried, but because of the lack of controlled trials, it is difficult to know if it or other drugs like it help.⁸⁰

Hepatitis C, as a cause of ALF, is rare in northern Europe and the United States but has been described.⁸¹ There is a wide spectrum of clinical presentation associated with acute infection with the more florid presentation associated with a more rapid clearance rate, suggesting that the magnitude of the initial immune response is important.⁸² Liver failure associated with acute infection appears to be more common in India and the Far East.⁸³ Acute infection may contribute to decompensation in patients with preexisting liver disease, and hepatitis C seropositivity may predispose to liver failure when coinfection with another hepatotropic virus is present.⁸³

Hepatitis E is likely the most common cause of ALF worldwide and certainly for the Indian subcontinent.⁸³ In the Far East acute HBV infection is the most common cause of ALF due to the high levels of endemicity.⁸⁴

The existence of hepatitis E was inferred before serologic evidence was available by a process of exclusion. It was long assumed that most if not all epidemic enteric hepatitis was due to the A virus. When serologic markers for hepatitis A became available in the early 1980s it was apparent that the majority of waterborne epidemic hepatitis were due to other agents, producing a syndrome similar clinically to hepatitis A.⁸⁵ Hepatitis E does not produce a chronic infection and in the vast majority is a self-limiting infection that occurs most commonly in young adults, in contrast to hepatitis A, which is primarily an infection of children. The incidence of hepatitis E associated with ALF is low, with a case-related mortality rate reported at about 0.5% to 4% in the general population but with a much higher mortality rate in pregnancy, as high as 20% in the third trimester. Pregnancy itself appears to be a risk factor for ALF, with a quarter of all infected female patients reported as pregnant in one series. However, this may not be particular to hepatitis E but rather due to the high incidence of epidemic hepatitis E in a relatively immunosuppressed state and pregnant patients do not have a worse prognosis compared to nonpregnant patients with ALF due to hepatitis E.^83,86

Five genotypes have been described with 1 to 4 infecting humans and genotype 5 infecting only birds. Genotype 1 is the most common in Asia, with genotype 2 more common in Africa and South America. Genotype 3 can infect both human and animals, whereas genotype 1 and 2 have been described only in humans.⁸⁷ In the West, travel to endemic areas is a risk factor, but sporadic cases are now being seen more commonly in the developed world. Some of these cases have been associated with contact with animals.⁸⁷

Seronegative hepatitis is the second most common cause of ALF worldwide in most published series. In northern Europe and the United States it comes in behind paracetamol toxicity, and in the developing world it is second to acute viral hepatitis (Figs. 75.6 and 75.7).

Seronegative hepatitis can be conveniently thought of as a single entity. In reality it is probably an amalgam of various causes that have defied definition or characterization, including acute presentations of autoimmune hepatitis, idiosyncratic drug reactions, and viruses.88,89 Seronegative hepatitis has a variable clinical presentation including a slow insidious onset of general malaise, jaundice, and ascites followed by progressive signs and symptoms of liver failure. At presentation the patient may be deeply jaundiced and may already have ascites and splenomegaly. It can also present with a hyperacute picture. The pattern of signs, symptoms, and organ failure is dictated by the rate of progression. In subacute seronegative hepatitis, the presenting clinical picture can be similar to that of decompensated chronic liver disease, causing occasional diagnostic difficulty. A liver biopsy is sometimes needed to differentiate between the two.

Acute Presentation of Autoimmune Hepatitis

Autoimmune hepatitis can occur at any time of life from childhood until old age. It is more common in women with a male/female ratio of 1:3. Presentation can be asymptomatic, discovered following routine laboratory testing, or more commonly, the infection may present with jaundice and general malaise. In rare cases autoimmune hepatitis can present as ALF.⁹⁰ Unfortunately there are no serologic tests with sufficient sensitivity or specificity to make the diagnosis certain. Patterns of markers in the right clinical setting and in the absence of other causes may be useful.⁹¹ The diagnosis of autoimmune hepatitis in the setting of ALF is difficult and a degree of uncertainty often lasts. Classically there is a combination of elevated immunoglobulin levels, autoantibodies, and confirmatory histologic evidence of hepatitis in the absence of active viral markers. Elevation of autoantibodies is often seen in patients with ALF due to other causes such as drug-induced liver disease.⁹⁰ Liver failure should be assessed in the same way as for other causes, and once signs of encephalopathy become apparent, standard prognostic criteria apply. The role of steroids is unproved but should be considered in patients prior to the onset of encephalopathy. Once the patient is listed for transplantation steroid use is controversial because of increased risk of infection.

Drug-Induced Liver Disease

The liver is a major site for drug metabolism in the body. Metabolism of xenobiotics (a chemical which is found in an organism but which is not normally produced or expected to be present in it) takes place in a series of specialized enzyme reactions that increase the water solubility of lipophilic molecules by the incorporation of polar groups. Drug metabolism often involves a number of processes. Intermediates produced during the process are sometimes more toxic than the parent drug and can cause liver damage by a number of mechanisms.

Drug-induced liver disease may be due to a known dose-dependent toxicity, as with paracetamol. Alternatively, unpredictable, rare, idiosyncratic reactions can occur with any drug with a frequency of about 1 in 1000 to 1 in 100,000 patient prescriptions.⁶⁸ Drug-induced liver failure can mimic all forms of acute and chronic liver disease. However, the predominant clinical presentation consists of either acute hepatitis or cholestatic liver disease. The former has a reported mortality rate of 10% irrespective of the drug.

The patterns of injury associated with these idiosyncratic reactions relate to the mechanism of damage and the cells involved.⁹² Many patterns have been described but it is massive hepatic necrosis that most often presents as ALF. Liver failure associated with severe cholestasis and veno-occlusive disease is also seen.⁹²

Liver injury usually is seen within 6 months following the initiation of therapy. Even if the diagnosis of drug-induced liver failure is considered, a search for other possible causes should be performed. Although any drug is capable of inducing liver injury, more common causes include herbal remedies and recreationally used drugs such as “ecstasy” and cocaine. If suspected, a comprehensive history with a timetable of drug initiation should be constructed. Management includes stopping the offending drug and supportive care. Transplantation should be considered once liver failure occurs as the outcome from drug-induced liver failure, other than that induced by paracetamol, can be poor.⁹³ Presentation profiles for various drugs causing ALF are shown in Table 75.1.⁶⁸

Pregnancy-Induced Liver Disease

In general, pregnancy-associated liver failure has the best prognosis when compared to all other causes of ALF, and prompt recovery can be expected with delivery of the fetus in most cases, if recognized early enough. Pregnancy-associated liver failure can present in several ways including the syndromes of preeclampsia and the HELLP syndrome (hemolysis, elevated liver function tests, and low platelets), liver rupture, and acute fatty liver of pregnancy.⁹⁴ Any cause of ALF can occur during pregnancy, and in particular viral hepatitis can be particularly fulminant in its course. This is especially true for hepatitis E and herpes simplex virus infection.

Although originally thought to be a variant of preeclampsia there is evidence that HELLP syndrome may be a separate entity and in fact more related to acute fatty liver of pregnancy.⁹⁵ Both HELLP and preeclampsia appear to be related to an endothelial injury, possibly immunologically initiated with activation of the coagulation and complement cascades and an imbalance of prostaglandin and thromboxane resulting in increased vascular tone, microangiopathic hemolytic anemia, and vascular thrombosis.⁹⁶ About 2% to 12% of severe preeclampsia is complicated by HELLP.⁹⁴ HELLP is thought to occur in approximately 1 in every 1000 live deliveries and patients usually present in the third trimester with nonspecific signs often seen in preeclampsia such as weight gain due to edema and hypertension. In addition, right upper quadrant pain accompanied by nausea and vomiting is commonly seen. Laboratory abnormalities include hyperbilirubinemia due to liver dysfunction and evidence of hemolysis. Transaminases are modestly raised and the platelet count is usually less than 100,000/µL. Liver biopsy, while commonly normal in preeclampsia, shows specific changes of periportal necrosis and fibrin microthrombi. Microvascular steatosis may also be present.⁹⁶ The liver failure associated with HELLP is manifest as a prolonged prothrombin time and ascites. Renal failure is common. Maternal mortality rate is low but fetal mortality rate has been reported to be between 20% and 60%, although some reports suggest this is lower at 7% and associated with twin pregnancies.^96–98 The treatment of choice is delivery of the baby. Conservative therapy is associated with an increase in both maternal and fetal complications.

Spontaneous rupture of the liver can occur in the setting of both preeclampsia and the HELLP syndrome, although it can occur de novo. It often presents with sudden onset of right upper quadrant pain accompanied by signs of hypovolemia or shock and is more common in multiparous women.⁹⁶ Spontaneous rupture of the liver has high maternal and fetal mortality rates. Its pathogenesis is unclear but it appears that periportal hemorrhage associated with HELLP syndrome may occur close to the capsule, resulting in lifting and bleeding into the potential space. These areas of the capsule then coalesce and rupture. Management of this devastating complication includes prompt delivery of the fetus, local surgical control with packs, and aggressive management of the accompanying coagulopathy. Embolization of any feeding vessels in the liver may be of utility if such skills are available. Hepatectomy followed by liver transplantation can be lifesaving and has been performed.

Acute fatty liver of pregnancy (AFLP) occurs during the third trimester of pregnancy and should be considered in any patient exhibiting signs of liver dysfunction. It is uncommon with an incidence of approximately 1 in 6659 live births.⁹⁹ If left untreated, maternal and fetal mortality rates are high. The treatment of choice is delivery and prompt recovery can then be expected. There is usually a prodromal illness over a couple of weeks with nonspecific symptoms progressing to jaundice and encephalopathy. Symptoms and signs of preeclampsia or HELLP syndrome are seen in a third of cases and there is some evidence of a common origin due to a fetal fatty acid metabolism disorder.⁹⁵ Diagnosis is critical and it should be differentiated from viral hepatitis or hepatic failure due to other causes. Liver biopsy can aid in the diagnosis and can be performed via the jugular route if coagulopathy precludes the conventional approach. Characteristic zone 3 microvesicular steatosis is seen. Delivery is the best treatment if diagnosed early. Characteristic features include normoblasts on blood smears and high serum urate. Bleeding can be a major problem during operative delivery. On occasion transplantation may be the only viable option. Triggers for transplantation in pregnancy-induced liver failure are not well defined and the Kings College Criteria perform poorly. Arterial lactate in the setting of encephalopathy appears to be the best predictor.⁹⁸

Wilson’s Disease

Wilson’s disease is a rare autosomal recessive disorder resulting from copper toxicity with primarily brain and liver manifestation. It usually presents in the second or third decade of life, although it can present from early childhood until late middle age.¹⁰⁰ The disease can present with predominantly liver or neurologic symptoms. Neurologic symptoms relate to the distribution of copper to the basal ganglia and result in movement disorders. Patients presenting with liver disease may presents with an active hepatitis, established cirrhosis, or ALF. Other signs such as Kayser-Fleischer rings are associated but not pathognomonic for Wilson’s disease. These greenish brown rings in the cornea result from the deposition of copper.

ALF due to Wilson’s disease can present at any age but more commonly presents in the early 20s. High urinary copper excretion is possibly the most predictable laboratory finding, although the patient may be anuric on presentation. A low serum ceruloplasmin is an additional indicator but again is unreliable in ALF. A high serum bilirubin in combination with modest elevations of transaminases and alkaline phosphatase is often seen, as is intravascular hemolysis, contributing to the raised bilirubin level. Patients with severe liver failure due to Wilson’s disease have an almost 100% mortality rate without liver transplantation, which should be considered as soon as the diagnosis is made.¹⁰⁰ There is debate as to whether liver failure secondary to Wilson’s disease is truly ALF, as cirrhosis is invariably present on liver biopsy at the time of presentation. Nevertheless, many patients present acutely and the presentation is often catastrophic. In this sense the timing of the onset and the lack of previous symptoms place fulminant Wilson’s disease in the ALF group. In an uncontrolled series the administration of D-penicillamine before the onset of encephalopathy was associated with survival.¹⁰¹

Neoplastic Infiltration

Poorly differentiated solid tumors such as breast and lung and hematologic malignancies can sometimes present with a syndrome of liver failure. There is often diagnostic delay and difficulty.

The syndrome can be considered as part of the hypoxic hepatitis group as zone 3 necrosis is often seen. The metabolic demand of the neoplastic cells and congestion within the liver sinusoids results in infarction of hepatocytes. Hepatosplenomegaly and a raised alkaline phosphatase are often present. Other stigmata including palpable lymphadenopathy and marrow or peripheral blood film changes may be present. Imaging may be diagnostic, especially with massive hepatomegaly, but biopsy may be required.¹⁰²

Budd-Chiari Syndrome

ALF secondary to Budd-Chiari syndrome is usually fatal without transplantation. The syndrome is defined as outflow obstruction to the hepatic veins and the underlying pathogenesis is thrombosis in the majority but tumor invasion or vascular membrane obstruction may be the cause. This is a rare disorder that occurs predominantly in young adults and affects more women than men. Overall, the 5-year survival rate varies from 50% to 80% in different series.¹⁰³ The vast majority of patients with the syndrome have at least one predisposing clotting abnormality, either congenital or acquired, such as a malignancy, myeloproliferative disorders, protein C or S deficiency, polycythemia rubra vera, lupus anticoagulant, antithrombin III deficiency, antiphospholipid syndrome, etc.¹⁰⁴ The fulminant form of the syndrome in which the patient develops encephalopathy within 8 weeks of the onset of symptoms is rare, and it is much more common for Budd-Chiari syndrome to present in a subacute form over a 3- or 4-month period, characterized by ascites, abdominal pain and hepatomegaly, jaundice, coagulopathy, and raised AST and alkaline phosphatase. Others present with signs of portal hypertension, including refractory ascites and variceal bleeding, and relatively intact hepatocellular function. The diagnosis is made with the combination of clinical presentation and imaging, including Doppler ultrasound studies of the hepatic vessels, plus or minus liver histologic examination, usually via the jugular route because of coagulopathy. Management of the syndrome depends on the manner in which it presents and the underlying cause. Medical management of the syndrome involves the use of anticoagulants and diuretics in an attempt to control ascites. Thrombolysis can be attempted in selected patients with recent onset disease.¹⁰⁵ In patients in whom there is progression to signs and symptoms of liver cell failure some sort of portosystemic shunting procedure may reduce symptoms and prevent progression of the disease, allowing time for collateral vessels to develop. Transjugular intrahepatic portosystemic shunt (TIPSS) is most often attempted unless there is evidence of a hypertrophied caudate lobe and inferior vena cava compression, making mesoatrial shunting a better option. In patients with signs of liver failure care must be used when considering a TIPSS procedure, as this can precipitate decompensation and rapid progression to ALF.¹⁰⁶ Liver transplantation is ultimately the only option in many patients in which there is a failure of medical and shunt therapy as well as in the fulminant presentation of the syndrome.¹⁰⁷ Anticoagulation is usually necessary in the immediate postoperative period.

Veno-occLusive Disease of the Liver

Veno-occlusive disease (VOD) of the liver is a nonthrombotic obstruction of the sinusoids, which may extend to the central veins, in the absence of thrombosis or other underlying disorder of the hepatic veins.¹⁰⁸ As a result of a toxic challenge there is acute damage to the endothelial cells, followed by their detachment and their embolization in the central area of the lobule, where they cause a postsinusoidal outflow block.¹⁰⁸ The most common cause is myeloablative chemotherapy induction regimens in preparation for bone marrow transplantation (BMT), being seen in up to 54% in some older series.¹⁰⁹ Other toxins are known to cause it and it was first described in children following the ingestion of herbal teas in South Africa and it represents a nonspecific response to certain noxious stimuli. Particular induction regimens such as high-dose cyclophosphamide and total body irradiation are implicated in the pathogenesis. The more aggressive induction regimens appear to result in a higher incidence of VOD. Recent reduction in incidence may be due to a reduction in the use of myeloablative regimens and better monitoring of plasma drug concentrations.¹¹⁰ The symptoms of VOD usually occur within 2 weeks of BMT. The development of jaundice, hepatomegaly, abdominal pain, and encephalopathy in the setting of recent BMT strongly suggests the diagnosis. Severe cases are characterized by evidence of hepatocellular necrosis and a high AST concentration. In 25% of cases, which are characterized as severe, the syndrome is progressive, leading to ALF.¹¹¹ Treatment options in these patients are limited as the outcome is poor with medical management or liver transplantation, although there is hope that newer therapies such as defibrotide (a deoxyribonucleic acid derivative anticoagulant with multiple modes of action), if initiated early before the onset of multiple organ failure, may improve the outlook. In addition, the prophylactic use has been tried in several noncontrolled reports.¹⁰⁸

Hypoxic (Ischemic) Hepatitis

“Shock liver,” “ischemic hepatitis,” or more recently hypoxic hepatitis is the most common cause of significant rise in serum aminotransferase (S-AT) seen in hospitalized patients (Fig. 75.8).

There is often an underlying chronic reduction in oxygen delivery to the liver due to comorbid disease states such as congestive cardiac failure or chronic respiratory failure. There is then a subsequent sudden acute drop in oxygen delivery due to a decrease in cardiac output or further hypoxia.

Diagnostically, there are three conditions that should be met: the appropriate clinical setting of circulatory, cardiac, or respiratory failure with a massive rise in S-AT and the exclusion of other causes of massive hepatic necrosis such as viral or drug-induced liver failure.¹⁰²

In patients with chronic congestive heart failure (CCHF), liver congestion is common. This is usually manifest as mild abnormalities of liver function tests, a prolonged prothrombin time, and mild ascites in some. Hepatic congestion is usually clinically unapparent unless jaundice is present, which can occur following multiple bouts of CCHF. Chronic congestion can lead to fibrosis and ultimately cirrhosis in some patients. Acute rises in serum transaminase and prolongation in prothrombin time, representing acute hepatic necrosis, most commonly develop in patients with CCHF when there is a sudden drop in cardiac output due to an event such as an arrhythmia or myocardial infarction. It is relatively uncommon for the liver to become involved during shock states because of the huge redundancy in blood supply and the ability of the portal system to compensate for any reduction in hepatic arterial flow. If, however, portal flow is already compromised due to passive congestion, then an acute drop in hepatic blood flow can result in ischemia. It is uncommon for hypoxic hepatitis to occur without a recognizable precipitant, but it can occur due to a silent myocardial infarction or arrhythmia, for example. It can occur before the diagnosis of CCHF has been made or be the primary diagnostic event in a younger patient with a cardiomyopathy. Clinically, severe ischemic hepatitis becomes apparent between 24 and 48 hours following an event and is manifest as huge rises in S-AT (up to 10-20 times normal). There is prolongation of the prothrombin time, encephalopathy, hypoglycemia, jaundice, and renal failure. The syndrome is usually self-limiting once the hemodynamic disturbance has receded, and there is a rapid fall in serum transaminases (usually 50% in the first 72 hours).¹¹² Occasionally, progressive liver cellular failure leads rapidly to death. Management should be aimed at investigating and supporting the underlying cause.

Heat Stroke

Liver failure in the setting of heat stroke can be considered to be part of the hypoxic hepatitis group of causes. The argument for its inclusion here is the zone 3 necrosis seen in the liver following autopsy in patients who survive long enough for a reperfusion injury to occur.¹⁰² The pathophysiology is complex but is probably related to dehydration and cardiovascular collapse plus increased oxygen demand and acute cardiac failure.¹⁰² Exertional heat stroke may occur in new recruits to the army or police force engaging in physical initiation programs. It can also occur in unacclimatized athletes in hot conditions or with drug overdoses such as cocaine and hyperpyrexia syndrome such as those induced by MDMA (methylenedioxy-N-methylamphetamine). It is a potentially devastating syndrome that can lead to multiple organ failure and death. It ranges from mild involvement to ALF and is seen to develop during the first few days following the event. Management is supportive and the majority improves over a period of days to weeks. Liver transplantation has been used in severe cases but the outcome is poor owing to coincident organ failure.¹¹³

Mushroom Poisoning

There are many types of poisonous fungi in the world that are responsible for a variety of disorders that can be classified according to the type of poisoning and the timing of onset.¹¹⁴ There are a number of fungi associated with the induction of liver failure following ingestion. Of these, the most common and most deadly are of the genus Amanita. Amanita associated hepatotoxicity follows a triphasic response after ingestion. The first is a self-limiting, nonspecific gastrointestinal upset that occurs within the first 6 to 24 hours. Nausea and vomiting, abdominal cramps, and diarrhea are often seen and it can mimic food poisoning. This is followed by a period of recovery and a few days later by progressive liver failure.

Management is essentially supportive, although many specific therapies have been tried in the treatment of Amanita toxicity such as high-dose penicillin, silibinin, cimetidine, and NAC, but none has been shown to improve outcome. Liver transplantation should be considered for patients with severe liver failure and standard criteria apply.¹¹⁴

History and Physical Examination

The presentation and clinical course of ALF depends on its cause and the rate of progression of the syndrome. This varies widely from admission via an emergency department following a paracetamol overdose or acute viral hepatitis versus admission from a hepatology outpatient department in a patient with progressive jaundice and ascites. Owing to its relative rarity the diagnosis can often be missed during initial contact and this delay may detrimentally influence the outcome.

The history will initially focus on the rate of progression of the illness and any clues to the cause. The first symptoms are often the onset of jaundice (typically noticed by a relative). Any history of foreign travel or high-risk behavioral activity (intravenous drug use or unprotected sex) associated with the contraction of viral hepatitis should be investigated. A thorough drug history should be taken for prescribed and recreational drug use for the preceding 6 to 10 weeks. Drug therapy or recreational use that can induce or inhibit hepatic enzymes should be noted. If the patient is unable to provide this information, the relatives and the patient’s primary care physician should be contacted for help.

The history may be self-evident in the case of paracetamol hepatotoxicity, especially if the patient is self-presenting following deliberate self-harm. However, therapeutic misadventure, which is a relatively common cause of hepatotoxicity, especially in the United States, may not be obvious unless considered by the physician.¹¹⁵ Any patient presenting with coma should have a drug screen (including paracetamol).

Subacute liver failure has, by definition, a more insidious onset. Jaundice is often preceded by nonspecific symptoms of fatigue and general malaise. Abnormal liver enzymes will often be revealed during the initial workup. Subsequent investigations will include viral, iron, copper and genetic studies and, in addition, attempt to rule out decompensation of chronic liver disease as a cause the current symptoms and signs. Liver biopsy may be considered in subacute liver failure (Fig. 75.9).

Initial Resuscitation and Emergency Care

Patients presenting with acute or hyperacute liver failure tend to follow a similar course irrespective of cause. Initial therapy and emergency care will be dictated by the condition of the patient at presentation. Liver failure is a multisystem disease and can progress very rapidly to multiple organ failure.

Patients presenting with rapidly progressive hepatic encephalopathy via the emergency care system will often be intubated and ventilated at the time of or shortly after admission. The emergency physicians will often perform a head computed tomography (CT) scan because of diagnostic uncertainty.

The symptoms and signs of hepatic encephalopathy in ALF are subjectively different from those seen in decompensated chronic liver disease or in patients with stable chronic encephalopathy. Agitation and aggressive behavior are more common in ALF. This may be based on an increased turnover of the excitatory neurotransmitter glutamate in ALF associated with an acute increase in cerebral ammonia uptake.¹¹⁶

The West Haven criteria, designed to assess coma grade in patients with cirrhosis, are often applied to patients with ALF and are useful because of familiarity.¹¹⁷ However, once the patient becomes unconscious at grade IV encephalopathy, the scale does not provide any further information and is too crude to provide a clinically useful description of the level of consciousness. The Glasgow Coma Scale score, while not assessed specifically in this setting, is useful in relating clinical information to others.¹¹⁸ Encephalopathy grade can progress very quickly, especially with hyperacute presentation. Intubation and sedation are recommended once grade III encephalopathy is achieved because of the attendant risks to airway and possibilities of raised intracranial pressure, discussed later. Figure 75.10 describes encephalopathy grade and Glasgow Coma Scale score.

Early contact with a regional liver center should be made in any patient with signs of acute severe liver dysfunction as serial blood results and clinical signs can be relayed to the center over the phone. POD patients can often be managed over the phone but plans for transfer can be made well in advance, if necessary. As liver failure progresses over the next several days, a number of organ systems may become affected.

Following the safe and appropriate management of airway and breathing, focus can be directed to the correction of any circulatory dysfunction. Patients with ALF can progress rapidly to circulatory shock. The circulatory changes associated with ALF are predictable, usually associated with systemic vasodilatation and relative hypovolemia. This can be profound and require significant volume resuscitation. It is easy to underestimate the amount of fluid required in the early stages of ALF and the use of prognostic markers is unreliable before adequate circulatory function is restored. Monitoring at this stage should include a central venous catheter and direct arterial access for both blood pressure monitoring and for repeated blood tests. Care must be given to serum electrolytes because they often become deranged during this initial period. In particular, hyponatremia and hypophosphatemia are common.119–121 This may be due to excess quantities of hypotonic fluid administration. A typical flowsheet of investigations of a patient presenting with paracetamol poisoning from a referring hospital is shown in Box 75.2.

Regardless of cause, patients with significant liver damage or signs of secondary organ dysfunction should be managed within the ICU. The speed at which patients deteriorate can be very rapid and it is not uncommon for hepatic encephalopathy to progress from grade 0 to grade IV over several hours.

For prognostic reasons it is important not to avoid correcting any biochemical coagulopathy at this stage if possible. Despite quite significant prolongation of prothrombin time, bleeding from line sites is uncommon in the initial stages of ALF. In fact, there is evidence that the patients are prothrombotic in vivo.¹²²

Investigation in a Patient with Suspected Acute Liver Failure

Initial investigations provide a baseline from which important diagnostic and prognostic information is taken. Serial blood test measurements should be performed as severity and prognosis are assessed over time from initial presentation (Table 75.2). Depending on the manner and speed of presentation, a complete blood count, clotting tests, liver function tests, arterial blood gas measurements, and ammonia levels should be performed twice daily, if not more often, in the early stages to assess progression of the illness. A liver ultrasound scan to assess liver size and blood supply should be performed.

Transfer Criteria Guide

ALF is a sporadic syndrome with a case incidence of about 2000 per year in the United States.¹²³ Management is complex and liver transplantation is the only effective therapy in severe cases. Transfer to a unit with experience in the management of these patients, preferably one with a liver transplant program, will provide optimal care. It is often difficult to decide when or whether to transfer a patient with acute liver dysfunction, and this decision will vary according to cause and presentation. The best described clinical course is that following severe paracetamol poisoning after a deliberate overdose.⁵² Staggered overdose and therapeutic misadventure are less predictable in their clinical course but often have a poor outcome and can be considered a poor prognostic risk factor.¹²⁴

The following criteria for transfer are based on expert opinion and have not been subjected to rigorous study and err on the side of caution⁷² (Fig. 75.11):

Supportive Care

Intracranial Hypertension

Infection and Immunosuppression

Patients with ALF have multiple immune defects and are susceptible to infections.²⁰⁰ Infection is a common cause of progression and complication in ALF.²⁰¹ Antibiotic prophylaxis has been shown to reduce the incidence of infection and enable transplantation to proceed but has not been shown to improve survival. Selective decontamination of the digestive tract has not been shown to be superior to intravenous antibiotics alone.^200,202 More recent work has shown how the microbiologic flora of a liver unit has changed over the past 20 years—for example, bacteremia appearing later in the ICU stay and being predominantly gram-negative in nature.²⁰³

It is current practice to prescribe broad-spectrum antibacterial and antifungal medication to patients with ALF depending on local sensitivities. There is a general trend to the timing of infection with gram-positive infections occurring earlier than gram-negative. Early gram-negative infections tend to be less resistant “endogenous” bacteria followed later by resistant hospital-acquired organisms.204,205

Nutrition

Within the general intensive care literature there is a consensus toward enteral nutrition (EN) as the route of choice.²⁰⁶ There are few additional data on which to base decisions in patients with ALF. There is, however, wide regional variation in the prescribing of parenteral nutrition (PN) compared to EN. The reason for this is unclear as EN is associated with a reduction in infectious complications.²⁰⁶ However, it is clear that some centers prefer PN.²⁰⁷ Nutritional requirements in ALF are not well understood.

Energy expenditure is raised during ALF. This is surprising considering the normal contribution of the liver, a large metabolically active organ, on the overall energy expenditure, illustrated by the effects of hepatectomy on energy expenditure during elective liver transplantation.²⁰⁸ There is organ-specific lactate production in both the liver and the lungs and evidence of a systemic inflammatory response in many patients.^201,209,210 The cause of systemic inflammation in ALF is activation of inflammatory cells (leukocytes and endothelium) and the release of systemic cytokines. This may be initiated by infection.²⁰¹ Patients in the early stages of ALF are markedly catabolic with insulin resistance despite the frequent presence of a hypoglycemic state.²¹¹ The Harris-Benedict equation is inaccurate in ALF and indirect calorimetry should be used if energy requirements are sought.

Hypoglycemia is common as a result of the failure of both glycogenolysis and gluconeogenesis. Massive hepatic necrosis can result in a precipitous fall in serum glucose concentration. For this reason an infusion of 50% glucose should be used at least until feeding is established. Low-volume, high concentrations of glucose are preferred to reduce the infusion of large quantities of water and the resultant hyponatremia if lower concentrations are used.

Serum amino acids are consistently deranged during liver failure. There is a low or normal concentration of glutamine, branched chain amino acids, and tryptophan and an increase in others.²¹² High brain concentration of ammonia is thought to contribute to cerebral edema and encephalopathy in ALF. Manipulation of ingested amino acids has been investigated in an attempt to reduce ammonia concentration. L-Ornithine and L-arginine (LOLA) infusion encourages alternate pathway metabolism and reduces hepatic encephalopathy in chronic liver disease.²¹³ LOLA has been investigated in animal models of ALF and resulted in normalization of plasma ammonia concentration, significant delay in the onset of encephalopathy, and a reduction in brain water concentration.²¹⁴ LOLA has been investigated in 2009 with a randomised controlled clinical trial in ALF. Despite theoretical promise, the investigators were unable to show any reduction in mortality rate or ammonia between the groups.²¹⁵

N-Acetylcysteine (NAC) is primarily used as a glutathione precursor and antidote in paracetamol poisoning but is used widely in patients with ALF induced by other causes and later on in its subsequent course. Results of a recent randomized controlled clinical trial have shown efficacy with NAC in patients with low-grade encephalopathy and nonacetaminophen-induced liver failure. The mechanism of action is unknown.⁷⁰

There is little evidence that protein restriction has any role in ALF, and protein requirements based on total calorie ingestion should be used.

Serum electrolytes are often deranged in the early stages of ALF. Hypophosphatemia is common in patients with ALF and is a good prognostic sign. High or normal phosphate may indicate a lack of hepatic regeneration and renal impairment.¹²⁰ Hypomagnesemia is also common and should be corrected.

Biologic Systems

Biologic systems consist of a bioreactor within which the cellular biomass is contained, and a mechanism of containing and separating the biomass from the circulation of the patient. They require an extracorporeal system to deliver blood or plasma to the bioreactor and may also contain an adsorption or dialysis component. Data from liver resection suggest that approximately 250 mL of liver by volume is required to prevent death from liver failure. This typically represents 20% to 30% of liver mass.²¹⁷

Possible cell types to use as the biomass include animal or human primary hepatocytes or other forms of cell line with hepatocyte phenotype. Primary hepatocytes outperform other cells lines but are of limited availability and tend to have a time-dependent loss of hepatic phenotype. In addition, scaling up production with primary hepatocytes is difficult, as they do not readily undergo cell division under laboratory conditions. Instead, they have to be directly seeded into the bioreactor either immediately following harvest or following a period of storage and cryopreservation. Human cells are limited in availability but can be obtained from unused livers, following donation, and cut-down grafts. Theoretically, animal cells are readily available but uncertainty about possible cross-infection from animal pathogens to the patient with organisms such as PERV (porcine endogenous retrovirus) and incompatibility of secreted antigens render them far from ideal, and regulatory authorities are often reluctant to sanction their use.

Immortalized cell lines that proliferate in culture, while retaining some liver-specific functionality, can be used in an attempt to overcome the limitations of primary hepatocytes. Many lines have been created by retroviral transfection with regulatory genes that stimulate cell division. The insertion of “terminator” genes that give the cells a limited life or enable switching the immortalizing gene off have also been developed to improve safety.²¹⁸ Other sources of immortal and readily cultured cells are tumor derived such as the ubiquitous Hep G2/C3A hepatoblastoma line. Finally, stem cell sources appear to offer the most hope in terms of a readily available and functional supply of differentiated hepatocytes.²¹⁹

Clinical trials in the use of bioartificial liver support have been relatively disappointing. The bioartificial liver (BAL) uses porcine hepatocytes and a charcoal column in series. The largest trial published so far in the field was powered for survival advantage in ALF and primary nonfunction following liver transplantation.²²⁰ The study was terminated early by the data and safety-monitoring board because the trial was likely to be futile based on the results at interim analysis.²²⁰ Post hoc analysis suggested some effect in the ALF group alone. The extracorporeal liver assist device (ELAD) system uses Hep G2/C3A hepatoblastoma line and has been investigated in a number of phase 1 and phase 2 studies designed to report safety and activity. In a randomized controlled study, not powered for mortality, showed a trend for improved survival in the treatment group.^221,222 Since then, two further studies of the ELAD machine have been conducted in patients with AoCLD, both published as abstracts, both suggesting an improvement in outcome.^223,224

Nonbiologic Systems

Many of the molecules that accumulate within the blood during ALF are small or middle-sized.²¹⁶ These molecules can be targeted by a variety of extracorporeal purification techniques, including dialysis through various types of membranes and adsorption onto carriers such as charcoal, resins, or albumin.

Nonbiologic systems are attractive because they are relatively inexpensive (compared to biologic systems) and logistically much easier to implement.

Early work with hemodialysis was unsuccessful and was largely abandoned with the conclusion that the toxemia of ALF was not due solely to small water-soluble molecules. The advent of synthetic membranes in the 1970s rekindled the interest in convective therapy for ALF. These allowed larger molecules to pass through compared to the cuprophane alternatives. Opolon reported clinical improvement with the use of high-permeability membrane hemodialysis and hemofiltration in patients with ALF.²²⁵ Hemofiltration, as a form of renal support, is used in most liver critical care units as part of general supportive care and there is some evidence that increased convective exchange, with high-volume (>35 mL/kg/hour) hemofiltration, is associated with improved hemodynamic stability and improved encephalopathy scores.^145,225

Charcoal hemoperfusion has been extensively investigated. Initial trials were encouraging, but later larger randomized controlled trials were unable to show an improvement in outcome.¹³⁷ Large volume plasma exchange showed some improvement in hemodynamics and other parameters in initial studies.²²⁶ The therapy is logistically difficult to perform. However, in 2010 a large randomized controlled clinical trial of high-volume plasma exchange (10 L/day for 3 days) was presented and published in abstract form, showing improved survival, and it may become a standard form of therapy.²²⁷

In an attempt to improve the efficacy of dialysis techniques, adsorbents have been added to the dialysis fluid to widen the range of molecules removed. There are a number of approaches to doing this. One is dialysis of blood or plasma against albumin solution. This is done via a recycled circulation in the MARS machine or via single pass albumin dialysis. Another is the use of plasma separation, adsorption, and filtration and then recombining the “cleaned” plasma with the patient’s blood.²²³

Nonbiologic systems have been shown to improve blood pressure, increase vascular resistance, and improve short-term encephalopathy scores in patients with AoCLF. Three large studies have been reported, two in the management of AoCLF (the RELIEF study and the HELIOS study) and the FULMAR study in patients with ALF. Unfortunately, none of the studies has shown an improvement in outcome.²²³

When and Whom to Transplant

Liver transplantation for ALF was used sporadically during the 1980s but gained pace in the late 1980s and now has a huge impact. It remains the only definitive form of therapy for some.

Timing is important, and in those with severe liver injury there is a window of opportunity beyond which transplantation often becomes futile because of deteriorating organ function.²²⁸ It was recognized early in the history of transplantation for ALF that the challenge was to develop robust prognostic indicators. These have to be sensitive, early enough to provide maximum advantage to the patient, and specific enough not to result in unnecessary transplants.

A “super-urgent” designation exists in the national transplant sharing scheme in the United Kingdom with a similar “category 1A” designation in the United States (see http://www.unos.org/ for details). These categories recognize the role of early transplantation in ALF and the detrimental effect of delay in this setting.

In the United Kingdom, the super-urgent designation (Box 75.5) is closely linked to the prognostic score developed in King’s College Hospital in the late 1980s using retrospective multivariate analysis with prospective validation.²²⁹ The prognostic criteria have been subsequently validated in other centers and shown to be robust.²³⁰ Other criteria have been developed.²³¹

The criteria are not perfect. First, despite their good specificity (i.e., if the patient meets criteria the patient is likely to die), the sensitivity and negative predictive value are not as good, and there is a substantial proportion of patients who will die without ever reaching transplant criteria. In addition, awaiting positive criteria can lead to delay in listing and worsening of organ failure that often then preclude listing. This contributes to the fact that published rates of transplantation in those who reach criteria are only 50% following POD.²³² Clinical practice has changed since this designation was first defined. For example, it is rare to see a patient following POD with a pH below 7.3 or a creatinine above 300 mmol/L because of improved resuscitation and early renal support at the referring hospital. Because of these factors, ongoing efforts to establish markers that increase sensitivity and occur even earlier in the course of the syndrome, while maintaining good specificity and not reducing the positive predictive value to unacceptable levels leading to unnecessary transplants, continue.

Serum phosphate levels are higher in nonsurvivors following both POD and in other causes of ALF.120,233 However, there appears to be an unacceptable overlap and others have suggested that the use of serum phosphate does not provide any additional benefit to existing markers.^121,234,235 Other factors investigated include α-fetoprotein levels and nuclear magnetic resonance (NMR) analysis of peripheral blood.^120,236 Acute physiologic scoring as a basis for prediction has also been utilized.²³⁷

The liver plays a central role in lactate metabolism. In fact, in patients with severe liver necrosis the liver changes from being a consumer of lactate to being a net producer.²⁰⁹ Arterial blood lactate levels have been shown to improve the sensitivity and maintain the specificity if added to the original King’s College Hospital criteria and are achieved earlier in the course of the syndrome.¹⁴⁹ However, the additional advantage of lactate over the original criteria has been questioned by some.²³⁸

On the practical issue of actually managing patients with fulminant hepatic failure some room for clinical interpretation has been included in the super-urgent listing rules. For example, there is a group of patients who do not achieve King’s College Hospital criteria but subsequently die, usually of cerebral edema or multiple organ failure secondary to sepsis.172,175 These patients often have worse acute physiologic scores compared to survivors.^232,237 As a result the U.K. super-urgent criteria allow an assessment of deteriorating acute physiology based on cardiovascular, respiratory, or cerebral disease. Similarly, the UNOS 1A criteria allow for patients “not expected to survive a further 7 days.”

Outcome from Transplantation

In Europe the 1-year survival rate following transplantation for ALF is worse than that seen in chronic liver disease. The excess mortality rate is seen in the first month or so after transplantation. This represents the severity of organ dysfunction seen prior to transplantation in ALF. Following this initial period, the curve flattens and the survival rate is actually better than that of patients with chronic liver disease (Fig. 75.15). This probably represents a younger age group and less disease recurrence. There is a huge degree of heterogeneity in ALF, and those transplanted with seronegative hepatitis display a better survival profile than patients transplanted for other causes, although they exhibit a similar early mortality rate while in the ICU.⁸⁹

A tremendous amount of research effort has been put into the search for prognostic criteria on which to base the decision to transplant patients with ALF; however, much less information is available about the prediction of fatality following transplantation. This is important, as decisions to withdraw from the waiting list based on severity are difficult.

There appear to be both recipient and donor factors that help predict the outcome from transplantation in ALF.89,232,239 In theory, the severity of illness and organ dysfunction prior to transplantation should predict outcome. However, because unstable patients tend to be either not listed or withdrawn from the waiting list, there is inherent bias in retrospective analysis. Age of the recipient is a significant factor, certainly for seronegative ALF, but also in POD, in which age is often used to exclude listing.²³² In non-paracetamol ALF, serum creatinine at the time of transplantation is a predictor of 2-month survival. Following POD, time from ingestion to transplantation has been shown to be a good predictor of 2-month survival; all patients transplanted later than 6 days from ingestion died. APACHE III score at transplantation and the severity of metabolic acidosis are also predictive.²³⁹

Donor factors found to be important are the use of reduced size grafts in paracetamol-induced ALF and evidence of early graft dysfunction as defined by a high AST or INR in the early postoperative period. In addition a high donor body mass index (BMI) is a risk factor for death in seronegative hepatitis.89,232

In 2012 a review of the European liver transplant database for patients transplanted following ALF was done in which 4903 patients were evaluated. The 1-, 5-, and 10-year patient and graft survival rates were 74%, 68%, and 63%, respectively. Death and graft loss were independently associated with male recipients, recipients older than 50 years, incompatible ABO matching, donors older than 60 years, and reduced size graft. Recipients over 50 receiving a graft >60 years old had a 57% 1-year mortality rate or graft loss.²⁴⁰

The conclusions from this review suggest that older recipients with severe preoperative organ dysfunction are less able to tolerate poor early graft function, often seen with marginal grafts. Therefore, in order to achieve the best graft and patient survival there should be matching of the organ to the recipient, but this is difficult because of time constraints.

Auxiliary Transplantation

Auxiliary partial liver transplantation has many theoretical advantages compared to standard orthotopic transplantation in ALF. It can be performed orthotopically (i.e., in the same place as the original liver) or heterotopically (e.g., in the left iliac fossa). These days it is always performed as a partial orthotopic transplant with a native left lobe in situ in adults and a right lobe in children using an adult left lobe graft, depending on size.

It provides the potential to support the patient during the acute phase of liver failure, enabling regeneration of the native liver. This is attractive because in a number of patients immunosuppressive drugs can be withdrawn, allowing the graft to atrophy or be removed, and eliminating the risks associated with lifelong immunosuppression. Data on this procedure have been accumulating since the mid-1990s. Initial reports suggested that the procedure was associated with a high incidence of technical problems, primary dysfunction, and retransplantation. Later reports, however, suggest that many of these issues are resolving with greater experience in patient and graft selection. The best outcome has been seen in patients aged younger than 40 years with either acute viral hepatitis or paracetamol hepatotoxicity in which 1-year graft and patient survival are similar to those for standard transplantation for ALF. Withdrawal of immunosuppression can be achieved in 30% to 70% of patients transplanted.241–243

Living Related Lobe Donation

In many countries the only chance of transplantation for ALF is in a living related donation of a liver lobe. This is most often performed in children when an adult left lobe can be used. In adults, a right lobe is usually required, increasing the risk to the donor. With the worldwide shortage of donor organs, living related transplantation for ALF is widely accepted in many countries but not all. There are significant issues related to living related transplantation in ALF including a donor mortality rate of 1% and major morbidity rate of 40% to 60%. There are also ethical implications of adequately preparing the donor, medically and psychologically, in a time of acute crisis.²⁴⁴