PATHOPHYSIOLOGIC DERANGEMENTS OCCURRING WITH HEPATIC DISEASE

Bile Pigment Metabolism

Bilirubin Metabolism

Hepatobiliary excretion of bilirubin requires ade­quate uptake, conjugation, and secretion by the hepatocyte. Hepatic failure leads to hyperbiliru­binemia and icterus.

There must be considerable hepatocellular dis­ease or increase in the bilirubin load (hemolysis) to result in hyperbilirubinemia, because the liver's reserve capacity for bilirubin processing is up to 30 times the normal bilirubin load. Therefore the serum bilirubin concentration is an insensitive indicator of hepatocellular function, only increas­ing with severe hepatocellular disease. In general, total bilirubin concentrations above 2 to 3 mg/dl are detectable clinically as jaundice, whereas con­centrations above 0.6 to 0.8 mg/dl result in abnor­mal bilirubinuria and spun serum or plasma to be visibly icteric.

Because unconjugated bilirubin circulates in plasma bound to albumin, it does not undergo glomerular filtration and does not appear in the urine (unless there is coexisting glomerular dis­ease). Conjugated bilirubin, however, is freely fil­tered and appears in the urine and is readily detected with urine dipsticks. The dog has a very low renal threshold for conjugated bilirubin excre­tion; thus urine concentration of bilirubin increases far more readily than plasma concentration. It is normal to find a small amount of bilirubin in the urine of dogs, especially in a concentrated sample. Therefore there must be a considerable increase in the bilirubin load to increase plasma concentra­tions. Slight elevations in plasma bilirubin are sig­nificant, suggesting hepatobiliary disease. In the cat the renal threshold is much higher, so the finding of any degree of bilirubinuria is always abnormal. Renal tubular cells of the dog also possess a limited ability to convert hemoglobin into unconjugated bilirubin, which then appears in the urine. This can thus account for some of the bilirubinuria that occurs with hemolytic disease.

Hyperbilirubinemia is categorized into prehepatic, intrahepatic, and posthepatic causes. Prehepatic hyper­bilirubinemia occurs when production exceeds the liver's capacity for metabolism and secre­tion. Causes of this include immune-mediated hemolytic anemia, heavy metal toxicity (lead, cop­per), and methylene blue toxicity. There will be evidence on the hemogram of increased produc­tion of bilirubin, with the most notable change being a decreased hematocrit.

Intrahepatic causes of hyperbilirubinemia occur when there is abnormal hepatic uptake, conjugation, or secretion of bilirubin. In most hepatocellular diseases there is usually coexisting impairment of bilirubin uptake, conjugation, and secretion. Therefore there is usually a mixture of conjugated and unconjugated hyperbilirubinemia. The increase in conjugated bilirubin results from impaired bilirubin secretion from damaged hepa­tocytes or from impairment of bile flow through bile canaliculi due to hepatocyte swelling, inflam­mation, or fibrosis.

Intrahepatic or extrahepatic biliary obstruction causes posthepatic hyperbilirubinemia. When this occurs, conjugated bilirubin is regurgitated into the systemic circulation, so that there is primarily a conjugated hyperbilirubinemia. However, there can also be concurrent unconjugated hyperbiliru­binemia with posthepatic causes. This can result from deconjugation of bilirubin by damaged hepa­tocyte lysosomal and inflammatory cell enzymes (bile is hepatotoxic and cholestasis results in sec­ondary hepatocellular damage and inflammation) or because conjugated bilirubin once absorbed into the systemic circulation recirculates and com­petes with unconjugated bilirubin for uptake by hepatocytes. The causes of extrahepatic biliary obstruction are listed in Box 9-1.

The relative increases of conjugated or unconjugated bilirubin are variable with all three general categories of hyperbilirubinemia and therefore do not aid the clinician in localizing the nature of the lesion. Ultrasonography, laparoscopy, and laparotomy localize the cause of hyper­bilirubinemia.

288 chapter 9 I DiseasesoftheliverandhepatobiliarySystem

Delta-Bilirubin. Delta-bilirubin is a novel form of bilirubin first noticed when the sum of conjugated and unconjugated bilirubin was less than the total bilirubin concentration when meas­ured by high-performance liquid chromatography. The difference has been attributed to conjugated bilirubin covalently bound to albumin, subse­quently called delta-bilirubin.

Bile Acid Metabolism and Pathophysiology

Bile is composed of bile acids (salts), bile pigments (primarily bilirubin), cholesterol, phospholipids (primarily lecithin), and hepatic enzymes (such as alkaline phosphatase). Of these, bile acids are the most abundant and are the major solute in bile, constituting three fourths of the total solids. They are synthesized in the liver as a result of cholesterol metabolism and secreted into the bile. Feeding is a normal stimulus for bile acid secretion. They enter the intestine and undergo an efficient entero- hepatic circulation following passive and active absorption from the ileum. Both unaltered bile acids and those deconjugated and dehydroxylated by intestinal bacteria are reabsorbed and enter the enterohepatic circulation. They are efficiently removed by the liver, reconjugated if necessary, and resecreted in bile. Hepatocellular uptake is a highly efficient process with large excess capacity, operat­ing far from saturation under physiologic condi­tions. During a typical meal the total bile acid pool is recycled two to three times through this entero- hepatic pathway.

Fecal loss of bile acids represents the major pathway for cholesterol excretion from the body. In addition to their role in lipid absorption, bile acids also stimulate pancreatic enzyme release and activity.

Factors important in governing bile acid metabolism include hepatic function, the portal blood supply, the small intestine, intestinal bacteria, and dietary factors. The pathophysiologic effects of bile acids are hepatotoxicity, gastric hyperacidity, and diarrhea.

Abnormal hepatic function, biliary excretion, or portal circulation can interrupt the normal enterohepatic circulation and lead to an increase in serum bile acid concentration. This occurs with many hepatobiliary diseases. When the liver parenchyma is diseased, the inability of normal uptake, conjugation, and secretion results in decreased extraction of bile acids from the portal circulation and leads to increased systemic con­centrations. With intrahepatic or posthepatic cholestasis, bile acids diffuse from bile into the sys­temic circulation in a manner similar to that of bilirubin. With portosystemic shunting (either congenital or acquired), the enterohepatic circula­tion is directly interrupted and bile acids fail to be extracted by the bypassed liver. In this setting, hepatic synthesis of bile acids continues in order to maintain a normal bile acid pool. This can result in tremendous increases in systemic concentra­tions, especially following feeding. As will be dis­cussed in the section on laboratory evaluation of hepatic disease, serum bile acid concentrations represent a sensitive indicator of hepatic function.

Protein Metabolism

Albumin Metabolism

Albumin is an important protein synthesized by the liver that is important in many homeostatic functions, such as maintenance of plasma colloid oncotic pressure and as a plasma transport carrier for many electrolytes, hormones, pigments, and drugs.

Albumin concentration decreases with severe hepatic disease because of decreased synthesis and because ammonia (when elevated with hepatic disease) inhibits albumin release from hepatocytes. In addition, the abnormal insulin and glucagon concentrations that occur with hepatic disease also result in inhibition of albumin release from hepa­tocytes. Also, when ascites is present, there is an increased volume of distribution of albumin.

Clotting Factors

The liver is responsible for synthesizing many of the clotting factors, including factors I, II, V, VII, IX, and X. The liver also synthesizes activators and inhibitors of the fibrinolytic system (such as antiplasmins). In addition, the liver is involved in the synthesis, catabolism, and clearance of both proco­agulants and anticoagulants (such as antithrombin III, fibrin degradation products, and plasminogen activators). With hepatic disease, derangements of these processes can lead to a variety of hemostatic abnormalities. Causes of coagulopathies associated with hepatic disease are listed in Box 9-2.

Although spontaneous bleeding in patients with hepatic disease is unusual, excessive bleed­ing following surgical trauma or liver biopsy may occur. In clinical cases of hepatic disease, there may be multiple abnormal hemostatic tests. Prothrombin time, partial thromboplastin time, and activated clotting time can be prolonged with hepatic failure because of lack of synthesis of clot­ting factors. This usually occurs with massive

BOX 9-2

Causes of Coagulopathies With Hepatic Disease

Decreased synthesis of clotting factors Disseminated intravascular coagulation (DIC)

Decreased antithrombin III synthesis

Excessive fibrinolysis (decreased antiplasmin synthesis, decreased clearance of plasminogen activator)

Circulating anticoagulants normally removed by the liver remain elevated, such as fibrin degradation products (FDPs)

Decreased vitamin K availability

Increased tissue thromboplastin with massive hepatic destruction

Abnormal platelet function acute hepatic necrosis and with cirrhosis. In a pub­lished study, dogs with chronic hepatitis that died within 1 week of presentation had significantly pro­longed prothrombin and partial thromboplastin time compared with dogs that survived.

Decreased absorption of fat-soluble vitamin K leads to prolongation of clotting times. This cofactor is necessary for the hepatic synthesis and activation of factors II, VII, IX, and X. Chronic biliary obstruction can cause vitamin K malab­sorption. However, intestinal bacteria synthesize vitamin K, making a deficiency of this vitamin a less common cause of bleeding during hepatic dis­ease (unless the use of long-term intestinal antibi­otics decreases bacterial vitamin K synthesis). If clotting times are prolonged, administration of parenteral vitamin K₁ followed by normalization of clotting times within 24 hours confirms vita­min K deficiency as a contributor to the coagu­lopathy. Recently reported studies in dogs and cats using the PIVKA test (proteins induced by vita­min K antagonism/absence) suggest that this test is the most sensitive in detecting coagulopathies in patients with hepatic disease. In these studies the PIVKA test was more than twice as sensitive in detecting coagulopathies in dogs and more than three times as sensitive in detecting coagulopathies in cats compared with routine coagulation tests (prothrombin time, activated partial thromboplas­tin time).Vitamin K administration may be helpful in certain situations. In one report, Vitamin K administration improved PIVKA times in 10 of 23 dogs with hepatic disease and normalized PIVKA times in 12 of 48 cats. It has been my experience that bleeding following hepatic biopsy does not correlate with coagulation findings, including the PIVKA test. Patients with coagu­lopathies are no more likely to bleed than patients without coagulopathies. In most cases of sig­nificant bleeding following hepatic biopsy, there are technical problems. In my experience, the rapidity of bleeding and/or necropsy examina­tion suggest that a large vessel has been damaged rather than hemorrhage being due to persistent oozing from needle biopsy sites. The exception to this is that patients with disseminated intravascular coagulation (DIC) often have significant hem­orrhage regardless of biopsy technique used. Controlled studies in veterinary patients will be necessary to make final conclusions regarding postbiopsy hemorrhage in the patient with a coag­ulopathy.

DIC is the most common coagulopathy occur­ring with hepatic disease in my experience and the one most likely to result in hemorrhage fol­lowing hepatic biopsy. Thrombosis and hemor­rhage are both potential sequellae of DIC. DIC can result from decreased hepatic synthesis of antithrombin III, decreased clearance of activated clotting factors, and increased release of tissue thromboplastin associated with massive hepatic destruction. These mechanisms may be further complicated by events leading to excess fibrinoly­sis. The latter situation can occur from excessive activity of the fibrinolytic enzyme plasmin (occur­ring because of increased plasminogen activator and decreased antiplasmin concentrations). The net result of excessive fibrinolysis is the formation of fibrin degradation products (FDPs), which have potent anticoagulant effects and are not cleared efficiently by a diseased liver. Laboratory test results suggesting the presence of DIC include prolongation of prothrombin, partial thrombo­plastin, and thrombin times, thrombocytopenia, elevated FDPs, hypofibrinogenemia, and schisto- cytosis.

Abnormal platelet function can also occur with hepatic disease. These defects may be evaluated by platelet aggregation studies, but these studies are not routinely performed in clinical patients because of the lack of equipment availability. Platelet function defects may explain bleeding ten­dencies in patients with normal coagulation tests. Platelet function can be estimated by evaluating toenail or lip bleeding time.

Spontaneous hemorrhage is unusual with hepatic disease with the exception of gastrointesti­nal (GI) hemorrhage. The latter can result from increased gastrin concentration (due to decreased hepatic clearance of gastrin and increased gastrin release stimulated by elevated bile acid concentra­tions), which causes an increase in gastric acid pro­duction. In addition, DIC can lead to abnormal GI mucosal microcirculation due to microthrombi formation, thus decreasing the ability of the mucosa to withstand injury. One of the conse­quences of GI hemorrhage is exacerbation of hepatic encephalopathy because blood is a sub­strate for ammonia production in the large intes­tine. In addition, GI hemorrhage can result in partial depletion of clotting factors, and, when reduced further by hepatic biopsy, massive or prolonged bleeding can result.

When evaluating patients with hepatic disease for hemostatic abnormalities, the clinician must be aware of the relative insensitivity of clotting times. These times are prolonged only when coagulation factors are reduced to 30% of normal. In addition, multiple defects may be present, some of which are not detected by routine coagulation tests, such as abnormal platelet function and excessive fibrinol­ysis. Sudden demand for clotting factors, as would occur following hepatic biopsy or laparotomy, may precipitate massive or prolonged hemorrhage in a patient with normal coagulation test results. Because the exact nature of the defect is often unknown or multifactorial, treatment with fresh whole blood collected in a plastic blood collection bag (to preserve platelet activity and prevent acti­vation of factor XII) is usually indicated to treat these patients. If possible, efforts such as this should be taken before hepatic biopsy to correct a known coagulopathy.

Ammonia Metabolism

Ammonia has long been considered one of the most important encephalopathic toxins in patients with hepatic disease. The most important source of ammonia is the large intestine, where intralu­minal bacteria convert proteins and other nitrogen-containing compounds to ammonia. Once the ammonia is absorbed into the portal circulation, the liver normally extracts most of it, converting it to urea via the urea cycle. Hepatic failure results in increased blood ammonia and decreased blood urea nitrogen (BUN) concentra­tions.

Gram-negative enteric bacteria are quantita­tively the most important organisms for convert­ing nitrogenous substrates to ammonia, although certain anaerobes are also capable of synthesizing ammonia. Dietary proteins are the most important substrate for ammonia production, but other sub­strates such as urea (which freely diffuses from the systemic circulation into the colon), sloughed intestinal epithelial cells, and GI hemorrhage are also quantitatively important. Therefore reduction of these substrates and of large intestinal bacterial numbers will have a beneficial effect on ammonia absorption. Treatment measures used to decrease ammonia absorption are discussed in the section on management of hepatic disease.

Portal blood in the dog normally contains approximately 350 μg∕dl of ammonia (and about double this in the cat because of the higher dietary protein content of this species). The liver is normally able to extract approximately 85% of this, resulting in a systemic venous ammonia con­centration of approximately 50 μg∕dl (± 30 μg∕dl). Because the liver has a large capacity for ammonia removal, there must be considerable hepatic dysfunction or abnormal portal circula­tion to raise systemic plasma concentrations. The normal liver can tolerate up to twice the normal ammonia load. This degree of tolerance can be a sensitive indicator of hepatic function and is used clinically when performing the ammonia tolerance test.

Hepatic Encephalopathy

Hepatic encephalopathy is defined as a clinical syndrome characterized by abnormal mental sta­tus occurring in patients with severe hepatic insufficiency. This can result from primary hepa­tocellular disease or from portosystemic shunting of blood away from the liver. Clinical signs in patients with this condition include a wide vari­ety of behavioral changes, ranging from only mild depression and anorexia to coma. Many signs are nonspecific and can be seen with a wide variety of unrelated disorders. These include depression, anorexia, vomiting, diarrhea, polydip­sia, and polyuria. Neurologic signs are also com­mon. These signs are variable and often cannot be localized to a specific anatomic lesion.When this occurs, or when the nature of the neurologic abnormalities vary with time, hepatic encephalopa­thy should be considered as a cause. The most common neurologic manifestation is decreased mentation and responsiveness. Often patients will appear confused, have compulsive pacing and wandering, and appear transiently blind. Some patients will have abnormal patterns of urination and defecation and appear no longer housebroken. Signs can progress to include seizures, severe dementia, and coma. The severity of these signs often wax and wane, sometimes in response to feeding, but do not always correlate with the severity of the hepatic lesion.

Etiology of Hepatic Encephalopathy Several factors have been implicated in contribut­ing to hepatic encephalopathy. Most of these fac­tors relate to an accumulation of neurotoxic substances that have not been metabolized prop­erly by the liver, including ammonia, benzodi­azepine-like substances, amino acids, mercaptans, and fatty acids. Other causes include changes in the blood-brain barrier, abnormal neurotransmit­ter balance, abnormal cerebral metabolism, and metabolic abnormalities.

There is experimental and clinical evidence that hepatic encephalopathy is multifactorial. The concentrations of ammonia, mercaptans, and free fatty acids necessary to produce coma individually are much higher than when more than one or all are elevated. Both mercaptans and free fatty acids will increase ammonia concentration. Likewise hyperammonemia will contribute to amino acid imbalances. In addition to the synergistic effects of encephalopathic toxins, metabolic derangements aug­ment these effects. These changes include azotemia, hypoxia, electrolyte imbalances, hypoglycemia, tranquil- ization, alkalosis, and hypovolemia. Patients with these derangements are more likely to develop encephalopathy, and correction of these derangements will significantly improve the encephalopathic state. For example, the hypokalemia that frequently accompanies hepatic failure is one of the most common metabolic derangements that contribute to depression and anorexia.With potassium supplementation there is often dramatic clinical improvement in appetite and attitude. Factors that can precipitate meta­bolic changes that lead to encephalopathy include increased dietary protein intake, GI hemor­rhage, diuretic administration, sedative adminis­tration, uremia, infection, constipation, large intestinal bacterial overgrowth, and methionine administration.

The importance of synergistic effects and mul­tiple interactions of encephalopathic factors help explain the different clinical presentations and severity of encephalopathy with varying blood concentrations of encephalopathic toxins. It also explains the occurrence of encephalopathy in the absence of a striking abnormality in any single factor, including ammonia concentration. The therapeutic manipulations of all these factors repre­sent the cornerstone of symptomatic management of hepatic encephalopathy. These will be discussed in the section on management of hepatic disease.

Ascites and Portal Hypertension

Ascites (the accumulation of free fluid in the peri­toneal cavity) is a common sign of hepatic disease and occurs as a result of chronic portal hyperten­sion, hypoalbuminemia, and increased renal salt and water retention. The development of ascites occurs when there is an alteration of Starling’s forces, including increased venous or lymphatic hydrostatic pressure, decreased capillary oncotic pressure, increased vascular permeability, and increased intraperitoneal oncotic pressure.

Portal hypertension is one of the most impor­tant factors leading to the development of ascites in patients with hepatic disease. Portal hyperten­sion can be caused by increased total portal blood flow; increased resistance to portal, intrahepatic, or posthepatic blood flow; or a combination of these changes. The most common cause of portal hypertension is cirrhosis, resulting in increased resistance in sinusoidal vessels caused by swelling of hepatocytes or fibrosis around sinusoids causing postsinusoidal outflow block. The combination of increased portal pressure and blood flow causes an increase in hepatic lymph formation.When this is excessive, ascites results. Another common effect of chronic portal hypertension is the development of acquired portosystemic shunts.Unlike congeni­tal portosystemic shunts, acquired shunts are usu­ally multiple, extremely tortuous, and variable in their location.

It was formerly thought that portal hyperten­sion and hypoalbuminemia initiate ascites forma­tion. This results in decreased effective circulating plasma volume. The compensatory response to this is renal conservation of fluid and electrolytes, mediated by changes in renal blood flow, glomeru­lar filtration rate, and activation of the renin- angiotensin-aldosterone axis. This retention of salt and water perpetuates the problem by leading to increased splanchnic lymph and portal blood flow.

However, more recent evidence contradicts this theory and suggests that the renal mechanisms leading to retention of water and electrolytes are the primary initiating events in the formation of ascites with hepatic disease. In this setting there is renal salt and water retention before the develop­ment of ascites, thus expanding the circulating plasma volume and contributing to the develop­ment of portal hypertension. Eventually portal hypertension leads to the development of ascites, with hypoalbuminemia continuing to perpetuate it. Factors that may initiate renal salt and water retention include increased sensitivity to aldos­terone and failure to release or respond to natri­uretic hormone in response to an expanded circulating plasma volume. The latter situation results in the inability to excrete a salt and water load in response to volume expansion. In addition, the normal negative feedback system that governs the renin-angiotensin-aldosterone system does not shut off and reduce aldosterone secretion in the presence of portal hypertension and ascites. This is because the high concentrations of aldosterone do not return effective circulating plasma volume to normal in the presence of ascites, despite the retention of sodium. Because of these mecha­nisms, therapeutic interventions for managing ascites include salt restriction and inhibition of the renin-angiotensin-aldosterone axis with drugs such as spironolactone, enalapril, and benazepril. This will be discussed in the section on manage­ment of hepatic diseases.

The presence of ascites acts to increase albu­min’s volume of distribution, which lowers blood albumin concentration. This lowers plasma oncotic pressure and exacerbates the formation of ascitic fluid. The presence of portal hypertension is necessary for the development of ascites and leakage of albumin into the abdominal cavity. In this setting, ascites is present when plasma albumin concentrations are higher than when ascites can be attributed to hypoalbuminemia alone.With nor­mal portal pressure, plasma albumin concentration must be below approximately 1.5 g/dl to result in ascites, as occurs with GI or renal protein loss. When this occurs, subcutaneous edema often predominates over ascites.

Other Metabolic Abnormalities

Carbohydrate Metabolism

The liver plays a central role in carbohydrate metabolism. It is the primary organ for glucose storage (converting glucose by glycogenic enzymes) and also provides glucose during fasting (through glycogenolysis). When there are inade­quate stores of glycogen, as might occur with hepatic disease, the glucose need is supplied through catabolism of muscle proteins to amino acids and conversion to glucose via gluconeogenic pathways. This causes muscle wasting and increases the nitrogen load and aggravates hyperammone­mia. Because of the importance of gluconeogene­sis in the liver for maintaining blood glucose concentrations, complete hepatectomy rapidly results in death from hypoglycemia.

Hepatic failure can result in either preprandial hypoglycemia or postprandial hyperglycemia. Loss of approximately 70% of the hepatic mass may cause fasting hypoglycemia because of inadequate glyco­gen storage and gluconeogenesis. Additional causes of hypoglycemia include congenital deficiency of glycogen-metabolizing enzymes (as occurs with glycogen storage diseases), tumor hypoglycemia, and portosystemic shunts (associated with decreased hepatic mass and lack of tropic portal blood to the liver). In patients with hypoglycemia associated with hepatic disease, it is usually easy to get the blood glucose concentration into the normal range with intravenous glucose supplementation, in contrast to patients with insulin-producing tumors in which it can be very difficult to get the blood glucose con­centration into the normal range despite aggressive intravenous glucose administration.

Causes of postprandial hyperglycemia with hepatic disease include deficient hepatic enzymes to handle the carbohydrate load, leading to inade­quate glycogenesis, and increased plasma concen­tration of glucocorticoids (because of decreased hepatic clearance).

Fibrinogen

Fibrinogen is a protein that is synthesized by the liver. Synthesis of fibrinogen is diminished only in the late stages of severe hepatic failure. Other factors are usually more important in determin­ing fibrinogen concentration than the rate of hepatic synthesis. Factors that will more com­monly lead to decreased fibrinogen concentra­tion include increased fibrinogen consumption, as occurs with DIC or primary fibrinolysis. Factors that result in increased fibrinogen con­centration include inflammatory diseases (involv­ing or not involving the liver) and major surgery. In this setting there is increased synthesis and release by the hepatocyte.

Drug and Hormone Metabolism

The microsomal enzyme system of the liver is important for drug and hormone metabolism. Hepatic failure can result in abnormally delayed drug metabolism and clearance. In addition, drugs that are highly protein bound can have increased biologic effects when there is hypoalbuminemia associated with hepatic disease. In this setting there is less albumin to bind to the drug and therefore more unbound (active) drug to exert its effects. Therefore drugs that undergo hepatic clearance or that are highly protein bound should be admin­istered with caution in patients with hepatic failure.

Many hormones are metabolized by the liver and can be abnormally elevated with hepatic disease. The more important hormones to have prolonged clearance are the steroid hormones, including cortisol, estrogens, androgens, and pro­gesterones. As with many drugs, the degree of protein binding and therefore the concentra­tion of unbound, active hormone can be altered with hypoalbuminemic states. Other hormones that undergo altered metabolism in patients with hepatic disease include insulin, glucagon, thyroxine, pituitary hormones, gastrin, and aldosterone. Many of these alterations were dis­cussed in reference to their specific physiologic effects.

Reticuloendothelial System Function

The reticuloendothelial system (RES) removes toxic or foreign substances, cellular debris, bacte­ria, drugs, and endotoxins from the blood. The hepatic RES is more important than that in the rest of the body for appropriate processing of these materials. Primary hepatocellular disease or portosystemic shunting (either congenital or acquired) can cause failure of the hepatic RES. With hepatic disease other tissues with RES activ­ity can only partially compensate for the dimin­ished hepatic RES function. Deficiencies of specific roles of the hepatic RES function can lead to characteristic changes that other RES tissues cannot compensate for. The liver is directly responsible for clearing absorbed GI products, because they pass through the liver before gaining access to the systemic circulation. These products include intestinal bacteria, endotoxins, and GI mucosal antigens. The effects of decreased clear­ance of GI products can be the systemic access of bacteria or their toxins, resulting in potential sepsis and/or endotoxemia. In addition, there can be positive bacterial growth from hepatic biopsy specimens even when the underlying cause of hepatic disease is not bacterial in origin. In my experience it is not unusual to culture Escherichia coli or other enteric bacteria from hepatic biopsy specimens obtained from patients with various hepatic diseases.

One of the consequences of abnormal expo­sure of GI antigens to the systemic circulation is the development of hyperglobulinemia. These immunoglobulins are produced by nonhepatic tissues in response to the systemic antigen load. Another potential source of hyperglobulinemia occurring with hepatic disease is the release of antigens from injured hepatocytes. Many of the intracellular structures of the hepatocyte, especially the nucleus and mitochondria, are recognized as foreign and elicit an immune response character­ized by an influx of lymphocytes and plasma cells. The effects of this cellular infiltration include the potential for further hepatocyte damage and thus perpetuate a vicious cycle (this will be dis­cussed further in the section on chronic active hepatitis). In addition, the plasma cells will manu­facture gamma globulins, which lead to a hyper- globulinemia.

Loss of Compartmentalization Function

The maintenance of the integrity of the hepato­cyte membrane is an important function. Any insult that damages the cell membrane can lead to loss of intracellular contents, including organelles, enzymes, and antigens. In addition to loss of intra­cellular contents, hepatocyte function may be compromised.

Loss of intracellular enzymes (with the excep­tion of certain proteases) does not lead to abnor­mal function or clinical signs but can be a useful laboratory test for diagnostic purposes. Those enzymes that leak into plasma following increased hepatocellular membrane permeability include alanine aminotransferase (ALT, formerly glutamic- pyruvic transaminase [GPT]), aspartate amino­transferase (AST, formerly glutamic-oxaloacetic transaminase [GOT]), arginase, sorbitol de­hydrogenase (SDH), lactic dehydrogenase (LDH), and ornithine carbamoyltransferase (OCT). Enzyme activities that increase with biliary obstruction include alkaline phosphatase (ALP), gamma glutamyl transpeptidase (GGT), and 5'- nucleotidase.