Hepatic encephalopathy may be classified as two general types. In patients with cirrhosis , portal hypertension, and large portosystemic shunts, ammonia from intestinal sources is not cleared effectively on first-pass through the liver . Also, the relief of portal hypertension by surgical creation of a portosystemic shunt or placement of a transjugular intrahepatic portosystemic shunt (TIPS) may precipitate encephalopathy. This ineffective clearance, combined with generally poor hepatic function, may result in chronic encephalopathy, punctuated by acute exacerbations often precipitated by gastrointestinal bleeding from esophageal varices (resulting in an increased intestinal ammonia load), infection, excessive protein intake, or overzealous diuresis to treat ascites . Chronic pathologic changes in astrocytes in the central nervous system may be present. This type of encephalopathy is referred to as portosystemic encephalopathy . The other category of encephalopathy is observed in the patient with acute, severe liver disease (usually fulminant hepatitis ) who develops progressive encephalopathy due primarily to severe liver dysfunction with inadequate ammonia detoxification . Acute liver failure with encephalopathy often rapidly progresses to cerebral edema and death. The cerebral edema is thought to be a direct result of ammonia toxicity. In fact, the edema may actually be a result of the osmotic effect of ammonia-induced elevation of brain glutamine levels.

It should be stressed that in encephalopathy associated with liver disease, other factors may contribute to the central nervous system dysfunction in addition to hyperammonemia. In fact, the degree of hyperammonemia does not always correlate with the degree of encephalopathy, suggesting that other mechanisms may be involved. In acute liver failure, other neurotoxic substances, such as mercaptans and short–chain fatty acids , may play a role. There is evidence that hepatic encephalopathy may result in part from the action of endogenous substances that bind to the GABA–benzodiazepine receptor complex in the brain. This is supported clinically by the observation that portosystemic encephalopathy and encephalopathy associated with acute liver failure may improve transiently with treatment with benzodiazepine receptor antagonists. However, there are limited data to support their clinical use. There may be increased entry of ammonia into the central nervous system due to increased permeability of the blood–brain barrier and conversion of positively charged ammonium ion to ammonia, which more readily crosses the blood–brain barrier, secondary to changes in blood pH. Accumulation of glutamine in the brain results in enhanced central nervous system uptake of tryptophan , which is converted into both neuroactive and neurotoxic metabolites, including serotonin and tryptamine.

Clinically, the presentation of the first stage of hepatic encephalopathy may be subtle. There may be personality changes and inversion of sleep patterns. The patient may exhibit a short attention span and easy forgetfulness. With portosystemic encephalopathy , it is now recognized that very mild impairment may affect social skills and emotional behavior, and evaluation of driving skills may be a practical index to diagnose what is termed minimal hepatic encephalopathy (MHE). An early physical sign of hepatic encephalopathy is asterixis. This sign represents an inability to maintain posture and is usually elicited by asking the patient to dorsiflex the hand with the arm extended. After several seconds a positive sign is characterized by the hand falling forward followed by a brisk recovery, thereby resulting in the typical “flapping” tremor. This sign is dependent upon the patient being able to understand and follow directions, and is highly variable over short periods of time, even in the same individual. Asterixis is not specific for hepatic encephalopathy and may be elicited in other disorders, including uremia. In stage 2, the individual becomes lethargic and disoriented with other abnormal reflexes in addition to asterixis. In stage 3, the patient is somnolent, but arousable. However, when awake the patient is unable to communicate or perform mental tasks such as calculation. Stage 4 encephalopathy is characterized by total inability to arouse the patient accompanied by a positive Babinski sign and decerebrate posturing, and usually immediately precedes the development of cerebral edema and death. Abnormal changes on electroencephalogram (EEG) are detectable as early as stage 1 and generally worsen in parallel with clinical progression to stage 4.

Treatment of hyperammonemia should be directed toward reducing the production of ammonia and enhancing its clearance. Moderate protein restriction had been recommended in the past. However, since restriction results in enhanced catabolism of endogenous protein, and a significant positive effect on outcomes has yet to be proven, such restriction is not currently recommended. Branched–chain amino acid supplementation may have a modest beneficial effect, but is prohibitively expensive. Attention should be directed to sources of gastrointestinal bleeding, such as esophageal varices , which may result in a large intestinal ammonia load. Lactulose is a non-absorbable carbohydrate administered enterally and is fermented by colonic bacteria to form organic acids, which lower the luminal pH. Since only ammonia in the form of NH₃ is readily absorbed, an increase in the NH₄ ⁺/NH₃ ratio results in trapping of ammonia in the gut and elimination in the feces. Also, the osmotic property of lactulose results in a significant laxative effect and may effectively clear ammoniagenic substances from the gastrointestinal tract. The non-absorbable antibiotic, rifaximin , is used to suppress intestinal ammonia-forming bacteria. In urgent situations, high ammonia levels may also be cleared by hemodialysis or exchange transfusion. Use of external liver support systems has generally not significantly impacted outcomes. The molecular absorbent recirculating system (MARS) has shown some benefit in more severe cases. In cases of encephalopathy associated with liver failure, liver transplantation may result in prompt resolution of severe encephalopathy, providing that cerebral edema has not developed.

The liver is responsible for the biotransformation and clearance of a variety of endogenous and exogenous toxic compounds. Exogenous organic substances entering the body that have no nutritive value for energy production, structural function, or enzyme cofactor function are called xenobiotics. The liver is capable of numerous reactions which generally serve to make the substance to be eliminated more polar and water soluble to subsequently be excreted in bile or urine (Phase I reactions: oxidoreductases and hydrolases) and to make the substance less toxic (Phase II reactions: transferases). As will also be demonstrated, these reactions do not always result in detoxification , but may actually form toxic intermediary metabolites. Apical canalicular excretion of these biotransformed molecules into bile for elimination or basolateral membrane transport into the circulation to be cleared by the kidney occurs via specific ATP–binding cassette (ABC) transporters and is termed Phase III transport.

Although the biotransformation reactions just described generally function to detoxify and enhance the elimination of xenobiotics, there are instances in which the substrates are actually rendered more toxic or carcinogenic. There are five classes of such biotransformation. The xenobiotic may be transformed into a stable, but toxic metabolite. Examples include acetonitrile and methoxyflurane. A second class involves transformation into a reactive, electrophilic metabolite. Acetaminophen and furosemide are in this class. Third, the substrate may be converted to a free radical, as in the case of carbon tetrachloride. Fourth, the biotransformation reaction may lead to the formation of reduced oxygen metabolites, as occurs with paraquat and quinones. Finally, the biotransformation reaction itself may generate a metabolic derangement within the cell, as in the case of galactosamine–induced liver injury, where there is a depression of uracil nucleotide dependent biosynthesis of nucleic acids, glycolipids, glycoproteins , and glycogen, which results in cell organelle injury.

Review of the biochemical events occurring in acetaminophen toxicity serves as an excellent example of these metabolic pathways. These events are summarized in Fig. 12.3. When taken in appropriate doses, most of the acetaminophen is conjugated with sulfate and glucuronic acid and eliminated. About 5-15 % is converted to a reactive, electrophilic intermediate, N–acetyl–p–benzoquinone imine (NAPQI), which reacts with sulfhydryl groups in proteins. The NAPQI is normally immediately conjugated with glutathione before it can do any damage to the cell and is converted into a mercapturic acid for mainly renal elimination. However, in the case of an overdose the conjugation pathway is saturated and available glutathione is quickly depleted, allowing accumulation of significant amounts of NAPQI. The NAPQI causes cell injury and death resulting in the hepatic necrosis seen with acetaminophen overdose, which can result in liver failure and death. Obviously, one therapeutic strategy would be repletion of the liver’s glutathione stores. Although this cannot be done directly, another successful approach is to administer N–acetylcysteine (Mucomist ^R ), which restores glutathione levels by enhancing synthesis. If administered early enough in the course of intoxication, this intervention can effectively prevent significant liver injury.

Bilirubin is a pigment derived from the catabolism of heme. It is a toxic waste product, which undergoes hepatic biotransformation and excretion in bile. Bilirubin has an open–chain tetrapyrrole structure with eight side chains (Fig. 12.4). The IX-α isomer is the most abundant naturally occurring isomer of bilirubin. From the chemical structure of bilirubin, one would predict a water-soluble compound at physiological pH. However, in reality, unconjugated bilirubin has only very limited water solubility. This phenomenon may be explained by the presence of extensive internal hydrogen bonding within the molecule as shown in Fig. 12.5. This results in the involvement of all of the polar groups of the molecule in the hydrogen bonding, so that none are available for hydration.

Normally, serum bilirubin levels are very low, and unconjugated bilirubin predominates. In normal individuals, men have slightly higher serum bilirubin levels (0.6 mg/dL) than females (0.4 mg/dL), and any level above 1.0 mg/dL is considered abnormal. Jaundice with the appearance of the pigment in sclerae, skin, and mucus membranes generally is noted when the bilirubin level exceeds 3 mg/dL in adults and 6 mg/dL in infants.

The major site of bilirubin toxicity is the central nervous system , particularly in the newborn infant. Bilirubin inhibits central nervous system RNA and protein synthesis, uncouples oxidative phosphorylation, and inhibits ATPase activity in brain mitochondria. Clinically, bilirubin toxicity can produce severe central nervous system dysfunction resulting in permanent injury or death. Accumulation of bilirubin in the brain, primarily in the basal ganglia, hippocampus, and cochlear and cerebellar nuclei, with associated toxicity is termed kernicterus .

Bilirubin is the major degradation product of heme in mammals. Degradation of hemoglobin from senescent red blood cells by reticuloendothelial cells in the spleen accounts for 80 % of bilirubin production. The other 20 % is derived from ineffective erythropoiesis in the bone marrow, as well as the turnover of heme-containing proteins and myoglobin. The series of reactions responsible for the conversion of heme into bilirubin is shown in Fig. 12.6. The first step is the conversion of heme to biliverdin mediated by the enzyme heme oxygenase, which exists as three isoforms. The activity of this microsomal enzyme is highest in the spleen and Kupffer cells in the liver and requires NADPH and oxygen. This is the only reaction in the body that produces carbon monoxide, which is excreted in expired air and may be quantitated as an index of bilirubin production. Carbon monoxide is also an important signaling molecule and functions as a potent vasodilator. Interestingly, biliverdin is a non-toxic, water-soluble compound and is the end-product of heme catabolism in birds and other non-mammalian vertebrates. However, in mammals biliverdin is converted to bilirubin, which is toxic and requires energy-dependent biotransformation for excretion. Conversion of biliverdin to bilirubin also occurs in reticuloendothelial cells by biliverdin reductase, a cytosolic enzyme that requires NADPH, and utilizes NADH at lower pH. Both bilirubin and biliverdin may have beneficial effects as anti–oxidants under certain conditions and may affect progression of atherosclerosis.

After its formation in reticuloendothelial cells, bilirubin is released into the bloodstream, where it is transported bound to albumin via one primary and two secondary binding sites. This binding prevents the diffusion of free bilirubin into tissues, particularly the central nervous system , thereby preventing toxicity. However, other ligands such as drugs (salicylates, sulfonamides, furosemide, etc.) and fatty acids can displace bilirubin from albumin binding sites and precipitate toxicity.

At the hepatocyte plasma membrane, bilirubin enters the hepatocyte via a specific uptake mechanism, as shown in Fig. 12.7. Once inside the cell, bilirubin binds to a group of cytosolic carrier proteins, glutathione–S–transferases (GSTs), also termed ligandin or Y protein, keeping the bilirubin in solution and within the cell. The bilirubin is then conjugated with glucuronide by the microsomal enzyme, bilirubin UDP–glucuronosyltransferase (UGT1A1). The resulting bilirubin monoglucuronide and diglucuronide are excreted at the canalicular membrane as a component of bile by the ATP–dependent transporter MRP2 (ABCC2). The transcription factors, constitutive androstane receptor (CAR) and pregnane X receptor (PXR), regulate the various proteins involved in bilirubin uptake, glucuronidation and secretion. Conjugation renders bilirubin non–toxic, water–soluble, and non–absorbable from the gastrointestinal tract. In the distal small intestinal and colonic lumen, the conjugated bilirubin is converted to urobilinogens by bacteria and eliminated in stool. However, a small fraction of these tetrapyrroles may be reabsorbed and re-excreted in bile, and the kidney excretes a small fraction.

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