Describe the basic hepatic functions that are of immediate concern to anesthesiologists

Describe the basic hepatic functions that are of immediate concern to anesthesiologists.

Because of the myriad of liver functions that may be affected, no single laboratory test effectively measures the overall state of liver function. An understanding of hepatic functions and coexisting physiologic problems associated with liver failure will illuminate where the anesthetic concerns are and which preoperative test should be performed. In any given patient with hepatic disease, their ability to carry out normal hepatic functions will be char-acterized by the extent of liver failure. It is auspicious that the liver has an enormous reserve capacity. In experimental animal models, as well as in normal humans, the removal of greater than 80% of hepatic parenchyma is still compat-ible with normal liver function. Cirrhosis is characterized as scarring within the liver by fibrosis and the conversion of normal architecture into structurally abnormal modules throughout the liver. This abnormal architecture leads to obstruction of flow within the portal system and portal hypertension with all its clinical ramifications. The ulti-mate consequence of progressive liver diseases is hepatic failure and loss of liver function. Hepatic functions can be broken down into three main categories: endocrine, synthetic (anabolic), and metabolic (catabolic and detoxi-fying) functions.

Endocrine Functions

The liver has several endocrine functions and is a major target organ for glucose homeostasis. The liver produces somatomedin (insulin-like growth factor-1), a growth stimulator; thrombopoietin, which stimulates bone mar-row to produce platelets; and angiotensinogen, which is closely involved in fluid and electrolyte balance.

Decreased production of angiotensinogen can have profound effects on the kidneys and fluid and electrolyte balance. Extravasation of fluid from the intravascular volume results in relative intravascular depletion. The kid-ney responds by producing increased amounts of renin. Two physiologic ramifications of increased renin produc-tion are constriction of the renal afferent arteries and fluid retention. Renin also converts angiotensinogen into angiotensin I. Angiotensin I diminishes renin production by the kidneys. Without production of angiotensinogen, the negative feedback that inhibits renin production is eliminated, and production of renin and its physiologic ramifications go unconstrained. This cycle can cause massive fluid retention, electrolyte abnormalities, and may play a role in the development of hepatorenal syndrome in end-stage liver disease (ESLD).

The liver plays a role in calcium homeostasis. It is respon-sible for the hydroxylation of vitamin D. Additionally, the liver is responsible for the homeostasis of other hormones. Thyroxine and triiodothyronine are deiodinated by the liver. Steroid hormones, such as testosterone, estradiol, glucocor-ticoids, and aldosterone, are first metabolized (inactivated) and conjugated in the liver and then excreted in the urine. In liver disease, normal estrogen and testosterone metabolism is prevented because of shunting to the systemic circulation, which results in gynecomastia.

Furthermore, the liver is a target organ for insulin and glucagon. These two hormones are involved in the metabolism and storage of carbohydrates. Glycogen is formed from glucose, under the influence of insulin, in a process called glycogenesis. Glycogen is broken down to glucose by glucagon in a process called glycogenolysis.

In this way, glucose becomes available for muscle and brain metabolism.

Anabolic Functions

The liver has numerous clinically important synthetic functions. It is involved in hemostasis by virtue of its anabolic functions. In addition to producing coagulation factors, the liver also synthesizes many anticoagulants, such as antithrombin III, α₁-antitrypsin, protein C and S, plas-minogen, α₂-antiplasmin, and plasminogen activator inhibitor. Severe liver disease can lead to reduced synthesis of factors I (fibrinogen), II (prothrombin), V, VII, IX, X, XI, XII, XIII, prekallikrein, and high molecular weight kinino-gen. High molecular weight kininogen and factors II, VII, IX, and X are vitamin-K-dependent clotting factors. Vitamin K is a cofactor of an enzyme that catalyzes the γ-carboxylation of selected glutamyl residues in clotting factor precursors. When coagulopathies result from impaired hepatocellular function, exogenous vitamin K is unlikely to correct or improve the problem. Vitamin K-dependent clotting proteins have a substantially shorter serum half-life than albumin; therefore, coagulopathy can precede the development of other signs of liver failure, e.g., hypoalbuminemia. In cirrhosis, coagulopathy may be further aggravated by thrombocytopenia resulting from either decreased synthesis of thrombopoietin and/or from hypersplenism. Since the liver produces non-vitamin K-dependent clotting factors, severe liver disease may lead to decreased plasma concentrations of factor I (fibrinogen), V, XI, XII, and XIII. Initially, a damaged liver may actually produce increased amounts of fibrinogen; therefore, it is unusual for fibrinogen to be reduced significantly, unless there is an associated disseminated intravascular coagulation.

Several other clinically important proteins are made by the liver. They include acute phase reactants (C-reactive proteins, haptoglobin, ceruloplasmin, and transferrin), pseudocholinesterase, angiotensinogen (discussed above), α-acid glycoprotein, and albumin. The last two are the main drug-binding moieties. Derangements in albumin synthesis have several important clinical ramifications. It is the principal binding and transport protein for numerous substances, including some hormones, fatty acids, trace metals, bilirubin, and drugs. Many of the intravenous drugs employed by anesthesiologists are highly protein-bound. Low serum concentrations of plasma proteins, especially albumin, produce an increase in unbound drug concentrations and potentially exaggerate drug responses. This enhanced response may be seen with serum albumin concentrations of 2.5 g/dL or less. Additionally, decreased serum concentrations will lead to reduced oncotic pressure in the plasma, which may result in edema and ascites. When this is coupled with portal hypertension, there may be increased hepatic lymph production with extravasation into the peritoneal cavity. In a patient with ascites, the degree and ramifications of hypoalbuminemia may be accentuated by further loss of albumin in ascitic fluid.

Other important anabolic functions of the liver include production of saturated fatty acids, cholesterol, and bile salts, maintenance of glycogen storage (glucose storage), and production of ketones, i.e., β-hydroxybutyrate, which is the main energy source used by the brain during starva-tion. Decreased synthesis of bile salts can lead to malab-sorption of fat and fat-soluble vitamins (vitamin K). Alterations in cholesterol production (and related sub-stances) may lead to significant changes in the composition and morphology of erythrocytes. The presence of erythro-cytes with spur and burr cell forms are usually an ominous sign of significantly advanced liver disease.

Abnormalities of glucose maintenance are common in cirrhosis. As stated above, carbohydrate metabolism and glucose production are important liver functions. Hypoglycemia, which is more commonly associated with acute fulminant hepatic failure, may occur with ESLD. Cirrhotic patients are at risk for perioperative hypoglycemia due to decreased hepatic glycogen stores (decreased capacity secondary to decreased liver mass or decreased intrinsic ability to synthesize glycogen), diminished response to glucagon, or compromised nutritional status. Additionally, these patients may have elevated serum lactate levels, reflecting the decreased capacity of the liver to utilize lactate for gluconeogenesis via the Cori cycle (Figure 35.1).

Catabolic Functions

The liver is responsible not only for elimination and metabolism of toxins and other xenobiotics absorbed by the gastrointestinal tract, but also for metabolism of drugs and alcohol.

The liver is the central organ responsible for biochemi-cal intermediate metabolism. It shuffles many endogenous biological intermediate compounds into various pathways that lead to either the creation of new compounds or the complete metabolism of the intermediate ones. A perfect example of intermediate metabolism is the citrate pathway (Figure 35.2). Citrate is used as an anticoagulant in banked blood products. 

Citrate works as an anticoagulant via chelation of calcium, thereby blocking its availability for the coagulation cascade. Exogenously administered citrate, such as that from fresh frozen plasma or other blood prod-ucts, is mainly metabolized by the liver. Citrate toxicity can occur when blood products are transfused at a rapid rate, or when the liver is unable to metabolize citrate appropri-ately. Toxicity results from chelation of ionized calcium by citrate. As citrate accumulates, ionized calcium levels decrease, resulting in a coagulopathy and myocardial depression leading to hypotension.

Carbohydrate and other biological intermediate metab-olism is a vital function of the liver. The liver metabolizes glucose, fructose, lactate, citrate, acetate, and other biolog-ical intermediates. As function declines, the liver loses its ability to orchestrate intermediate metabolism. Frequently, cirrhotics may develop insulin resistance and consequently hyperglycemia and glucose intolerance. The hyperinsulin-emia associated with ESLD suggests a decrease in the liver’s intrinsic ability to handle a glucose load secondary to a decrease in hepatocellular function and/or mass. Lactic acid is produced peripherally but is metabolized in the liver. Elevated serum lactate levels may reflect the decreased capacity of the liver to utilize lactate and may result in metabolic acidosis (Figure 35.1).

The liver is responsible for amino acid degradation (and production of glucose), fatty acid metabolism (β-oxidation), and the production of ketones during prolonged fasting.

The toxic byproduct of amino acid degradation is ammo-nia (NH₄⁺). Disposal of ammonia via the production of urea is an important liver function.