Varices

Bleeding from varices is a major cause of morbidity and mortality in patients with significant PHT. Life expectancy after variceal bleeding is considerably curtailed, both as an immediate consequence of hemorrhage (and related complications, such as sepsis and renal failure) and in the longer term due to rebleeding.

Two main mechanisms have been implicated in the pathogenesis of variceal hemorrhage in patients with established varices and PHT: erosions secondary to acid reflux and spontaneous rupture. Effects related to ascites and changes in plasma volume also have been implicated in the genesis of bleeding. Ascites may be a factor in variceal hemorrhage, because ascites can transmit intraabdominal pressure and thereby increase the pressure inside the esophageal varices. Some studies have shown a decrease up to 10% in the hepatic vein pressure gradient (HVPG) and a decrease in portal flow with paracentesis. Drainage of large volume of ascites can decrease intraabdominal pressure, leading to splanchnic dilation and increased blood flow against a fixed resistance in the liver.⁵ This circumstance would increase portal pressure and, hence, the risk of bleeding. The pressure inside the varices does seem to be affected by intraabdominal pressure, but whether this affects the risk of bleeding is not known. Erosions secondary to esophagitis also have been suggested as an important factor for the bleeding process.^6,7 However, there was no evidence of acid reflux in patients studied with a pH electrode, and treatment with cimetidine did not affect the rates of rebleeding from varices.⁸

The pressure inside the varices is directly dependent on the portal pressure and also on the radius of the varix. The pressure within the varix is inversely proportional to wall thickness. Therefore, varices are more likely to bleed when they are larger and have a thinner wall. Large, thin-walled varices are generally located near the gastroesophageal junction where the veins are more superficial and less surrounded by other tissues. There is a relationship between the risk of bleeding and portal pressure. If the HVPG is greater than 20 mm Hg after an initial bleed, it is a poor prognostic sign, and there is a substantial risk of rebleeding and mortality.⁹ In a recent study, patients underwent portal pressure measurement after initial endoscopy and control of bleeding. Those whose pressure was above 20 mm Hg were randomized to early transjugular intrahepatic portosystemic shunt (TIPS) or conventional treatment. The group who underwent TIPS shunt insertion had an improved outcome compared to the standard-of-care high-risk group and similar to that of the low-risk group. Recent work has also suggested that portal pressure may be equally predicted by Child-Pugh score, and thus in this group of patients, consideration should be given to early TIPS shunt insertion.

It may be equally possible to measure variceal pressure at the time of endoscopic band ligation. This appears to be feasible and safe, although it remains at present an experimental method, and more studies are required.¹⁰

The main risk factors for rebleeding and mortality according to the North Italian Group of Portal Hypertension are the Child-Pugh class, the size of the varix, and the presence or absence of red wale markings and/or cherry spot at endoscopy.

There is increasing evidence to suggest that an episode of infection is the precipitating event in most cases of variceal bleeding. Infection is thought to trigger the release of cytokines and other proinflammatory mediators, resulting in increased hepatic resistance and possibly increased portal venous flow, with a sudden rise in portal pressure. A postprandial increase in splanchnic blood flow also may contribute to an acute rise in portal pressure.

Gastroesophageal varices are present in approximately 50% of cirrhotic patients and are large in 20%. Approximately one-third of patients with varices have bleeding complications. The patients at greatest risk of bleeding are those with advanced liver disease and large varices and high-risk stigmata. It is important, therefore, to identify the population at risk and modify their risk of bleeding. In patients with cirrhosis, the incidence of varices is 5% per year.

Gastric varices can be classified into four different groups: GOV1 is the gastric varix that is a direct continuation of an esophageal varix; GOV2 are also a continuation of a esophageal varix, but are more extensive and reach the fundus of the stomach; IGV1 are fundal varices that are not in continuity with an esophageal varix; and IGV2 are gastric varices that do not originate from a esophageal varix and are located in the body of the stomach. GOV2 and particularly IGV1 bleed more commonly than other gastric varices.

Portal hypertensive gastropathy is a complication of PHT that causes flow and pressure changes in the gastric mucosa. Mild or chronic bleeding is observed in 35% of the patients with mild gastropathy and 90% of those with severe gastropathy. Overt bleeding happens in 30% of those with mild and in 60% of those with severe gastropathy.¹¹ The administration of propranolol decreases gastric mucosal blood flow and is effective in reducing bleeding in portal hypertensive gastropathy.^12,13 TIPS and transplant are effective modes of treatment.

Another form of gastropathy is gastric antral vascular ectasia (GAVE). This lesion is localized at the antrum, and is associated with poor hepatic function. GAVE carries a high risk of bleeding. It is best managed with endoscopic therapy, generally with sessions of argon plasma coagulation (APC) until hepatic transplantation can be performed.

Pharmacotherapy

At the same time as resuscitation, first-line treatment of suspected variceal hemorrhage in patients classified as high risk should include pharmacotherapy with a vasoactive drug prior to endoscopy. Treatment in this way will decrease portal flow, pressure, and variceal bleeding and frequently increase systemic arterial blood pressure.

Terlipressin (Glypressin) is a prodrug of vasopressin that has some intrinsic activity. It acts on vasopressin-1 receptors within arteriolar smooth muscle and induces vasoconstriction via phospholipase C–dependent signaling.¹⁷ Treatment with terlipressin results in splanchnic vasoconstriction and decreases splanchnic inflow, thereby reducing portal pressure. Terlipressin also reduces collateral blood flow and variceal pressure.¹⁸

Compared with vasopressin, terlipressin is associated with a lower incidence of systemic ischemic events, and unlike vasopressin, terlipressin can be used safely without coadministration of nitroglycerin or other organic nitrates. Terlipressin has a longer half-life than vasopressin and can be administered intermittently. A dose of 2 mg IV given four times daily is as effective as endoscopic sclerotherapy for achieving initial control of variceal bleeding and preventing early rebleeding.¹⁹ Terlipressin has been shown to decrease mortality and length of stay when administered to a high-risk population of patients presenting with acute upper GI hemorrhage.²⁰

Terlipressin is well tolerated and has few side effects and may represent first-line treatment in acute hemorrhage until endoscopy can be performed in a controlled environment. In a recent meta-analysis, terlipressin was more effective than placebo but less effective than octreotide for controlling bleeding.²¹ Despite these findings, a recent study showed equivalence between terlipressin and octreotide.^22,23

The duration of treatment should be governed by the clinical situation. After 48 hours of therapy, however, the dose should be tapered (initially halved), seeking to achieve a course of therapy lasting 6 to 7 days. A recent study compared endoscopic banding therapy and banding in addition to 5 days of terlipressin.²⁴ Outcome was improved in the cohort that received combined therapy.

Treatment with somatostatin also may be considered. The dose of somatostatin is 250 µg as a bolus followed by 250 µg every hour as an infusion. The efficacy of somatostatin in the control of bleeding is not totally clear. In a recent meta-analysis of studies of somatostatin compared to control or no treatment, the use of somatostatin was associated with initial hemostasis but not with a decrease in mortality or rebleeding.²⁵ The treatment effect of somatostatin amounted to lowering the transfusion requirement by 0.5 units of blood per patient. In view of these findings, somatostatin cannot be recommended as the first-line agent for the control of variceal bleeding.

The somatostatin analogue, octreotide, may act by blocking the acute rise in portal pressure associated with fluid resuscitation in the face of GI hemorrhage. Its use is associated with improved outcome after therapeutic endoscopy. Octreotide is a somatostatin analog that has much longer half-life and therefore can be given as a bolus or infusion. Octreotide acts by blocking the vasodilatory effects of glucagon and vasoactive intestinal peptide. The side-effect profile for octreotide is more favorable than the side-effect profiles for terlipressin or vasopressin. In a recent meta-analysis, octreotide was more effective than no treatment or vasopressin/terlipressin.¹⁸

In a recent study, vapreotide was given for 5 days to patients acutely bleeding from varices.^26,27 A decrease in the number of bleedings during the index endoscopy and in the next 5 days was observed.

Therapeutic Endoscopy

Endoscopy should be undertaken after the patient is resuscitated. With the advent of pharmacotherapy, endoscopy does not need to be performed immediately, but should be carried out at the earliest opportunity by an experienced operator in the appropriate environment. None of the endoscopic methods of therapy reduce portal pressure; instead, they act by interrupting the abnormal collateral flow either by occlusion (band ligation, glue techniques) or by the induction of thrombosis (sclerotherapy).

The timing of endoscopy has recently been addressed; one study suggested that the determinants of outcome following acute variceal hemorrhage were “door-to-needle time” (threshold value: 15 hours) and Model for End-stage Liver Disease (MELD) score.²⁸ A similar study from a Canadian group did not show any effect of door-to-needle time.²⁹ However, in this study, hemodynamically unstable patients were excluded and underwent endoscopy within 4 hours. Determinants of outcome were infection on admission, albumin level, and MELD score.

Sclerotherapy

In the sclerotherapy approach, a sclerosant is injected directly into the varix. A variety of sclerosants are in use, but ethanolamine and sodium tetradecyl sulfate are the most common. The immediate effect of controlling bleeding is probably due to edema caused by the injection of the sclerosant; thrombosis occurs later. Injection sclerotherapy can be accompanied by complications (Table 96-2). The rate of mortality related to severe complications is approximately 15%. The most common long-term complication is esophageal stricture.

TABLE96-2 Complications of Endoscopic Sclerosant Therapy

Band Ligation Therapy

In band ligation therapy, a rubber band is placed on a variceal column that has been aspirated into a cylinder attached to the endoscope. The initial hemostatic effect is caused by strangulation of the vessel that is the source of variceal hemorrhage; later, thrombosis and ischemia result, leaving a shallow mucosal ulcer. Endoscopic band ligation is associated with fewer complications than endoscopic sclerotherapy, and systemic complications are rare.³⁰

Although superficial ulceration is a side effect of endoscopic band ligation, stricture formation is rare. The most hazardous complication is rebleeding associated with early shedding of the band. In a recent meta-analysis, band ligation was as effective as sclerotherapy in the control of bleeding.³¹ But because it is associated with fewer side effects and better long-term control of the varices, band ligation is preferred. However, results from a recent study suggest that there is an increased risk of infections as the number of band ligations is greater.³²

A recently published meta-analysis demonstrated that combined pharmacologic and endoscopic treatments is better than each of these treatments alone.^33,34

Glue (Butyl Cyanoacrylate)

Results from a recent study of a small number of patients with decompensated liver disease and severe esophageal variceal hemorrhage suggest that injection of tissue glue rather than a sclerosant may result in improved initial hemostasis, reduced rebleeding, and improved survival.^35,36 However, this approach requires further study and comparison with endoscopic band ligation and other therapies before it is universally adopted.

Mechanical Salvage Methods

The use of balloon tamponade to control variceal hemorrhage has decreased dramatically with the widespread use of vasoactive agents and therapeutic endoscopy. Nonetheless, balloon tamponade still has a role in the emergency management of uncontrollable bleeding from varices. Inflation of the gastric balloon results in tamponade of the varices, reduces blood flow into the plexus, and controls bleeding. The use of balloon tamponade effectively controls bleeding in 90% of patients.³⁹

In the vast majority of cases, adequate control is achieved by inflation of the gastric balloon plus adequate traction without inflation of the esophageal balloon.^40,41 It is rarely necessary to inflate the esophageal balloon, and it is important to appreciate that this maneuver contributes significantly to the incidence of potentially life-threatening complications. Constant pressure on the gastroesophageal junction is achieved with skin traction or fixed traction using a helmet.

In approximately 50% patients, bleeding recurs upon deflation of the gastric balloon.^42,43 Potential complications associated with the use of compression devices include pulmonary aspiration, esophageal mucosal ischemia and ulceration, and misplacement of the device with gastric balloon inflation in the esophagus, leading to esophageal perforation.

Ideally, the balloons should be filled with a mixture of water and radiocontrast material, allowing good delineation of position on chest radiograph. It is normally essential to endotracheally mechanically intubate and ventilate patients who require balloon tamponade, to minimize the risk of aspiration and provide control of the airway. Balloon tamponade should be viewed as a short-term solution only (ideally for not > 12 hours duration). It should be viewed as a temporizing measure until either endoscopic therapy or another definitive therapy (e.g., TIPS) can be undertaken. Regardless of other forms of salvage therapy, intermittent deflation of the gastric balloon is essential to avoid mucosal perfusion.

A recent study proposes an alternative in the form of a self-expandable metal stent to compress the esophageal varices. Placement of this device does not require endoscopy. Experience with this device is limited, and therefore more studies are needed on this topic.⁴⁴ In addition, it should be recognized that this option would not be effective if bleeding is originating from gastric varices.

Shunt Surgery/Interventional Radiology

Traditionally, two types of surgical interventions have been used in the management of PHT: operations aimed at decompressing the portal system and devascularization procedures. A third and more definitive alternative is liver transplantation.

Acute shunt surgery has been performed for more than 50 years. Although effective at lowering portal pressure (and thus decreasing the risk of further bleeding), shunting procedures can precipitate acute deterioration of hepatic function and encephalopathy by diverting portal blood flow away from the liver. The degree of these predictable events is somewhat dictated by whether the shunt is total, partial, or selective, as well as the ability of the hepatic arterial autoregulation buffer response to increase hepatic arterial flow.

Side-to-side portacaval shunt is an example of a total shunt that is achieved either by direct anastomosis of the portal vein to the inferior vena cava or anastomosis using a short interpositional graft. Traditionally, the graft diameter is greater than 12 mm, producing total portal decompression. This procedure controls variceal bleeding in 95% to 98% of patients and controls ascites in more than 90% of patients. The encephalopathy rate is 30% to 40%. If the diameter of the graft is reduced to 8 mm, this type of shunt is known as a partial shunt. It does not provide total portal decompression, thus the risk of rebleeding is higher, but rates of both encephalopathy and ascites/liver failure are lower.^45,46

“Selective” shunts, such as the distal splenorenal shunt, aim to address the issue of portal flow diversion. The aim of this shunt is to decompress the gastroesophageal junction and the spleen through the splenic vein to the renal vein. PHT is thus maintained in the superior mesenteric and portal vein to maintain blood flow to the liver.^47,48

TIPS achieves the same effect in terms of decompression of the portal system without the operative risk. Depending on the diameter of the intrahepatic shunt, TIPS can be viewed as either a total or a partial shunt. It can be used in the setting of refractory acute hemorrhage when both endoscopic and pharmacologic strategies have failed. Use of TIPS, however, is not clearly associated with a survival benefit. TIPS carries a higher risk of precipitating encephalopathy and is significantly more expensive than either endoscopic or pharmacologic strategies.^49,50 The exact subgroup of patients for whom salvage TIPS leads to a favorable outcome has not been characterized.^51,52

New radiologic methods have been developed that can be performed with fluoroscopy or even at the bedside of the patient in an intensive care environment. One such method is percutaneous transhepatic variceal embolization (PTVE) with 2-octyl cyanoacrylate (2-OCA). The effectiveness of PTVE with 2-OCA for controlling bleeding from esophageal varices is dependent upon the site and range of embolization. If the lower-esophageal and periesophageal varices and/or the cardial submucosal and perforating vessels are sufficiently obliterated, PTVE with 2-OCA can preventing variceal recurrence and rebleeding.⁵³

Devascularization procedures combine components of splenectomy and gastric and esophageal devascularization. The aim of these procedures is to reduce inflow to variceal beds and thereby reduce the risk of bleeding. Because portal flow is maintained, the risk of encephalopathy is low (10%-15%). In patients with extensive portomesenteric venous occlusion or previous splenectomy, devascularization may offer an alternative decompressive strategy in selected cases when anatomic considerations make surgical or radiologic shunting impossible. Generally, it is felt that Child-Pugh B and C patients are likely to do less well with a surgical operative procedure than a TIPS shunt, owing to the risks of hepatic decompensation. Recent studies compared surgical and medical shunts and showed that outcomes were similar, although proper selection of patients was important.^54,55

Liver Transplantation

Liver transplantation provides the ultimate in decompressive therapy, but its role in the salvage management of refractory variceal hemorrhage remains minor due to the scarcity of donor organs. In selected circumstances, however, orthotopic liver transplantation can successfully arrest both ongoing bleeding and, in the longer term, remodeling of the splanchnic circulation.

Sepsis, Renal Failure, Multiple Organ Dysfunction Syndrome

As mentioned earlier, failure to control initial bleeding is associated with high risk of death in the short term. The high risk of death is due to both the immediate consequences of massive blood loss and ongoing shock, as well as to the consequences of end-organ insults, leading to multiple organ dysfunction syndrome.

Significantly, bacterial infection is associated with both an increase in failure to control bleeding and early rebleeding. Bacterial infection is associated with poor short-term prognosis. The use of broad-spectrum antibiotics after variceal hemorrhage has been shown to reduce the infection rate, decrease the rebleeding rate, and more importantly, improve early survival.⁶¹

A large proportion of the deaths attributed to variceal bleeding are not directly caused by hemorrhage but a complication of variceal bleeding and decompensated liver disease. Importantly, renal failure in association with advanced liver disease (e.g., Child-Pugh score > 10) and variceal hemorrhage predicts a very poor short-term prognosis and correlates strongly with early death (<30 days). Development of renal failure is associated with severity of bleeding (reflected by hemodynamic parameters, transfusion requirement, and findings at endoscopic examination), severity of liver disease (determined by Child-Pugh score), and presence or absence of bacterial infection. The prognosis of renal failure developing in association with variceal bleeding is similar to that for patients developing renal failure in association with spontaneous bacterial peritonitis and type 1 hepatorenal syndrome.

Ascites

Accumulation of fluid in the peritoneal cavity is called ascites. The most common cause is cirrhosis.⁶⁷ Ascites is present in 20% to 60% of cirrhotic patients at the time of presentation. Leakage of sinusoidal fluid in cirrhosis happens as a result of sinusoidal hypertension due to the regenerative nodules and surrounding fibrosis. The other factor related to the pathogenesis of ascites in cirrhosis is expansion of plasma volume as a consequence of excessive renal retention of salt and water. The symptoms are increased abdominal girth, weight gain, and frequently edema. Tense ascites can result in respiratory compromise due to diaphragmatic splinting and or hydrothorax. The best method for diagnosing ascites is abdominal ultrasound, which can detect as little as 100 mL of ascites. Ascites total protein and serum ascites albumin gradient (SAAG) are important in determining the etiology of the ascites. If total protein concentration in ascitic fluid is greater than 25 g/dL, the diagnosis is likely malignancy, tuberculosis, or a post-sinusoidal form of PHT such as Budd-Chiari syndrome. In these cases, the SAAG will be less than 1 : 1. If the SAAG is more than 1 : 1 is and the total protein concentration in ascetic fluid is less than 2.5 g/dL, then the most likely diagnosis is cirrhosis.

Ascites should be treated with sodium restriction. Sodium restriction to 90 mEq day (i.e., 2 g of salt per day) is a realistic goal for outpatients. Diuretics should be used, knowing that they can promote deterioration of renal function. Spironolactone is the drug of choice, since these patients have secondary hyperaldosteronism. However, this drug can take from 1 to 3 days to achieve full effect, so a faster-acting drug such as furosemide is frequently needed. The goal is to achieve a loss of 0.3 to 0.5 kg/d in patients without edema or 0.5 to 1 kg/d in patients with edema. If that is not achieved in 3 days, the dose of spironolactone and furosemide should be increased. If ascites cannot be controlled and/or renal deterioration appears, then there is evidence of refractory ascites, a condition associated with a very poor prognosis. A short course of terlipressin can be considered. Refractory ascites should be treated with paracentesis for the comfort of the patient. TIPS should also be considered as a bridge to liver transplantation, if this is deemed appropriate.

Abdominal Compartment Syndrome

Abdominal compartment syndrome is relatively common in patients with massive ascites, but it can occur in other situations such as ileus or abdominal trauma with active bleeding. The intraabdominal pressure can be measured with a urinary catheter or nasogastric tube. Normal values are less than 10 cm H₂O. A value over 15 cm H₂O defines the abdominal compartment syndrome and may be associated with failure of other organs. Treatment with paracentesis, nasogastric and rectal tubes (even decompressive colonoscopy), or surgery may be considered. In the context of liver disease, decompression can be achieved easily with small-volume paracentesis.

Large-volume paracentesis puts patients at risk of further central volume depletion and, hence, cardiovascular and renal dysfunction. It is normal to administer 20% albumin IV to prevent these complications. Most papers suggest that removing less than 5 L of ascites will not put the patient at risk of a post paracentesis cardiovascular disfunction syndrome; however, most physicians administer a vial of 100 mL of 20% albumin for every 2 L evacuated.⁶⁸

Spontaneous Bacterial Peritonitis

Spontaneous bacterial peritonitis (SBE) is the development of infection in ascites in the absence of an obvious source of infection (intestinal perforation or abdominal abscess) or another site of inflammation, such as cholecystitis or pancreatitis. The most common pathogens are Escherichia coli, Streptococcus pneumonia, and Klebsiella spp., although there has been an increase in other gram-positive organisms in the last decade, possibly related to the increased use of norfloxacin in the community setting as primary prophylaxis to decrease the incidence of bacterial peritonitis.⁶⁹ Recent data suggest that some genetic variants of NOD2 are related not only to the development of SBP but also with risk of death.⁷⁰

SBE is the most common type of infection in cirrhotic patients and accounts for about 25% of all infections.⁷¹ Patients may present with signs of generalized peritonitis (diffuse pain, abdominal tenderness, fever, decreased bowel sounds), however, the clinical picture may be very mild, and a high level of suspicion is needed in any patient with cirrhosis who presents unwell with ascites. A diagnostic paracentesis should be performed in all patients with suspected SBP and also in those admitted to the hospital for the first time with ascites and in those presenting with encephalopathy or renal failure.

Ascitic cultures are negative in up to 40% of patients with clinical suspicion of SBP. Accordingly, an increase in polymorphonuclear (PMN) count is diagnostic when it reaches 250 PMN/µL. In hemorrhagic ascites, 1 PMN should be subtracted from the count for every 250 red blood cells. Normally, antibiotic treatment consists of a third-generation cephalosporin, but drug choice should be guided by hospital and community bacterial resistance patterns.

Renal impairment is a major cause of death in SBP. In addition to antibiotic therapy, albumin therapy decreases renal dysfunction and in-hospital mortality. The albumin dose should be 1.5 g/kg during the first 6 hours and 1 g/kg on the third day.

Patients with recent previous SBP or total ascitic protein less than 1 g/dL should be considered for prophylaxis to prevent SBP, with norfloxacin, 400 mg once a day, or twice a day if the patient has had a variceal bleed.

Hepatorenal Syndrome

Hepatorenal syndrome (HRS) is a clinical condition that appears in patients with advanced chronic liver disease, impaired renal function, and abnormalities in the renal circulation. HRS is characterized by renal vasoconstriction and decreased glomerular filtration rate. At the same time, marked arterial vasodilatation is apparent in the systemic (extrarenal) circulation.⁷²

HRS usually occurs in patients with advanced cirrhosis, although it can also be seen in other situations such as acute liver failure or severe alcoholic hepatitis. There are two types of HRS: type I, associated with a worse prognosis and generally rapidly progressive; and type II, defined as impairment in renal function that does not meet criteria for type I and probably involves several different types of renal injury. HRS is characterized by oliguria, a rapid and progressive rise in serum creatinine concentration in less than 2 weeks, and urinary sodium of less than 10 mEq/L. It is also necessary to differentiate HRS from the more common prerenal azotemia. Whereas prerenal kidney dysfunction responds to intravascular volume expansion, HRS does not respond to IV fluid administration or the removal of diuretics. In addition, renal causes of renal dysfunction should be excluded by urinalysis, imaging, blood tests, and if necessary, renal biopsy (usually via the transjugular route). Venovenous hemofiltration as well as terlipressin or noradrenaline are beneficial in some cases.⁷³ In a recent meta-analysis, administration of terlipressin and albumin increased short-term survival in HRS type I, but there is a lack of data to provide clear recommendations for HRS type 2.⁷⁴ Recently, a study has shown that a positive response to midodrine, octreotide, and albumin can select a population of patients whose renal function can respond completely to TIPS as a second-line treatment.⁷⁵

Hepatic Encephalopathy

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome in patients with liver disease and/or major portosystemic shunting. The classic definition of Adams and Foley^76,77 led to several different definitions of HE. Currently, three different types of HE are recognized. Type A (A is for acute) refers to HE seen in acute liver failure. In Type A HE, cerebral edema is almost always present. Cerebral edema can lead to intracranial hypertension and its associated complications. Type B (B is for bypass) appears in patients with significant portosystemic shunts without intrinsic liver disease and is very rare. Finally, type C (C is for chronic or cirrhosis) is seen in patients with chronic liver disease and PHT. In these patients, many of the products that normally are filtered and eliminated by the liver are delivered to the systemic circulation and, hence, the brain. There are several hypotheses for the pathogenesis of HE, including excessive production of ammonia, systemic inflammation, high levels of the neurotransmitter, gamma-aminobutyric acid (GABA), false neurotransmitters, and endogenous benzodiazepines.^78,79 In patients presenting with HE, possible triggering factors should be identified and treated. These potential triggering factors include infection, bleeding, constipation, and electrolyte and acid-base abnormalities. There are five grades of HE. Grade 0, or subclinical, can only be detected with psychometric tests. In grade 1, the patient is euphoric or depressed and has sleep pattern alterations, frequently associated with vivid nightmares. In grade 2, the patient tends to sleep but is easily arousable, while in grade 3, calling vigorously or inflicting pain are needed to wake the patient. In grade 4, the patient is in a coma, and diagnosis is based on the previous medical history of the patient, physical examination that can show extrapyramidal signs such as rigidity of the limbs or clonus, and the electroencephalogram, which will show triphasic delta waves in the frontal lobe. Treatment is based on avoidance and prevention of precipitating factors and in improving protein intake by feeding dairy products and vegetable-based diets. Laxatives in the form of lactulose or other disaccharides may be used, aiming for two to three soft bowel movements per day. Antibiotics are reserved for patients who respond poorly to disaccharides. Rifaximin recently has been proposed in this context, and it appears to be an effective and safe treatment option for HE.⁸⁰ Artificial liver support devices, specifically the MARS device, have been shown to result in more rapid resolution of HE.⁸¹ L-Ornithine L-aspartate (LOLA) also may ameliorate encephalopathy,⁸² although further studies are required. A recent randomized controlled study in acute liver failure was not able to demonstrate any improvement in HE or survival in the LOLA-treated population.⁸³ The definitive treatment for HE is liver transplantation.^84,85

Patients with grade III-IV HE require endotracheal intubation to protect the airway from aspiration. In acute liver failure, pathogenesis and treatment are different and centered in early detection and aggressive treatment of intracranial hypertension.

Key Points