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to effectively increase drug uptake in the central nervous system. The promise of biotechnology, as exemplified in the studies presented in this month's UCLA Interdepartmental Conference, is that an understanding of the physiologic mechanisms by which organisms regulate biologic processes will suggest novel approaches to the development of both preventive and treatment strategies for a broad spectrum of diseases. An understanding of the mechanisms by which the blood-brain barrier physiologically transports molecules that must enter the brain for proper function and excludes those molecules that are noxious to it will greatly complement efforts to design strategies to enhance the uptake of therapeutic agents into the brain. As our knowledge of the biochemical basis for the physiologic transport of substrates across the barrier increases, new opportunities for both the design of drugs and the targets at which therapeutic intervention might be directed will emerge. Some hints of this future, as reviewed in this month's journal, are now available for view: chimeric molecules that incorporate the physiologic substrates of specific blood-brain barrier transport mechanisms as vectors may be feasible; identifying transport systems that are specifically or selectively expressed in the brain may provide a degree of targeted drug delivery not otherwise possible; and biologically active mediators of vascular permeability that may have a role in selectively enhancing the permeability of vessels affected by pathologic disorders can be identified. Beyond these one might imagine drugs specifically engineered to include the molecular signals that are likely to specify recognition by a specific transport system and even agents that specifically modify transporter systems in a manner to facilitate their effectiveness in mediating drug transfer. Each of these possibilities holds in common an origin in the physiologic basis upon which the blood-brain barrier functions and as such can be rationally approached rather than relying upon the legacy of drug discovery that historically rested largely upon trial and error spiced with

serendipity. MARK A. ISRAEL, MD Departments ofNeurological Surgery and Pediatrics Brain Tumnor Research Center University of California, San Francisco, School of Medicine San Francisco, California

REFERENCE 1. Pardridge WM, Boado RJ, Black KL, Cancilla PA: Blood-brain barrier and new approaches to brain drug delivery. West J Med 1992 Mar; 156:281-286

Utility of 'Liver Function Tests' in Alcoholic Patients ALCOHOLISM IS widespread throughout the United States. The illness and disaster associated with ethanol abuse are costly on both a personal and societal level. Although medical complications are common and frequently encountered by all medical practitioners, alcoholism often goes undiagnosed. In order to reduce the incidence of alcohol-related medical illness, alcoholism and its complications need to be identified early. Laboratory tests may play an important role in this endeavor. Equally important, once complications of alcoholism are identified, it is imperative to be able to accurately determine their magnitude. Because ethanol affects virtually all organs in the body, as described by Magarian and

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colleagues in this issue,' a wide array of laboratory results frequently are abnormal.

test

Liver involvement is probably the most common and best characterized form of organ injury encountered in the alcoholic patient. Not surprisingly, then, the most prominent laboratory test results encountered in alcoholic patients often are those that reflect disease ofthe liver. Therefore, liver tests serve three major functions. First, in a patient who refuses to admit ethanol abuse, they may alert the physician to the presence of alcoholic liver disease and hence alcoholism. Second, in a patient with apparent liver disease, they are useful to help differentiate alcoholic liver disease from nonalcoholic liver disease. Third, also in a patient with known liver disease, they help the clinician ascertain the degree of injury. Because optimal diagnosis and management depend on recognizing and interpreting the results of such tests, it is essential that physicians be familiar with them. Laboratory tests are important because they provide a simple, noninvasive method for evaluating diseases. Unfortunately, no laboratory test is pathognomonic for alcoholism. Since ethanol is metabolized in the liver and has a propensity for causing damage to this organ, tests of liver injury often provide the first clues to alcohol abuse. Although biochemical tests related to the liver tend to be diffusely abnormal and may be confusing, certain patterns of change are often present and can be recognized. Commonly referred to as liver function tests (LFTs), the serum aspartate aminotransferase (AST, formerly SGOT), serum alanine aminotransferase (ALT, formerly SGPT), alkaline phosphatase, -y-glutamyl transferase (GGT), leucine aminopeptidase (LAP), 5'-nucleotidase, and bilirubin levels may demonstrate evidence of alcoholic liver disease. When evaluating patients with alcoholic liver disease (or any other liver disease), it is useful to group tests into the following general

categories:

* Tests that detect injury to hepatocytes (AST, ALT); * Those that detect cholestasis (alkaline phosphatase,

LAP, 5'-nucleotidase); * Tests of the liver's capacity to transport organic anions

(bilirubin); and * Tests of the liver's biosynthetic capability (true liver

.function tests) including the serum albumin and prothrombin

time, the latter of which reflects the liver's synthesis of blood clotting factors.

The most sensitive tests for detecting ethanol-induced liver injury are the aminotransferases. These intracellular enzymes are released during hepatocyte damage or death. Relatively large amounts (> 1,000 IU per liter) may be released during viral or toxic liver injury as cell membranes are disrupted, but because of the vast number of hepatocytes present in normal human liver, liver function may remain intact. Thus, aminotransferases are tests of hepatocyte integrity rather than liver function. The AST level is elevated in 43% to 100% of patients with alcoholic liver disease, although the degree of elevation does not correlate with the severity ofthe pathologic lesion.2 For example, the AST level may be elevated with only fatty changes yet may be normal with advanced cirrhosis. In patients with alcoholic liver disease, the AST level is usually elevated only twofold to fivefold, regardless of the extent of hepatocellular damage. Very high (such as > 10 times normal) AST levels are distinctly unusual in alcoholic liver disease, and their presence should

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raise the suspicion of other causes of liver injury, particularly those in which hepatocellular injury is prominent. In contrast to AST (which is found in skeletal muscle, heart, kidney, and brain, as well as liver), ALT is found only in liver and thus is attractive as a potentially specific indicator of liver disease. Serum ALT levels, however, are frequently normal or minimally elevated in patients with alcoholic liver disease, even in those with severe histologic damage, and are therefore a poor marker for this disease. Determination of the AST:ALT ratio has been extolled as useful for confirming the diagnosis of alcoholic liver disease or differentiating it from liver disease not related to alcoholism.3-5 The reason for the elevation of the AST level out of proportion to the ALT level appears to be a differential reduction in hepatic ALT due to deficiency of the cofactor, pyridoxine-5-phosphate.6 Early studies indicated that an elevated AST: ALT ratio (such as > 1) suggested that alcoholic liver disease was more likely than other liver disease.3 For example, 91% of patients with alcoholic liver disease had an AST:ALT ratio of > 1.0 and 70%, a ratio above 2.0. Further, only 11% of patients with postnecrotic cirrhosis, chronic hepatitis, and viral hepatitis had an AST: ALT ratio >2.0. Later studies have tempered this initial enthusiasm. For example, in the Veterans Affairs cooperative study on alcoholic hepatitis, 93% of patients had an AST: ALT ratio of > 1.0, but only 58% had a ratio of >2.0.5 Patients with mild alcoholic hepatitis were more likely to have a ratio closer to 1.0 while those with severe alcoholic hepatitis were more likely to have a ratio above 2.0. From a practical standpoint, an AST:ALT ratio of >2.0 strongly suggests the diagnosis of alcoholic liver disease but does not preclude other diagnoses. Additionally, an AST:ALT ratio of < 1.0 is most compatible with nonalcoholic liver disorders but may be seen with alcoholic liver disease, especially with the less $evere lesions. Thus, determining both aminotransferase levels is important in patients suspected of having alcoholic liver disease, since these tests may be helpful not only in identifying these patients but also in differentiating them from those with other forms of liver disease. Enzymes that detect cholestasis are often diffusely abnormal in alcoholic liver disease. The alkaline phosphatase, elevated in many liver disorders, is not useful for distinguishing alcoholic liver disease from other forms of liver disease. In a patient with an alkaline phosphatase measurement out of proportion to other liver tests, it is essential to document that the alkaline phosphatase is derived from the liver by confirming elevation of at least one other enzyme that denotes cholestasis. The alkaline phosphatase level is elevated in most patients with alcoholic liver disease, generally less than threefold normal. A small subset of patients with alcoholic liver disease may present with a cholestatic picture and an alkaline phosphatase level above four times normal, however.7 These patients characteristically have notably higher bilirubin, aminotransferase, and lower albumin levels than their "noncholestatic" counterparts. Pathologically, they have not only marked cholestasis but also substantial hepatocellular injury and fibrosis. -y-Glutamyl transferase levels are usually elevated in patients with alcoholic liver disease. The mechanism of hepatic GGT elevation is different from that for alkaline phosphatase and appears to be via induction by ethanol rather than release by necrosis. For this reason, it has been proposed as a sensitive predictor of alcoholism and of alcoholic liver injury.8 Unfortunately, it has not proved to be useful for this purpose. Leucine aminopeptidase and 5'-nu-

EDITORIALS

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cleotidase levels tend to parallel the alkaline phosphatase levels and typically are moderately elevated in most patients with alcoholic liver disease. Serum levels of bilirubin tend to be extremely variable in patients with alcoholic liver disease but are generally elevated. As with enzymes that detect cholestasis, bilirubin levels are also elevated in a wide variety of hepatic diseases, making bilirubin an insensitive test for identification of alcoholic liver disease. Bilirubin, however, may be helpful as a prognostic indicator in these patients. For example, extremely high levels (such as > 342 itmol per liter [20 mg per dl]) in patients with severe alcoholic hepatitis portend a poor prognosis..5 The laboratory tests that most accurately assess liver function in patients with alcoholic liver disease as well as in other liver diseases are the prothrombin time (PT) and serum albumin concentration. The clotting factors reflected in the PT and albumin are synthesized exclusively by hepatocytes and therefore reflect hepatocyte function. An elevated prothrombin time that does not correct after vitamin K administration-correction suggests nutritional deficiency-is the best indicator of impaired synthetic function and should alert the clinician to the presence of severe functional impairment. For example, an elevated PT in a known alcoholic patient with upper gastrointestinal hemorrhage greatly increases the likelihood of portal hypertension with bleeding esophageal varices. Likewise, abnormal mental status in a patient with an elevated PT raises the specter of hepatic encephalopathy. As with the serum bilirubin, the PT may be an important prognostic indicator. In patients with severe alcoholic hepatitis and a PT high enough to preclude liver biopsy, mortality is estimated at 42%.9 The combination of PT and the serum level of bilirubin has been used to assess prognosis by a discriminant function analysis'0: Discriminant function= 4.6 x (PT - control time) + bilirubin mg per dl Patients with alcoholic hepatitis and a discriminant function above 30 generally have a poor prognosis.5 Albumin levels tend to parallel PT levels in most patients; albumin levels of less than 30 grams per liter (3 grams per dl) suggest severe hepatic functional impairment. Several concepts are important when interpreting PT and serum levels of albumin in patients with alcoholic liver disease. First, these determinations are of no value in differentiating alcoholic liver disease from other liver disorders, and second, they are generally not sensitive predictors of early alcoholic liver disease. Also, they may be abnormal in malnourished patients without liver disease. Under the proper circumstances, however, they offer the best and most important means by which to assess liver function. Other laboratory tests, including the level of desialylated transferrin (dTf), have shown promise for both detecting alcoholic liver disease and distinguishing it from other forms of liver disease.4 Although the mechanism of production of dTf is unknown, it may be through the inhibition of glycosylation of glycoproteins by ethanol. The ratio of dTf to total transferrin is significantly higher (> 1.3%) in patients with alcoholic liver disease than in healthy controls, patients with nonalcoholic liver disease, and those with nonalcoholic steatohepatitis.4 This test appears to have a higher sensitivity and specificity than any of the conventional liver tests examined (AST:ALT ratio, GGT). The major drawback is that it is not widely available for clinical use.

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Liver biopsy remains the "gold standard" test for diagnosing alcoholic liver disease and for judging its severity. Pathologically, ethanol-induced liver disease can be grouped under three major forms of injury: * Fatty liver is characterized by replacement of the hepatocyte cytoplasm with macrovesicular fat droplets. * Alcoholic hepatitis is typified by ballooning degeneration of hepatocytes, polymorphonuclear leukocyte infiltration, and the presence of Mallory's hyaline. * Cirrhosis is characterized by bridging fibrosis joining portal and central zones in the liver. Individual patients may display evidence of any one or more of these lesions. Indeed, histologic evidence of all three often is present in the same patient. Fatty liver and alcoholic hepatitis are typically reversible; cirrhosis is not. Cirrhosis often progresses to liver failure, especially in the face of continued ethanol consumption. Histologic features of alcoholic liver disease may be seen in patients with diabetes mellitus, obesity, amiodarone toxicity, and jejunal-ileal bypass. A particularly troubling entity, nonalcoholic steatohepatitis, is encountered predominantly in obese women, and histologically resembles alcoholic liver disease. In the appropriate clinical setting, liver tests are useful in differentiating these two entities. An AST:ALT ratio of > 3, a bilirubin level of 34 Amol per liter (2 mg per dl), a PT of >2 seconds, prolonged, and an elevated dTf level all suggest the diagnosis of alcoholic liver disease.4'11 It is difficult to precisely correlate abnormal laboratory test results with specific histologic lesions, but trends may be prominent. Careful inspection of the liver test profile often allows a rough assessment of the patient's histopathology. For example, mildly elevated aminotransferase levels alone are most compatible with fatty liver or mild alcoholic hepatitis and a good prognosis. Alternatively, the patient with hyperbilirubinemia, an elevated prothrombin time, and depressed serum albumin levels is more likely to have severe alcoholic hepatitis or cirrhosis and a poor prognosis. Thus, laboratory tests in an alcoholic patient may reflect pathologic lesions that in turn dictate ultimate outcome. An important point is that although the liver test profile is often helpful in differentiating alcoholic liver disease from nonalcoholic liver disease, up to 20% of patients with alcoholism may have

histologic evidence of nonalcoholic liver disease, emphasizing the role of a liver biopsy in confusing cases.12 In summary, the diversity of laboratory test abnormalities encountered in alcoholic patients is remarkable. Familiarity with patterns of biochemical derangement in alcoholic liver disease will increase the likelihood of detecting this process and, thus, alcoholism. The medical history remains the best means for detecting the presence of alcoholism, however. When the history and physical examination are equivocal or misleading, laboratory tests in the alcoholic patient may be the only clues to the correct diagnosis. Moreover, in patients with known alcoholism and alcoholic liver disease, laboratory tests may yield clues to hepatic function and therefore patient management. Finally, though often useful, these tests are not infallible and cannot replace liver biopsy in patients whose diagnosis and prognosis are uncertain. DON C. ROCKEY, MD Instructor in Medicine University of California, San Francisco School of Medicine Liver Center Laboratory San Francisco General Hospital Medical Center

REFERENCES 1. Magarian GJ, Lucas LM, Kumar KL: Clinical significance in alcoholic patients of commonly encountered laboratory tests. West J Med 1992 Mar; 156:287-294 2. Zakim D, Boyer TD, Montgomery C: Alcoholic liver disease, chap 33, In Zakim D, Boyer TD (Eds): Hepatology, 2nd Ed. Philadelphia, Pa, WB Saunders, 1990, pp 821-869 3. Cohen JA, Kaplan MM: The SGOT/SGPT ratio-An indicator of alcoholic liver disease. Dig Dis Sci 1979; 24:835-838 4. Fletcher LM, Kwoh-Gain I, Powell EE, Powell LW, Halliday JW: Markers of chronic alcohol ingestion in patients with nonalcoholic steatohepatitis: An aid to diagnosis. Hepatology 1991; 13:455-459 5. Mendenhall CL: Alcoholic hepatitis, chap 18, In Schiff L, Schiff ER (Eds): Diseases of the Liver, 6th Ed. Philadelphia, Pa, JB Lippincott, 1987, pp 669-685 6. Diehl AM, Potter J, Boitnott J, et al: Relationship between pyridoxal 5'phosphate deficiency and aminotransferase levels in alcoholic hepatitis. Gastroenterology 1984; 86:632-636 7. Perillo RP, Griffin R, DeSchryver-Kerskemeti K, Lander JJ, Zuckerman GR: Alcoholic liver disease presenting with marked elevation of serum alkaline phosphatase. Dig Dis Sci 1978; 23:1061-1066 8. Morse RM, Hurt RD: Screening for alcoholism. JAMA 1979; 242:2688-2690 9. Galambos J: Alcoholic hepatitis, In Schaffner F, Sherlock S, Leevy C (Eds): The Liver and Its Diseases. New York, Intercontinental Medical Book Co, 1974, pp 254257 10. Carithers RL, Herlong F, Diehl AM, et al: Methylprednisolone therapy in patients with severe alcoholic hepatitis. Ann Intern Med 1989; 110:685-690 11. Diehl AM, Goodman Z, Ishak KG: Alcohol-like liver disease in nonalcoholics. Gastroenterology 1988; 95:1056-1062 12. Levin DM, Baker AL, Riddell RH, Rochman L, Boyer JL: Nonalcoholic liver disease: Overlooked causes of liver injury in patients with heavy alcohol consumption. Am J Med 1979; 66:429-434

Utility of 'liver function tests' in alcoholic patients.

THE WESTERN JOURNAL OF MEDICIN-E o MARCH 1992 9 156 o 3 to effectively increase drug uptake in the central nervous system. The promise of biote...
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