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Evaluation of patients with portal hypertension
Evaluation of Patients with Portal Hypertension John T. Galambos, MD, Atlanta,Georgia In order to select the most suitable management of portal hypertension, a full evaluation of the patient is desirable. The aspects studied should include the possible causes of portal hypertension and the disease and function of the liver, as well as the psychosocial aspects of this condition. The usual reason to investigate the presence and causes of portal hypertension is the detection of gastroesophageal varices. The estimated probability of bleeding from the varices and the cause of the varices should be investigated. If cirrhosis is detected, then its cause or mechanism should be clarified and the activity of the process estimated in semiquantitative terms. If therapy is available, it should be initiated. The evaluation of liver function is based on quantitative measurements of hepatocellular metabolic function (such as the galactose elimination capacity or antipyrine clearance), liver volume (weight), liver blood flow, and systemic hemodynamics (cardiac output index).
G
astroesophageal varices are usually caused by portal hypertension. Patients with varices are evaluated in order to determine the need for therapy and to select the most suitable treatment for the patient. The treatment choices are either expectant or definitive. Definitive therapy can be either noninvasive or invasive: noninvasive therapy can be aimed at the underlying disease, such as alcoholic hepatitis, the resolution of which can convert large varices with risk factors to small varices with low risk of bleeding. Drug therapy for portal hypertension, such as propranolol or nadolol, is suitable for some patients. Invasive therapies include endoscopic sclerotherapy and surgery. Surgical options for these patients include nonshunting procedures, selective decompression of the gastroesophageal varices, nonselective shunting of the entire or only the extrahepatic portion of the portal system, and orthotopic liver transplantation. Details of the various therapeutic modalities have been discussed previously. Because of the broad range of management options, a careful and detailed evaluation of the patient is desirable to select the optimum therapy. From the Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia. Requests for reprints should be addressed to John T. Galambos, MD, Emory University School of Medicine, 69 Butler Street, Atlanta, Georgia 30322.
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Full evaluation of a bleeding patient is possible only if the bleeding can be controlled long enough to stabilize the patient and complete the studies. Three areas should be examined in detail: (1) the cause of portal hypertension, (2) the type of liver disease, and (3) the extent of liver function. In addition, the psychosocial aspects of portal hypertension should be reviewed. EVALUATION OF PORTAL HYPERTENSION The usual reason for evaluating a patient for portal hypertension is that esophageal or gastric varices (or both) have been detected. Such varices may be due to a variety of mechanisms, such as portal vein thrombosis, splenic vein thrombosis, unexplained esophageal varices, "downhill" varices, and visible veins in hiatal hernia. Therefore, once varices are detected, one cannot assume that these are caused by portal hypertension due to cirrhosis. Other, albeit less common, causes must be considered (Table I). If portal hypertensive changes are detected during an imaging procedure (gastrointestinal series or computed tomography (CT) examination of the upper abdomen), then esophagogastroduodenoscopy is indicated to determine the presence and characteristics of vatices in the upper gastrointestinal tract. Endoscopy should be performed not only to identify the presence of varices, but to describe the various risk factors. These are: (1) size and number of the varices in the distal esophagus close to the z-line, (2) the presence or absence of red, blue, or other colored spots on the varix, (3) the proximal extension and size of the varices in the esophagus, (4) the extension of the varices across the z-line into the gastric mucosa, (5) the presence of obvious or suspected gastric varices, (6) the severity and extent of portal hypertensive changes of the gastric mucosa in the fundus and antrum, (7) the presence of atypical varices in the duodenum, and (8) the presence or absence of other upper gastrointestinal diseases not related to portal hypertension. If the patient is a candidate for surgery, then angiographic examination of the splanchnic circulation is necessary. These studies should include superior mesenteric angiography with good exposures of the venous phase to evaluate the main portal vein and opacification of the portal venous tributaries; splenic angiography to evaluate the location and size of the splenic vein; and left renal venography and hepatic venography with measurements of the pressures in the inferior vena cava, the right atrium, and the free and wedged hepatic vein. The direction and dynamics of blood flow in the portal and splenic veins, and in selected cases, in the hepatic veins are determined by real-time ultrasound sector-scan measurement of portal vein diameter and portal flow velocity measurement with a Doppler probe. EVALUATION OF LIVER DISEASE Although the most common cause of portal hypertension and gastroesophageal varices is cirrhosis of the liver,
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many patients have other causes (Table I). In cases of cirrhosis, the underlying etiologic mechanism may or may not be active. While the evaluation of liver disease is well known, certain points are worth emphasizing. A history of alcohol consumption does not prove alcoholic liver disease in a patient with portal hypertension. Such a history should include a quantitative estimate of daily consumption of alcohol and the duration of steady drinking or define a binge-drinking pattern. On the other hand, alcoholic cirrhosis can be the cause of portal hypertension even if the patient has been abstaining during recent years or decades. To simplify the evaluation of alcohol consumption, one may assume that an average drink (a highball, glass of wine, or can of beer) contains 15 g of ethanol and an ounce of whiskey contains 10 g, i.e., a pint contains 80 g of ethanol. A more precise estimate of the ethanol content of beverages can be obtained from the following formula: 0.117 • proof • ounce = g of ethanol [1]. The risk of cirrhosis is higher in women than in men at any level of daily alcohol consumption. Table II describes the risk of cirrhosis on the basis of a retrospective analysis of drinking patterns. A quantitative evaluation of past ethanol consumption can identify the cause of cirrhosis, particularly in former drinkers who are currently abstaining or alcoholic patients who are not currently drinking. The patient's history of transfusion of blood or blood products should be elicited. This may require the review of past hospital records, particularly those hospitalizations that were for surgical, obstetrical, or gynecological reasons. The recently developed serologic test for antihepatitis B core (HBc) may help in assigning posttransfusion hepatitis as a cause of cirrhosis. Although it is usually easy to identify hepatitis-B virus (HBV) as a cause of cirrhosis in hepatitis B surface antigen (HBsAg)-positive and anti-HBc-positive patients who do not have chronic alcoholism, the etiology is not as clear in those who are anti-HBs- and anti-HBc-positive but HBsAg-negative. The history, physical examination, and routine laboratory studies can estimate the clinical severity of the liver disease on the basis of modified Child's criteria (Table III). The clinical evaluation should estimate the degree of the patient's disability, based on what extent the liver disease interferes with the normal daily activities of the patient. This evaluation must consider the extent to which the apparent disability is affected by physical illness or by lack of motivation and depression. Indeed, the clinical judgment of an experienced physician is probably the most meaningful set of data for the assessment of the severity of liver disease. The activity of the liver disease that caused cirrhosis is usually evaluated by routine biochemical liver tests and by liver biopsy. While the pattern of abnormalities of the liver tests gives helpful dues, these tests are not sufficiently reliable indicators of the severity of parenchymal liver disease. Usually, the liver disease is either a chronic hepatitis-viral-, autoimmune-, drug-, or alcohol-mediated-or it is a eholestatic or vascular process. In a few patients, however, a new viral or drug hepatitis may be superimposed on a liver with stable cirrhosis. A more specific
TABLE I Causes of Portal Hypertension Budd-Chiari syndrome Chronic liver diseases Cirrhosis Alcoholic hepatitis Chronic active hepatitis Granulomatous hepatitis SarcoidosJs Schistosomiasis Hematologic malignancies Lymphomas Leukemia Myeloproliferative disorders Idiopathic (portal phlebosclerosis, Banti's syndrome) Intrahepatic vascular occlusion due to malignancy Nodular abnormalities Partial nodular transformation Nodular regenerative hyperplasia Sinusoidal occlusion Vitamin A toxicity Gaucher's disease Myeloid metaplasla Tropical splenomagaly Vascular abnormalities Arteriovenous fistula Veno-occlusive disease
estimate of the activity and nature of the liver disease must be based on histologic examination of the liver. When or where to do a liver biopsy is controversial. There is no general agreement on any specific criterion for safety; that is, what degree of abnormality of the coagulation parameters would preclude a safe liver biopsy. There is no proof that any specific prolongation of the prothrombin time can reliably predict the risk of postbiopsy bleeding, nor is there any evidence that would predict the risk of postbiopsy bleeding based on bleeding time. There is a strong suggestion that severe thrombocytopenia, i.e., less than 50,000 platelets, will increase the risk of postbiopsy bleeding. Furthermore, there is no general agreement among academic hepatologists or practicing gastroenterologists on what constitutes a prudent set of criteria for the performance of a liver biopsy. In various academic centers, the criteria for liver biopsy vary from a prothrombin time increase over normal of 1 second to an increase of 7 seconds. Some hepatologists use no preset criteria for the performance of a liver biopsy and evaluate each patient individually. There is also no general agreement regarding where the liver biopsy should be performed. Although some physicians will perform liver biopsies on outpatients, others insist on overnight hospitalization following liver biopsy. As a general rule, good- risk patients who do not have cirrhosis (i.e., abnormal size and shape of the liver), can easily be transported to the hospital if postbiopsy complications develop, and, most of all, do not have potential or overt clinical risk factors (i.e., can safely tolerate bleeding or bile leakage for several hours longer due to transportation problems) may undergo liver biopsy as outpatients with reasonable safety. On the other hand, serious side effects after liver biopsy are much more likely in patients with advanced stages of liver disease. These patients, if they undergo biopsy at all, should have it done
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TABLE II Amount of Daily Ethanol Consumption and Risk of Cirrhosis* Patients Ethanol per day (g)
with Cirrhosis
<60 60-120 120-180 180-240 >240
29 39 70 54 21
Total
with no Liver Disease
(13)% (18%) (33%) (25%) (10%)
217 100 37 17 7
213
(57%) (26%) (10%) (4%) (2%)
378
* Five of six French men with normal livers drank daily 120 g of ethanol or less, but two of three with cirrhosis drank more than that. (Gastroenterol Clin Biol 1979; 3:725-34)
TABLE III Modified Child's Criteria
1 Ascites Nutrition" Albumin (mg/dL) Bilirubin (mg/dL) BUN (mg/dL) Spontaneous encephalopathy
0 >85% > 3.5 < 1.5 <20 0
Grades 2 Controlled 70-85% 3-3.5 1.5-3 20-25 0
3 Resistant <70% <3 >3 >25 Yes
" Percent of predicted normal 24-hour urine creatinine/height ratio. Grade 6 = excellent: grades 7 to 8 = good; grades 9 to 12 = intermediate; grades 13 to 18 = poor. BUN = blood urea nitrogen.
in the hospital. Ultrasound marking of the liver biopsy site is strongly recommended in the case of cirrhosis. Because of the low incidence of complications associated with liver biopsy, it has not been done on a sufficient number of outpatients to clearly establish the safety of this procedure. In addition to the routine liver tests, patients with chronic liver disease and portal hypertension should undergo serologic and immunologic evaluation. Serologic testing should include tests for hepatitis A and B; if a high-risk patient (such as one addicted to drugs) is found to be HBsAg-positive, a test for hepatitis D (anti-HD) should also be done. Patients who are HBsAg-positive should also be tested for HBV-DNA. Those with a history of transfusion or administration of blood products should have serologic tests for hepatitis C (anti-HC) (Table III). Immunologic markers: The pattern of immunoglobulin (Ig) elevation is a helpful clue regarding the nature of the underlying liver disease. IgM globulins are usually elevated in primary biliary cirrhosis, although patients with primary biliary cirrhosis may occasionally have IgA elevation. However, in the vast majority of patients with alcoholic cirrhosis, IgA is elevated much more than the other immunoglobulins. In autoimmune chronic active hepatitis, the IgG globulins are usually elevated. There will be an occasional patient with cirrhosis who may have 16
T H E A M E R I C A N J O U R N A L OF S U R G E R Y
an M-peak on serum protein electrophoresis without having multiple myeloma or lymphoma. Antimitochondrial antibody is present in the vast majority of patients with primary biliary cirrhosis. Indeed, this diagnosis is most unlikely if both the IgM is normal and the antimitochondrial antibody is negative. Antinuclear antibody, antismooth muscle antibody (antiactin), or antimicrosomal antibody (antiendoplasmic reticulum) are seen in various subgroups of patients with autoimmune chronic active hepatitis. With disease remission, these immunologic markers usually return toward normal. Patients should also be evaluated for specific causes of cirrhosis. Ceruloplasmin should be looked for in any young patient with chronic liver disease; it is an acutephase reactant and may be in the low-normal range in patients with Wilson's disease who have active parenchymal liver disease. Hemochromatosis is identified by measuring iron, total iron-binding capacity, percent saturation, and serum ferritin level. It must be noted, however, that ferritin is also an acute-phase reactant that can be elevated in active liver disease: both acute and chronic active hepatitis or alcoholic hepatitis. Iron- binding capacity is often low in patients with cirrhosis; therefore, a high percent saturation must be interpreted with caution in these patients. Alpha] antitrypsin deficiency is a rare cause of cirrhosis. It is documented by the typical liver biopsy findings in patients with low alpha~ antitrypsin blood levels. Alpha-fetoprotein is usually obtained to identify hepatomas. Unfortunately, the majority of hepatomas in our patients are not associated with high alpha-fetoprotein levels, nor are hepatomas in the United States commonly associated with HBV infection in contrast to the experience in the Orient. Mild elevations (less than 100) of alpha-fetoprotein levels are not uncommon in chronic active liver diseases in the absence of hepatoma. Nutritional deficiencies are common in chronic liver diseases of all types, but are particularly frequent in patients with alcoholic liver disease. The prognosis of the patient with alcoholic hepatitis is related to the severity of malnutrition. Nutritional assessment is usually based on clinical estimates such as height and weight. This educated guess is often misleading in patients who do not have the marasmus type of malnutrition. Better estimates are based on measurements of prealbumin and transferrin plasma concentrations and the 24-hour urinary creatinine excretion. The latter permits the calculation of the creatinine/height ratio, which is an index of the lean body mass. Routine anthropomorphic studies consist of measurements of midarm circumference and skinfold thickness from which the midarm fat area and muscle areas can be calculated. All these calculated values can be expressed as percent of normal from standard tables. Tables of normal creatinine/height ratio and anthropometric values can be programmed into computers used in hospitals and laboratories so that nutritional assessment can be obtained readily without hand calculations. The nutritional database is a neglected, but very useful set of measurements and should be part of the routine physical examination of all patients with chronic disease.
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The clinical severity of the liver disease is assessed on the basis of the clinical evaluation of the patient such as the depression of the serum albumin, the prolongation of the prothrombin time, or the severity of jaundice. These estimates improve when based on one of the modifications of Child's criteria (Table III). The assessment of the severity of hepatic failure, particularly in alcoholic liver disease, is improved by consideration of the degree of depression of the serum cholesterol concentration and the T3 by radioimmunoassay level. Patients with portal hypertension commonly manifest features of hypersplenism. They have anemia, often macrocytic with elevated reticulocytes and red blood cell distribution width; leukopenia, often with a white blood cell count under 3,000/mm 3, and thrombocytopenia, often with a count below 100,000/mm 3. Despite the impressive hematologic abnormalities, these findings are rarely important clinically. These abnormalities make those physicians who are not seeing large numbers of cirrhotic patients with hypersplenism uneasy. Indeed, some hematologists are sufficiently alarmed by these laboratory abnormalities to recommend splenectomy. However, splenectomy for the correction of laboratory abnormalities should never be performed in order to reassure the physician without direct benefit to the patient. Despite their thrombocytopenia, the vast majority of these patients do not bleed because of low platelet counts. The low hemoglobin and hematocrit are almost never symptomatic. One must consider that the plasma volume is increased in cirrhosis, particularly in those with ascites. Therefore, the red cell mass is not as low as the peripheral venous hematocrit suggests. Although the anemia is usually macrocytic, these cirrhotic patients usually have normal B12 and red blood cell folate levels; indeed, the BI2 levels may be elevated. Leukopenia is rarely a cause of infection. Indeed, infection is usually associated with a rise of polymorphonuclear leukocytes. EVAULATION OF LIVER FUNCTION Patients with suspected cirrhosis are usually studied to detect abnormalities, establish a diagnosis, and define the severity and activity of the underlying liver disease. Quantitative tests are designed to evaluate normally functioning hepatic parenchyma in quantitative terms. These studies include measures of hepatic blood flow, hepatic function, and liver size [2-5]. Clinical evidence of active liver disease does not necessarily indicate severe loss of hepatic mass or function. Reasonably good hepatic functional reserve can be present in patients who have abnormalities on clinical evaluation and in routine liver tests. To assess the effect of progressive liver disease, either single or preferably, serial determinations of hepatic function can give a quantitative assessment of the progression of the disease [6-9]. Quantitative function tests predicted survival of orthotopic liver transplant candidates with cirrhosis [I 0,11]. The effect of shunt operations can be assessed by measurements of hepatic function [12,13]. Hepatic function improved in patients with chronic hepatitis B after clearance of hepatitis-B virus replication [14]. The incorporation of galac-
tose elimination capacity into modified Child's criteria improved its predictive value [15,16]. Indeed, quantitative liver function is suggested to replace survival analysis in randomized clinical trials [17]. Depending on the rate of disease progression, these measurements can be repeated at 6- or 24-month intervals. Serial determination of metabolic liver function predicts survival better than conventional liver tests [18]. When the chronic progressive liver disease has reached the point where it will no longer be compatible with survival, then a liver transplant could be offered if the patient is a candidate for orthotopic liver transplantation. For example, the quantitative assessment of the hepatic reserve in a patient with recurrent variceal hemorrhages may change a planned shunt operation to an orthotopic liver transplantation. Measurements of hepatic blood flow, cardiac output, hepatic function, and the liver-spleen volume are part of the hepatic database at Emory. In normal adults, the hepatic blood flow is 1,378 4- 218 mL/minute. The hepatic volume in these normal adults is 1,490 4- 230 mL and the normal hepatic function (expressed as the galactose elimination capacity) is 500 4- 50 mg/minute. The 1,378-mL hepatic blood flow represents 27% of the normal 5.1 L/minute cardiac output [19,20]. The portal blood flow contributes two thirds of the total blood flow, or 15 mL/second. The quantitative evaluation of the liver is based on the following measurements: (1) hepatocellular function, (2) total hepatic blood flow, (3) portal blood flow, (4) systemic hemodynamic changes, and (5) liver size. These measurements can aid in the estimation of the fraction of the cardiac output that goes to the liver, the degree of preservation of portal blood flow to the liver, and the function of the liver per unit of blood flow or per unit of liver volume. In the normal liver, there is 1 mL of blood perfusing 1 mL of hepatic parenchyma per minute. The functional liver mass of a normal liver can be based on the capacity to eliminate galactose; it takes 3 mL of hepatic parenchyma to eliminate 1 mg of galactose per minute in an average adult. After an overnight fast, liver function is quantitated by measuring the rate of decrease of plasma galactose concentrations after the intravenous injection of 30 g of galactose in 2 minutes or less [21] to estimate the galactose elimination capacity. Liver blood flow is measured by the galactose clearance method of Henderson and co-workers [19]. Continuous intravenous infusion of 5% galactose at 40 mg/ minute ensures a near steady-state plasma concentration by 60 to 100 minutes of less than 10 mg/dL. At these low galactose plasma concentrations, all sinusoidal galactose is removed from blood during a single pass. Because of the rapid equilibration of galactose between red cell and plasma water, galactose clearance is an estimate of hepatic blood flow. Galactose clearance is an estimate of the nutrient (i.e., sinusoidal, not total) hepatic blood flow. Galactose plasma concentrations in both studies are measured by the automated fluorometric method of Henderson and Fales [22].
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Cardiac output, an estimate of the effect of cirrhosis on systemic hemodynamics, is measured by first-pass nuclear angiocardiography. This noninvasive method corre, lates best with data obtained by Swan-Ganz thermodilution in the same patients at the same time. Portal blood flow (also splenic and mesenteric) is measured by pulsed Doppler flow meter. The transverse diameter of the portal vein is measured by real-time ultrasound, and the area of portal vein is calculated, assuming that the vein is a circle. The rate of flow is measured with the Doppler probe by placing a cursor in the center of the vein and gate about two thirds of the diameter. From this the total flow rate is calculated, assuming that the gate represents the average flow rate. The liver and spleen volumes are measured by C T scan [20]. One-centimeter cuts are integrated during quiet breathing, assuming no overlaps of these cuts. If contrast is given, then the extent of portal collateral circulation can also be evaluated. The CT images not only provide quantitative information on the liver size, but also estimate relative changes of the various lobes within the liver. In cirrhosis, the lateral segment of the right lobe of the liver is decreased. However, the left lobe and the caudate lobe are usually hypertrophied. Therefore, the change of total liver volume alone is not sufficient to understand the total changes the cirrhotic process has inflicted on the liver. Despite portal hypertension, the spleen is not enlarged in some patients, yet it can be massively enlarged in others. In general, splenomegaly is less in alcoholic cirrhosis. Clinical estimates of liver or spleen size are often erroneous when these changes are not pronounced. If one accepts the intact cell theory [23], then one could assume that normally perfused hepatocytes that contain normal structure retain their normal function and perform their normal metabolic activity. If that is the case, then different types of hepatic functions are preserved to approximately the same degree. The evaluation of a function based on the integrity of different organelles and enzyme systems in the hepatocyte shows a remarkably close correlation in both normal and cirrhotic livers. This indicates that all types of functions are similarly preserved or lost during acute and chronic liver disease. REFERENCES 1. Galambos JT. Alcoholic hepatitis. In: Galambos JT, Hersh T, eds. Digestive diseases. Boston: Butterworths, 1983: 386-400. 2. Bircher J, Blankart R, Halpern A, H/icki W, Laissue ,i, Preisig R. Criteria for assessment of functional impairment in patients with cirrhosis of the liver. Eur J Clin Invest 1973; 3: 72-85. 3. Khatra BS, Smith RB III, Millikan W J, Sewell CW, Warren WD, Rudman D. Activities of Krebs-Henseleit enzymes in normal and cirrhotic human liver. J Clin Lab Med 1974; 84: 708-15. 4. Rudman D, DiFulco T J, Galambos JT, et al. Maximal rates of urea synthesis in normal and cirrhotic subjects. J Clin Invest 1973; 52: 2241-9. 5. Rypins EB, Henderson JM, Fulenwider .IT, et al. A tracer
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method for measuring rate of urea synthesis in normal and cirrhotic subjects. Gastroenterology 1980; 78: 1419-24. 6. Pomier-Layrargues G, Huet P-M, Infante-Rivard C, et al. Prognostic value of indocyanine green and lidocaine kinetics for survival and chronic hepatic encephalopathy in cirrhotic patients following elective end-to-side portacaval shunt. Hepatology 1988; 8: i50610. 7. Poulsen HE, Loft S. Antipyrine as a model drug to study hepatic drug-metabolizing capacity. ,i Hepatol 1988; 6: 374-82. 8. Gross JB Jr, Reichcn ,i, Zeltner TB, Zimmerman A. The evolution of changes in quantitative liver function tests in a rat model of biliary cirrhosis: correlation with morphometric measurement of hepatocyte mass. Hepatology 1987; 7: 457-63. 9. Bircher J. Quantitative assessment of deranged hepatic function: a missed opportunity? Semin Liv Dis 1983; 3: 275-84. 10. Oellerich M, Burdelski M, Ringe B, et al. Lignocaine metabolite formation as a measure of pre-transplant liver function. Lancet 1989; 1: 640-42. 11. Oellerich M, Burdelski M, Lautz HU, Rodeck B, Schmidt FW. Assessment of short-term prognosis in transplant candidates with cirrhosis [Abstract]. J Hepatol 1989; 9(Suppl 1): $67. 12. Pomier-Layrargues G, Huet P-M, Infante-Rivard C, et al. Prognostic value of indocyanine green and lidocaine kinetics for survival and chronic hepatic r in cirrhotic patients following elective end-to-side portacaval shunt. Hepatology 1988; 8: 1506-10. 13. Galambos JT, Warren WD, Rudman D, Smith RB III, Salam AA. Selective and total shunts in the treatment of bleeding varices. N Engl J Med 1976; 295: 1089-=95. 14. Williams SJ, Farrell GC. Serial antipyrine clearance studies detect altered hepatic metabolic function during spontaneous and interferon-induced changes in chronic hepatitis B disease activity. Hepatology 1989; 10: 192-7. 15. Merkel C, Gatta A, Bolognesi M, Angeli P, Rondana M, Ruol A. Prognostic value of galactose elimination capacity, aminopyrine breath test, and ICG clearance in cirrhosis: comparison with the laugh score [Abstract]. J Hepatol 1989; 9(Suppl 1): $64. 16, Bircher J. Assessment of prognosis in advanced liver disease: to score or to measure, that's the question [Editorial]. Hepatology 1986; 6: 1036-7. 17. Lotterer E, Brunner E, von Knebel D, Foelsch U, Bircher J. Quantitative liver function tests should replace survival analysis in controlled clinical trials [Abstract]. J Hepatol 1989; 9(Suppl 1): $57. 18. CoRing J, Widmer T, Bircher J, Preisig R, Reichen J. Serial determination of galactose elimination capacity (GEC) in primary biliary cirrhosis (PBC) is of better prognostic value than serum bilirubin [Abstract]. J Hepatol 1987; 5(Suppl 1): $20. 19. Henderson JM, Kutner MH, Bain RP. First-order clearance of plasma galactose: the effect of liver disease. Gastroenterology 1982; 83: 1090-6. 20. Henderson JM, Heymsfleld SB, Horowitz J, Kutner MH. Measurement of liver and spleen volume by computed tomography. Radiology 1981; 141: 525-7. 21. Tygstrup N. The galactose elimination capacity in control subjects and in patients with cirrhosis of the liver. Acta Med Scand 1964; 175: 281-9. 22. Henderson JM, Fales FW. Continuous-flow fluorometry of low galactose concentrations in blood or plasma. Clin Chem 1980; 26: 282-5. 23. Wood A,IJ, Villeneuve JP, Branch RA, Rogers LW, Shand DG. Intact hepatoeyte theory of impaired drug metabolism in experimental cirrhosis in the rat. Gastroenterology 1979; 76: 135862.
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G
astroesophageal varices are usually caused by portal hypertension. Patients with varices are evaluated in order to determine the need for therapy and to select the most suitable treatment for the patient. The treatment choices are either expectant or definitive. Definitive therapy can be either noninvasive or invasive: noninvasive therapy can be aimed at the underlying disease, such as alcoholic hepatitis, the resolution of which can convert large varices with risk factors to small varices with low risk of bleeding. Drug therapy for portal hypertension, such as propranolol or nadolol, is suitable for some patients. Invasive therapies include endoscopic sclerotherapy and surgery. Surgical options for these patients include nonshunting procedures, selective decompression of the gastroesophageal varices, nonselective shunting of the entire or only the extrahepatic portion of the portal system, and orthotopic liver transplantation. Details of the various therapeutic modalities have been discussed previously. Because of the broad range of management options, a careful and detailed evaluation of the patient is desirable to select the optimum therapy. From the Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia. Requests for reprints should be addressed to John T. Galambos, MD, Emory University School of Medicine, 69 Butler Street, Atlanta, Georgia 30322.
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Full evaluation of a bleeding patient is possible only if the bleeding can be controlled long enough to stabilize the patient and complete the studies. Three areas should be examined in detail: (1) the cause of portal hypertension, (2) the type of liver disease, and (3) the extent of liver function. In addition, the psychosocial aspects of portal hypertension should be reviewed. EVALUATION OF PORTAL HYPERTENSION The usual reason for evaluating a patient for portal hypertension is that esophageal or gastric varices (or both) have been detected. Such varices may be due to a variety of mechanisms, such as portal vein thrombosis, splenic vein thrombosis, unexplained esophageal varices, "downhill" varices, and visible veins in hiatal hernia. Therefore, once varices are detected, one cannot assume that these are caused by portal hypertension due to cirrhosis. Other, albeit less common, causes must be considered (Table I). If portal hypertensive changes are detected during an imaging procedure (gastrointestinal series or computed tomography (CT) examination of the upper abdomen), then esophagogastroduodenoscopy is indicated to determine the presence and characteristics of vatices in the upper gastrointestinal tract. Endoscopy should be performed not only to identify the presence of varices, but to describe the various risk factors. These are: (1) size and number of the varices in the distal esophagus close to the z-line, (2) the presence or absence of red, blue, or other colored spots on the varix, (3) the proximal extension and size of the varices in the esophagus, (4) the extension of the varices across the z-line into the gastric mucosa, (5) the presence of obvious or suspected gastric varices, (6) the severity and extent of portal hypertensive changes of the gastric mucosa in the fundus and antrum, (7) the presence of atypical varices in the duodenum, and (8) the presence or absence of other upper gastrointestinal diseases not related to portal hypertension. If the patient is a candidate for surgery, then angiographic examination of the splanchnic circulation is necessary. These studies should include superior mesenteric angiography with good exposures of the venous phase to evaluate the main portal vein and opacification of the portal venous tributaries; splenic angiography to evaluate the location and size of the splenic vein; and left renal venography and hepatic venography with measurements of the pressures in the inferior vena cava, the right atrium, and the free and wedged hepatic vein. The direction and dynamics of blood flow in the portal and splenic veins, and in selected cases, in the hepatic veins are determined by real-time ultrasound sector-scan measurement of portal vein diameter and portal flow velocity measurement with a Doppler probe. EVALUATION OF LIVER DISEASE Although the most common cause of portal hypertension and gastroesophageal varices is cirrhosis of the liver,
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many patients have other causes (Table I). In cases of cirrhosis, the underlying etiologic mechanism may or may not be active. While the evaluation of liver disease is well known, certain points are worth emphasizing. A history of alcohol consumption does not prove alcoholic liver disease in a patient with portal hypertension. Such a history should include a quantitative estimate of daily consumption of alcohol and the duration of steady drinking or define a binge-drinking pattern. On the other hand, alcoholic cirrhosis can be the cause of portal hypertension even if the patient has been abstaining during recent years or decades. To simplify the evaluation of alcohol consumption, one may assume that an average drink (a highball, glass of wine, or can of beer) contains 15 g of ethanol and an ounce of whiskey contains 10 g, i.e., a pint contains 80 g of ethanol. A more precise estimate of the ethanol content of beverages can be obtained from the following formula: 0.117 • proof • ounce = g of ethanol [1]. The risk of cirrhosis is higher in women than in men at any level of daily alcohol consumption. Table II describes the risk of cirrhosis on the basis of a retrospective analysis of drinking patterns. A quantitative evaluation of past ethanol consumption can identify the cause of cirrhosis, particularly in former drinkers who are currently abstaining or alcoholic patients who are not currently drinking. The patient's history of transfusion of blood or blood products should be elicited. This may require the review of past hospital records, particularly those hospitalizations that were for surgical, obstetrical, or gynecological reasons. The recently developed serologic test for antihepatitis B core (HBc) may help in assigning posttransfusion hepatitis as a cause of cirrhosis. Although it is usually easy to identify hepatitis-B virus (HBV) as a cause of cirrhosis in hepatitis B surface antigen (HBsAg)-positive and anti-HBc-positive patients who do not have chronic alcoholism, the etiology is not as clear in those who are anti-HBs- and anti-HBc-positive but HBsAg-negative. The history, physical examination, and routine laboratory studies can estimate the clinical severity of the liver disease on the basis of modified Child's criteria (Table III). The clinical evaluation should estimate the degree of the patient's disability, based on what extent the liver disease interferes with the normal daily activities of the patient. This evaluation must consider the extent to which the apparent disability is affected by physical illness or by lack of motivation and depression. Indeed, the clinical judgment of an experienced physician is probably the most meaningful set of data for the assessment of the severity of liver disease. The activity of the liver disease that caused cirrhosis is usually evaluated by routine biochemical liver tests and by liver biopsy. While the pattern of abnormalities of the liver tests gives helpful dues, these tests are not sufficiently reliable indicators of the severity of parenchymal liver disease. Usually, the liver disease is either a chronic hepatitis-viral-, autoimmune-, drug-, or alcohol-mediated-or it is a eholestatic or vascular process. In a few patients, however, a new viral or drug hepatitis may be superimposed on a liver with stable cirrhosis. A more specific
TABLE I Causes of Portal Hypertension Budd-Chiari syndrome Chronic liver diseases Cirrhosis Alcoholic hepatitis Chronic active hepatitis Granulomatous hepatitis SarcoidosJs Schistosomiasis Hematologic malignancies Lymphomas Leukemia Myeloproliferative disorders Idiopathic (portal phlebosclerosis, Banti's syndrome) Intrahepatic vascular occlusion due to malignancy Nodular abnormalities Partial nodular transformation Nodular regenerative hyperplasia Sinusoidal occlusion Vitamin A toxicity Gaucher's disease Myeloid metaplasla Tropical splenomagaly Vascular abnormalities Arteriovenous fistula Veno-occlusive disease
estimate of the activity and nature of the liver disease must be based on histologic examination of the liver. When or where to do a liver biopsy is controversial. There is no general agreement on any specific criterion for safety; that is, what degree of abnormality of the coagulation parameters would preclude a safe liver biopsy. There is no proof that any specific prolongation of the prothrombin time can reliably predict the risk of postbiopsy bleeding, nor is there any evidence that would predict the risk of postbiopsy bleeding based on bleeding time. There is a strong suggestion that severe thrombocytopenia, i.e., less than 50,000 platelets, will increase the risk of postbiopsy bleeding. Furthermore, there is no general agreement among academic hepatologists or practicing gastroenterologists on what constitutes a prudent set of criteria for the performance of a liver biopsy. In various academic centers, the criteria for liver biopsy vary from a prothrombin time increase over normal of 1 second to an increase of 7 seconds. Some hepatologists use no preset criteria for the performance of a liver biopsy and evaluate each patient individually. There is also no general agreement regarding where the liver biopsy should be performed. Although some physicians will perform liver biopsies on outpatients, others insist on overnight hospitalization following liver biopsy. As a general rule, good- risk patients who do not have cirrhosis (i.e., abnormal size and shape of the liver), can easily be transported to the hospital if postbiopsy complications develop, and, most of all, do not have potential or overt clinical risk factors (i.e., can safely tolerate bleeding or bile leakage for several hours longer due to transportation problems) may undergo liver biopsy as outpatients with reasonable safety. On the other hand, serious side effects after liver biopsy are much more likely in patients with advanced stages of liver disease. These patients, if they undergo biopsy at all, should have it done
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TABLE II Amount of Daily Ethanol Consumption and Risk of Cirrhosis* Patients Ethanol per day (g)
with Cirrhosis
<60 60-120 120-180 180-240 >240
29 39 70 54 21
Total
with no Liver Disease
(13)% (18%) (33%) (25%) (10%)
217 100 37 17 7
213
(57%) (26%) (10%) (4%) (2%)
378
* Five of six French men with normal livers drank daily 120 g of ethanol or less, but two of three with cirrhosis drank more than that. (Gastroenterol Clin Biol 1979; 3:725-34)
TABLE III Modified Child's Criteria
1 Ascites Nutrition" Albumin (mg/dL) Bilirubin (mg/dL) BUN (mg/dL) Spontaneous encephalopathy
0 >85% > 3.5 < 1.5 <20 0
Grades 2 Controlled 70-85% 3-3.5 1.5-3 20-25 0
3 Resistant <70% <3 >3 >25 Yes
" Percent of predicted normal 24-hour urine creatinine/height ratio. Grade 6 = excellent: grades 7 to 8 = good; grades 9 to 12 = intermediate; grades 13 to 18 = poor. BUN = blood urea nitrogen.
in the hospital. Ultrasound marking of the liver biopsy site is strongly recommended in the case of cirrhosis. Because of the low incidence of complications associated with liver biopsy, it has not been done on a sufficient number of outpatients to clearly establish the safety of this procedure. In addition to the routine liver tests, patients with chronic liver disease and portal hypertension should undergo serologic and immunologic evaluation. Serologic testing should include tests for hepatitis A and B; if a high-risk patient (such as one addicted to drugs) is found to be HBsAg-positive, a test for hepatitis D (anti-HD) should also be done. Patients who are HBsAg-positive should also be tested for HBV-DNA. Those with a history of transfusion or administration of blood products should have serologic tests for hepatitis C (anti-HC) (Table III). Immunologic markers: The pattern of immunoglobulin (Ig) elevation is a helpful clue regarding the nature of the underlying liver disease. IgM globulins are usually elevated in primary biliary cirrhosis, although patients with primary biliary cirrhosis may occasionally have IgA elevation. However, in the vast majority of patients with alcoholic cirrhosis, IgA is elevated much more than the other immunoglobulins. In autoimmune chronic active hepatitis, the IgG globulins are usually elevated. There will be an occasional patient with cirrhosis who may have 16
T H E A M E R I C A N J O U R N A L OF S U R G E R Y
an M-peak on serum protein electrophoresis without having multiple myeloma or lymphoma. Antimitochondrial antibody is present in the vast majority of patients with primary biliary cirrhosis. Indeed, this diagnosis is most unlikely if both the IgM is normal and the antimitochondrial antibody is negative. Antinuclear antibody, antismooth muscle antibody (antiactin), or antimicrosomal antibody (antiendoplasmic reticulum) are seen in various subgroups of patients with autoimmune chronic active hepatitis. With disease remission, these immunologic markers usually return toward normal. Patients should also be evaluated for specific causes of cirrhosis. Ceruloplasmin should be looked for in any young patient with chronic liver disease; it is an acutephase reactant and may be in the low-normal range in patients with Wilson's disease who have active parenchymal liver disease. Hemochromatosis is identified by measuring iron, total iron-binding capacity, percent saturation, and serum ferritin level. It must be noted, however, that ferritin is also an acute-phase reactant that can be elevated in active liver disease: both acute and chronic active hepatitis or alcoholic hepatitis. Iron- binding capacity is often low in patients with cirrhosis; therefore, a high percent saturation must be interpreted with caution in these patients. Alpha] antitrypsin deficiency is a rare cause of cirrhosis. It is documented by the typical liver biopsy findings in patients with low alpha~ antitrypsin blood levels. Alpha-fetoprotein is usually obtained to identify hepatomas. Unfortunately, the majority of hepatomas in our patients are not associated with high alpha-fetoprotein levels, nor are hepatomas in the United States commonly associated with HBV infection in contrast to the experience in the Orient. Mild elevations (less than 100) of alpha-fetoprotein levels are not uncommon in chronic active liver diseases in the absence of hepatoma. Nutritional deficiencies are common in chronic liver diseases of all types, but are particularly frequent in patients with alcoholic liver disease. The prognosis of the patient with alcoholic hepatitis is related to the severity of malnutrition. Nutritional assessment is usually based on clinical estimates such as height and weight. This educated guess is often misleading in patients who do not have the marasmus type of malnutrition. Better estimates are based on measurements of prealbumin and transferrin plasma concentrations and the 24-hour urinary creatinine excretion. The latter permits the calculation of the creatinine/height ratio, which is an index of the lean body mass. Routine anthropomorphic studies consist of measurements of midarm circumference and skinfold thickness from which the midarm fat area and muscle areas can be calculated. All these calculated values can be expressed as percent of normal from standard tables. Tables of normal creatinine/height ratio and anthropometric values can be programmed into computers used in hospitals and laboratories so that nutritional assessment can be obtained readily without hand calculations. The nutritional database is a neglected, but very useful set of measurements and should be part of the routine physical examination of all patients with chronic disease.
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The clinical severity of the liver disease is assessed on the basis of the clinical evaluation of the patient such as the depression of the serum albumin, the prolongation of the prothrombin time, or the severity of jaundice. These estimates improve when based on one of the modifications of Child's criteria (Table III). The assessment of the severity of hepatic failure, particularly in alcoholic liver disease, is improved by consideration of the degree of depression of the serum cholesterol concentration and the T3 by radioimmunoassay level. Patients with portal hypertension commonly manifest features of hypersplenism. They have anemia, often macrocytic with elevated reticulocytes and red blood cell distribution width; leukopenia, often with a white blood cell count under 3,000/mm 3, and thrombocytopenia, often with a count below 100,000/mm 3. Despite the impressive hematologic abnormalities, these findings are rarely important clinically. These abnormalities make those physicians who are not seeing large numbers of cirrhotic patients with hypersplenism uneasy. Indeed, some hematologists are sufficiently alarmed by these laboratory abnormalities to recommend splenectomy. However, splenectomy for the correction of laboratory abnormalities should never be performed in order to reassure the physician without direct benefit to the patient. Despite their thrombocytopenia, the vast majority of these patients do not bleed because of low platelet counts. The low hemoglobin and hematocrit are almost never symptomatic. One must consider that the plasma volume is increased in cirrhosis, particularly in those with ascites. Therefore, the red cell mass is not as low as the peripheral venous hematocrit suggests. Although the anemia is usually macrocytic, these cirrhotic patients usually have normal B12 and red blood cell folate levels; indeed, the BI2 levels may be elevated. Leukopenia is rarely a cause of infection. Indeed, infection is usually associated with a rise of polymorphonuclear leukocytes. EVAULATION OF LIVER FUNCTION Patients with suspected cirrhosis are usually studied to detect abnormalities, establish a diagnosis, and define the severity and activity of the underlying liver disease. Quantitative tests are designed to evaluate normally functioning hepatic parenchyma in quantitative terms. These studies include measures of hepatic blood flow, hepatic function, and liver size [2-5]. Clinical evidence of active liver disease does not necessarily indicate severe loss of hepatic mass or function. Reasonably good hepatic functional reserve can be present in patients who have abnormalities on clinical evaluation and in routine liver tests. To assess the effect of progressive liver disease, either single or preferably, serial determinations of hepatic function can give a quantitative assessment of the progression of the disease [6-9]. Quantitative function tests predicted survival of orthotopic liver transplant candidates with cirrhosis [I 0,11]. The effect of shunt operations can be assessed by measurements of hepatic function [12,13]. Hepatic function improved in patients with chronic hepatitis B after clearance of hepatitis-B virus replication [14]. The incorporation of galac-
tose elimination capacity into modified Child's criteria improved its predictive value [15,16]. Indeed, quantitative liver function is suggested to replace survival analysis in randomized clinical trials [17]. Depending on the rate of disease progression, these measurements can be repeated at 6- or 24-month intervals. Serial determination of metabolic liver function predicts survival better than conventional liver tests [18]. When the chronic progressive liver disease has reached the point where it will no longer be compatible with survival, then a liver transplant could be offered if the patient is a candidate for orthotopic liver transplantation. For example, the quantitative assessment of the hepatic reserve in a patient with recurrent variceal hemorrhages may change a planned shunt operation to an orthotopic liver transplantation. Measurements of hepatic blood flow, cardiac output, hepatic function, and the liver-spleen volume are part of the hepatic database at Emory. In normal adults, the hepatic blood flow is 1,378 4- 218 mL/minute. The hepatic volume in these normal adults is 1,490 4- 230 mL and the normal hepatic function (expressed as the galactose elimination capacity) is 500 4- 50 mg/minute. The 1,378-mL hepatic blood flow represents 27% of the normal 5.1 L/minute cardiac output [19,20]. The portal blood flow contributes two thirds of the total blood flow, or 15 mL/second. The quantitative evaluation of the liver is based on the following measurements: (1) hepatocellular function, (2) total hepatic blood flow, (3) portal blood flow, (4) systemic hemodynamic changes, and (5) liver size. These measurements can aid in the estimation of the fraction of the cardiac output that goes to the liver, the degree of preservation of portal blood flow to the liver, and the function of the liver per unit of blood flow or per unit of liver volume. In the normal liver, there is 1 mL of blood perfusing 1 mL of hepatic parenchyma per minute. The functional liver mass of a normal liver can be based on the capacity to eliminate galactose; it takes 3 mL of hepatic parenchyma to eliminate 1 mg of galactose per minute in an average adult. After an overnight fast, liver function is quantitated by measuring the rate of decrease of plasma galactose concentrations after the intravenous injection of 30 g of galactose in 2 minutes or less [21] to estimate the galactose elimination capacity. Liver blood flow is measured by the galactose clearance method of Henderson and co-workers [19]. Continuous intravenous infusion of 5% galactose at 40 mg/ minute ensures a near steady-state plasma concentration by 60 to 100 minutes of less than 10 mg/dL. At these low galactose plasma concentrations, all sinusoidal galactose is removed from blood during a single pass. Because of the rapid equilibration of galactose between red cell and plasma water, galactose clearance is an estimate of hepatic blood flow. Galactose clearance is an estimate of the nutrient (i.e., sinusoidal, not total) hepatic blood flow. Galactose plasma concentrations in both studies are measured by the automated fluorometric method of Henderson and Fales [22].
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Cardiac output, an estimate of the effect of cirrhosis on systemic hemodynamics, is measured by first-pass nuclear angiocardiography. This noninvasive method corre, lates best with data obtained by Swan-Ganz thermodilution in the same patients at the same time. Portal blood flow (also splenic and mesenteric) is measured by pulsed Doppler flow meter. The transverse diameter of the portal vein is measured by real-time ultrasound, and the area of portal vein is calculated, assuming that the vein is a circle. The rate of flow is measured with the Doppler probe by placing a cursor in the center of the vein and gate about two thirds of the diameter. From this the total flow rate is calculated, assuming that the gate represents the average flow rate. The liver and spleen volumes are measured by C T scan [20]. One-centimeter cuts are integrated during quiet breathing, assuming no overlaps of these cuts. If contrast is given, then the extent of portal collateral circulation can also be evaluated. The CT images not only provide quantitative information on the liver size, but also estimate relative changes of the various lobes within the liver. In cirrhosis, the lateral segment of the right lobe of the liver is decreased. However, the left lobe and the caudate lobe are usually hypertrophied. Therefore, the change of total liver volume alone is not sufficient to understand the total changes the cirrhotic process has inflicted on the liver. Despite portal hypertension, the spleen is not enlarged in some patients, yet it can be massively enlarged in others. In general, splenomegaly is less in alcoholic cirrhosis. Clinical estimates of liver or spleen size are often erroneous when these changes are not pronounced. If one accepts the intact cell theory [23], then one could assume that normally perfused hepatocytes that contain normal structure retain their normal function and perform their normal metabolic activity. If that is the case, then different types of hepatic functions are preserved to approximately the same degree. The evaluation of a function based on the integrity of different organelles and enzyme systems in the hepatocyte shows a remarkably close correlation in both normal and cirrhotic livers. This indicates that all types of functions are similarly preserved or lost during acute and chronic liver disease. REFERENCES 1. Galambos JT. Alcoholic hepatitis. In: Galambos JT, Hersh T, eds. Digestive diseases. Boston: Butterworths, 1983: 386-400. 2. Bircher J, Blankart R, Halpern A, H/icki W, Laissue ,i, Preisig R. Criteria for assessment of functional impairment in patients with cirrhosis of the liver. Eur J Clin Invest 1973; 3: 72-85. 3. Khatra BS, Smith RB III, Millikan W J, Sewell CW, Warren WD, Rudman D. Activities of Krebs-Henseleit enzymes in normal and cirrhotic human liver. J Clin Lab Med 1974; 84: 708-15. 4. Rudman D, DiFulco T J, Galambos JT, et al. Maximal rates of urea synthesis in normal and cirrhotic subjects. J Clin Invest 1973; 52: 2241-9. 5. Rypins EB, Henderson JM, Fulenwider .IT, et al. A tracer
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method for measuring rate of urea synthesis in normal and cirrhotic subjects. Gastroenterology 1980; 78: 1419-24. 6. Pomier-Layrargues G, Huet P-M, Infante-Rivard C, et al. Prognostic value of indocyanine green and lidocaine kinetics for survival and chronic hepatic encephalopathy in cirrhotic patients following elective end-to-side portacaval shunt. Hepatology 1988; 8: i50610. 7. Poulsen HE, Loft S. Antipyrine as a model drug to study hepatic drug-metabolizing capacity. ,i Hepatol 1988; 6: 374-82. 8. Gross JB Jr, Reichcn ,i, Zeltner TB, Zimmerman A. The evolution of changes in quantitative liver function tests in a rat model of biliary cirrhosis: correlation with morphometric measurement of hepatocyte mass. Hepatology 1987; 7: 457-63. 9. Bircher J. Quantitative assessment of deranged hepatic function: a missed opportunity? Semin Liv Dis 1983; 3: 275-84. 10. Oellerich M, Burdelski M, Ringe B, et al. Lignocaine metabolite formation as a measure of pre-transplant liver function. Lancet 1989; 1: 640-42. 11. Oellerich M, Burdelski M, Lautz HU, Rodeck B, Schmidt FW. Assessment of short-term prognosis in transplant candidates with cirrhosis [Abstract]. J Hepatol 1989; 9(Suppl 1): $67. 12. Pomier-Layrargues G, Huet P-M, Infante-Rivard C, et al. Prognostic value of indocyanine green and lidocaine kinetics for survival and chronic hepatic r in cirrhotic patients following elective end-to-side portacaval shunt. Hepatology 1988; 8: 1506-10. 13. Galambos JT, Warren WD, Rudman D, Smith RB III, Salam AA. Selective and total shunts in the treatment of bleeding varices. N Engl J Med 1976; 295: 1089-=95. 14. Williams SJ, Farrell GC. Serial antipyrine clearance studies detect altered hepatic metabolic function during spontaneous and interferon-induced changes in chronic hepatitis B disease activity. Hepatology 1989; 10: 192-7. 15. Merkel C, Gatta A, Bolognesi M, Angeli P, Rondana M, Ruol A. Prognostic value of galactose elimination capacity, aminopyrine breath test, and ICG clearance in cirrhosis: comparison with the laugh score [Abstract]. J Hepatol 1989; 9(Suppl 1): $64. 16, Bircher J. Assessment of prognosis in advanced liver disease: to score or to measure, that's the question [Editorial]. Hepatology 1986; 6: 1036-7. 17. Lotterer E, Brunner E, von Knebel D, Foelsch U, Bircher J. Quantitative liver function tests should replace survival analysis in controlled clinical trials [Abstract]. J Hepatol 1989; 9(Suppl 1): $57. 18. CoRing J, Widmer T, Bircher J, Preisig R, Reichen J. Serial determination of galactose elimination capacity (GEC) in primary biliary cirrhosis (PBC) is of better prognostic value than serum bilirubin [Abstract]. J Hepatol 1987; 5(Suppl 1): $20. 19. Henderson JM, Kutner MH, Bain RP. First-order clearance of plasma galactose: the effect of liver disease. Gastroenterology 1982; 83: 1090-6. 20. Henderson JM, Heymsfleld SB, Horowitz J, Kutner MH. Measurement of liver and spleen volume by computed tomography. Radiology 1981; 141: 525-7. 21. Tygstrup N. The galactose elimination capacity in control subjects and in patients with cirrhosis of the liver. Acta Med Scand 1964; 175: 281-9. 22. Henderson JM, Fales FW. Continuous-flow fluorometry of low galactose concentrations in blood or plasma. Clin Chem 1980; 26: 282-5. 23. Wood A,IJ, Villeneuve JP, Branch RA, Rogers LW, Shand DG. Intact hepatoeyte theory of impaired drug metabolism in experimental cirrhosis in the rat. Gastroenterology 1979; 76: 135862.
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