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Hypoxic hepatitis in patients with cardiac failure
Journal of Hepatology 1994; 21 : 693-695 Prhaed in Demnark . All rights reserved Munksgaard. Copenhagen
Copyright © Journalof Hepatology 1994 Journal of Hepatology
ISSN 0168-8278
Leader
Hypoxic hepatitis in patients with cardiac failure Paul Mohacsi and B e r n h a r d Meier Department o f Cardiology, University Hospital Bern, Sn,itzerland
Hypoxic hepatitis (HH) commonly called "ischemic hepatitis" or "shock liver" refers to a sharp but transient increase in serum activity of one or both of the aminotransferases (AST and/or ALT) of at least 20 times the upper limit of normal following circulatory failure. The definition of the syndrome in patients with previously healthy livers was reviewed by Gibson & Dudley in 1984 (I). HH is characterized by a rapid fall in transaminases if the causing condition is treated successfully. HH has been described in cardiogenic shock, after hemorrhage, and with sepsis, postoperative hypotension and pulmonary embolism, although the cause of "shock" appears to be irrelevant for the development of the syndrome. The patlaophysiological mechanisms of HH are still not well known. Most published papers describe patients with cardiac diseases and consider the relative contributions of HH (hepatic ischemia, hypoxia and congestion) to be relevant. Hepatic injury of HH may thus occur as a result of a reduction in liver blood flow followed by ischemia. Another study, however, showed that there was a higher incidence of passive venous congestion and hypoxemia in patients who developed HH, compared with patients with cardiogenic shock who did not develop HH (2). The role of hypoxemia is controversial since it has been reported that hyperbaric oxygen does not prevent hepatic necrosis in experimental models of shock (3). Further contributing factors may be the simultaneous administration of different drugs (e.g., vasoconstrictor inotropes which may impair hepatic blood flow by splanchnic vasoconstriction, or cardiodepressing drugs like calcium channel blockers or anti-arrhythmic agents) (4,5), It might be useful to summarize briefly the wide spectrum of hepatic complications due to heart failure syndromes. Chronic heart failure, which may exacerbate to
acute heart failure (2), can cause "cardiac cirrhosis" with the typical "nutmeg" appearance, but the more common finding and the first step which normally occurs in cardiac cirrhosis is simple congestive hepatomegaly (6). This disorder is usually recognized by elevated serum transaminases, high bilirubin levels, up to 20 mg/dl, due to an increase in both direct and indirect fractions, and jaundice. The serum transaminases may be increased I0- to 15-fold and serum alkaline phosphatase is increased. When the prothrombin time is substantially prolonged, congestive hepatopathy is usually severe and the prognosis poor. The development of end-stage cardiac cirrhosis will produce all of the findings associated with chronic liver failure, including hypoalbuminemia, hypoglycemia, ascites, and hepatic coma. Hepatic disorders due to acute cardiac failure can be caused by sudden cardiac low output syndromes or may arise also as a consequence of aggravation of chronic heart failure. In one study (2), the onset of HH was usually preceded by an acute cardiac complicaton, e.g., arrhythmia, provoking a sudden decrease in cardiac output. Fig. 1 and 2 depict the histological correlates of two typical hypoxic states in the liver. In the article by Henrion and coworkers, published in this issue of the journal (7), the authors present for the first time a prospective study on the incidence of HH in a European coronary care unit and measure the effective hepatic blood flow in patients with low cardiac output and HH, using the method of galactose clearance at low concentration. In this setting, low cardiac output was defined clinically by: I) Existence of cardiac disease (chronic or acute); 2) Cutaneous signs of circulatory failure; and 3) Intravenous inotropic treatment with dobutamine. Shock (defined in Henrion's paper as a fall of systolic blood
Correspondence to: Paul Mohacsi MD, Cardiology, University Hospital Bern, CH-3010 Bern, Switzerland.
694
..',
P. M O H A C S I and B. M E I E R
" ~
": -'? J'~.,_~.'" i~P-' "+ ~~'' ~'i'~ ~-?
+,' j f
,
"
+ +.~+ ''~'+~" ~ "
,.
..~te] "~
,~ ~'+
-
'
Fig. l. Typical centrilobular necrosis in a case of hypoxic hepatitis (courtesy A. Zimmerman, Institute of Pathology, University of Bern).
Fig. 2. Ischemic cholangitis (14) without evidence of amiodarone-associated hepatopathy or HH in a patient evaluated for cardiac transplantation. Ischemic cholangitis occurred after cardiopulmonary resuscitation because of paroxysmal ventricular tachycardia (courtesy E. Renner, Department of Clinical Pharmacology, and A. Zimmermann, Institute of Pathology, University of Bern).
pressure below 90 m m H g for more than 1 h), however, was not required for inclusion in the low cardiac output group. The aforementioned criteria of low cardiac output are clinical for lack of invasive hemodynamic data. Only central venous and arterial pressures were monitored by internal jugular vein and radial artery catheters. So far, others have defined low cardiac output by using invasively obtained data such as hypotension (mean arterial pressure <65 mmHg) with low cardiac index (< 1.8 1. min- ~• m -2) and with high left pulmonary capillary wedge pressures (>25 mmHg) despite inotropic support (8). Although it is a rare hepatic disorder, in Henrion's coronary care unit H H was found in 2.6% of the 766 patients admitted to the unit and in about 22% of patients with low cardiac output. It is concluded by the authors that H H is due to the combination of a fall in hepatic blood flow with passive venous congestion of the liver. The high incidence of H H reported in Henrion's study
(7) may be due to the concentration of high-risk patients with low cardiac output in their specialized coronary care unit. In Switzerland the majority of intensive care units are organized and managed by general internists or anesthesiologists. These general intensive care units treat patients with diseases from the whole spectrum of internal medicine. Due to the widespread distribution of cardiological cases in less specialized intensive care units, information on the incidence of complications of low cardiac output syndromes is difficult to obtain. H H is, however, the most frequent cause of a serum AST activity greater than 1000 IU I -t in the general hospital population and in the intensive care unit (4,9). Based on the literature, the incidence of HH in coronary care units and intensive care units ranges from 1.0 to 5.4% (the latter percentage was in relation to all admissions without liver disease) (2,9,15). In Henrion's study the authors were able to identify a total of 91 patients suffering from low cardiac output within 1 year. The surprisingly high incidence of H H (2.6%) in this prospective study may be considered a valuable contribution to determining the true prevalence of HH. The definition of H H is reserved for hepatic disorders in patients with low cardiac output who have increases in serum aminotransferase activity of at least 20 times the upper limit of normal following circulatory failure with no other cause for hepatic necrosis. In the present prospective study, clinical, biological, and hemodynamic data were compared between patients with low cardiac output and H H (low cardiac output/HH group =20 pts), and patients with low cardiac output but no H H (low cardiac output/no H H = 4 8 pts). The latter group was only considered for the study if the patients survived more than 24 h. Less than 24 h observation time (defined as the time between the onset of low cardiac output and death) was too short a period to allow full expression of hypoxic liver injury.
,4ssessment of hepatic blood flow In 41/48 patients in the low cardiac output/no H H and in 20/20 patients in the low cardiac output/HH group, high blood flow was measured for the 12 h following diagnosis of low cardiac output syndrome, using the well-established and easily performed method of galactose clearance at low concentrations as described by Henderson and coworkers in 1980 (10,11). At low concentrations, galactose is eliminated almost exclusively by the liver during the first passage. Body clearance approximates hepatic clearance very closely and corresponds to hepatic blood flow. The systemic galactose clearance may overestimate liver blood flow, probably because of a small, but significant extrahepatic galactose elimination. So far, renal
HYPOXIC HEPATITIS AND CARDIAC FAILURE
clearance and red cell metabolism have been shown to contribute approx. 5-8% to clearance (11,12).
Validation of the method h7 vivo Hepatic blood flow was estimated in 13 control patients. It is doubtful whether patients with gastrointestinal hemorrhage (8 cases) and attempted suicide (3 cases) are good controls, however, since their hemodynamic status had stabilized. N o information is given on the severity of the hemorrhage and the mode of attempted suicide (drugs?). These factors may influence extrahepatic galactose elimination. The method was also evaluated in seven additional control patients and in five patients with HH. The five patients with HH were used as controls to assess the value of portal systemic collaterals and/or impaired hepatocellular activity. The goal of the investigators with these particular patients was to assess and validate the hepatic galactose extraction fraction by measuring the galactose concentration in the right and left hepatic veins. Thus, the study appears to be based on valuable control data. Validation of galactose clearance remains, however, quite tricky, irrespective of the fact that others have used well-established control methods like indocyanine green concentration measurements (according to Fick's principle) (13) or volumetric assessments (as in liver transplant patients) (12). The paper by Henrion and coworkers shows that patients with HH exhibit an increased central venous pressure (passive hepatic venous congestion) and a reduced hepatic blood flow. Yet, the pathophysiological mechanisms of HH remain insufficiently understood and need further investigations.
695
References
1. Gibson P, Dudley E Ischemic, hepatitis: clinical features, diagnosis and prognosis. Aust N Z J Med 1984; 14: 822-5. 2. Henrion J, Luwaert R, Colin L, Schmitz A, Schapira A, Heller FR. H6patite hypoxique: 6tude prospective, clinique et h~modynamique de 45 ~pisodes. Gastro~nterol Clin Biol 1990; 14: 836-41. 3. Ratcliff NB, Hackel DB, Mikat E The effect of hyperbaric oxygen on the myocardial lesions of hemorrhagic shock in dogs. Am J Pathol 1967; 51: 341-9. 4. Hickman PE, Potter JM. Mortality associated with ischemic hepatitis. Aust N Z J Med 1990; 20: 32~.. 5. Potter JM, Hickman PE. Cardiodepressant drugs and the high mortality rate associated with ischemic hepatitis. Crit Care Med 1992; 20: 474-8. 6. Wolke AM, Brooks KM, Schauffauer E The liver in congestive heart failure. Primary Cardiol 1982; 8: 130. 7. Henrion J, Descamps O, Luwaert R. Schapira M, Parfonry A, Heller E Hypoxic hepatitis in patients with cardiac failure: incidence in a coronary care unit and measurement of hepatic blood flow. J Hepatol [994; 21: 696-703. 8. Kantrowitz A, Cardona RR, Au J, Freed PS. Intraaortic balloon pumping in congestiveheart failure. In: Hosenpud JD, Greenberg BH eds. Congestive Heart Failure. New York: Springer, 1994; 534. 9. Graudins A. Hawker E Ischemic Hepatitis. Proceedings of the 9th NSW ANZICS Meeting, Sydney, Australia, 1992. 10. Henderson JM, Vales FW. Continuous flow fluorometry of low galactose concentration in blood or plasma. Clin Chem 1980;26: 282-5. 11. Henderson JM, Kumer MH, Bain RE First-order clearance of plasma galactose: the effect of liver disease. Gastroenterology 1982; 83: 1090-6. 12. Henderson JM, Mackay GJ, Kutner MH, Noe B. Volumetricand functional liver blood flow are both increased in the human transplanted liver. J Hepatol 1993; 17: 204-7. 13. Keiding S. Galactose clearance measurements and liver blood flow. Gastroenterology 1988; 94: 477-81. 14. Demetris AJ. Ischemic cholangitis (Editorial). Mayo Clin Proc June 1992; 67: 601-2. 15. Hawker E Critical care management. The Liver. Philadelphia: W. B. Saunders, 1993: 310-23.
Copyright © Journalof Hepatology 1994 Journal of Hepatology
ISSN 0168-8278
Leader
Hypoxic hepatitis in patients with cardiac failure Paul Mohacsi and B e r n h a r d Meier Department o f Cardiology, University Hospital Bern, Sn,itzerland
Hypoxic hepatitis (HH) commonly called "ischemic hepatitis" or "shock liver" refers to a sharp but transient increase in serum activity of one or both of the aminotransferases (AST and/or ALT) of at least 20 times the upper limit of normal following circulatory failure. The definition of the syndrome in patients with previously healthy livers was reviewed by Gibson & Dudley in 1984 (I). HH is characterized by a rapid fall in transaminases if the causing condition is treated successfully. HH has been described in cardiogenic shock, after hemorrhage, and with sepsis, postoperative hypotension and pulmonary embolism, although the cause of "shock" appears to be irrelevant for the development of the syndrome. The patlaophysiological mechanisms of HH are still not well known. Most published papers describe patients with cardiac diseases and consider the relative contributions of HH (hepatic ischemia, hypoxia and congestion) to be relevant. Hepatic injury of HH may thus occur as a result of a reduction in liver blood flow followed by ischemia. Another study, however, showed that there was a higher incidence of passive venous congestion and hypoxemia in patients who developed HH, compared with patients with cardiogenic shock who did not develop HH (2). The role of hypoxemia is controversial since it has been reported that hyperbaric oxygen does not prevent hepatic necrosis in experimental models of shock (3). Further contributing factors may be the simultaneous administration of different drugs (e.g., vasoconstrictor inotropes which may impair hepatic blood flow by splanchnic vasoconstriction, or cardiodepressing drugs like calcium channel blockers or anti-arrhythmic agents) (4,5), It might be useful to summarize briefly the wide spectrum of hepatic complications due to heart failure syndromes. Chronic heart failure, which may exacerbate to
acute heart failure (2), can cause "cardiac cirrhosis" with the typical "nutmeg" appearance, but the more common finding and the first step which normally occurs in cardiac cirrhosis is simple congestive hepatomegaly (6). This disorder is usually recognized by elevated serum transaminases, high bilirubin levels, up to 20 mg/dl, due to an increase in both direct and indirect fractions, and jaundice. The serum transaminases may be increased I0- to 15-fold and serum alkaline phosphatase is increased. When the prothrombin time is substantially prolonged, congestive hepatopathy is usually severe and the prognosis poor. The development of end-stage cardiac cirrhosis will produce all of the findings associated with chronic liver failure, including hypoalbuminemia, hypoglycemia, ascites, and hepatic coma. Hepatic disorders due to acute cardiac failure can be caused by sudden cardiac low output syndromes or may arise also as a consequence of aggravation of chronic heart failure. In one study (2), the onset of HH was usually preceded by an acute cardiac complicaton, e.g., arrhythmia, provoking a sudden decrease in cardiac output. Fig. 1 and 2 depict the histological correlates of two typical hypoxic states in the liver. In the article by Henrion and coworkers, published in this issue of the journal (7), the authors present for the first time a prospective study on the incidence of HH in a European coronary care unit and measure the effective hepatic blood flow in patients with low cardiac output and HH, using the method of galactose clearance at low concentration. In this setting, low cardiac output was defined clinically by: I) Existence of cardiac disease (chronic or acute); 2) Cutaneous signs of circulatory failure; and 3) Intravenous inotropic treatment with dobutamine. Shock (defined in Henrion's paper as a fall of systolic blood
Correspondence to: Paul Mohacsi MD, Cardiology, University Hospital Bern, CH-3010 Bern, Switzerland.
694
..',
P. M O H A C S I and B. M E I E R
" ~
": -'? J'~.,_~.'" i~P-' "+ ~~'' ~'i'~ ~-?
+,' j f
,
"
+ +.~+ ''~'+~" ~ "
,.
..~te] "~
,~ ~'+
-
'
Fig. l. Typical centrilobular necrosis in a case of hypoxic hepatitis (courtesy A. Zimmerman, Institute of Pathology, University of Bern).
Fig. 2. Ischemic cholangitis (14) without evidence of amiodarone-associated hepatopathy or HH in a patient evaluated for cardiac transplantation. Ischemic cholangitis occurred after cardiopulmonary resuscitation because of paroxysmal ventricular tachycardia (courtesy E. Renner, Department of Clinical Pharmacology, and A. Zimmermann, Institute of Pathology, University of Bern).
pressure below 90 m m H g for more than 1 h), however, was not required for inclusion in the low cardiac output group. The aforementioned criteria of low cardiac output are clinical for lack of invasive hemodynamic data. Only central venous and arterial pressures were monitored by internal jugular vein and radial artery catheters. So far, others have defined low cardiac output by using invasively obtained data such as hypotension (mean arterial pressure <65 mmHg) with low cardiac index (< 1.8 1. min- ~• m -2) and with high left pulmonary capillary wedge pressures (>25 mmHg) despite inotropic support (8). Although it is a rare hepatic disorder, in Henrion's coronary care unit H H was found in 2.6% of the 766 patients admitted to the unit and in about 22% of patients with low cardiac output. It is concluded by the authors that H H is due to the combination of a fall in hepatic blood flow with passive venous congestion of the liver. The high incidence of H H reported in Henrion's study
(7) may be due to the concentration of high-risk patients with low cardiac output in their specialized coronary care unit. In Switzerland the majority of intensive care units are organized and managed by general internists or anesthesiologists. These general intensive care units treat patients with diseases from the whole spectrum of internal medicine. Due to the widespread distribution of cardiological cases in less specialized intensive care units, information on the incidence of complications of low cardiac output syndromes is difficult to obtain. H H is, however, the most frequent cause of a serum AST activity greater than 1000 IU I -t in the general hospital population and in the intensive care unit (4,9). Based on the literature, the incidence of HH in coronary care units and intensive care units ranges from 1.0 to 5.4% (the latter percentage was in relation to all admissions without liver disease) (2,9,15). In Henrion's study the authors were able to identify a total of 91 patients suffering from low cardiac output within 1 year. The surprisingly high incidence of H H (2.6%) in this prospective study may be considered a valuable contribution to determining the true prevalence of HH. The definition of H H is reserved for hepatic disorders in patients with low cardiac output who have increases in serum aminotransferase activity of at least 20 times the upper limit of normal following circulatory failure with no other cause for hepatic necrosis. In the present prospective study, clinical, biological, and hemodynamic data were compared between patients with low cardiac output and H H (low cardiac output/HH group =20 pts), and patients with low cardiac output but no H H (low cardiac output/no H H = 4 8 pts). The latter group was only considered for the study if the patients survived more than 24 h. Less than 24 h observation time (defined as the time between the onset of low cardiac output and death) was too short a period to allow full expression of hypoxic liver injury.
,4ssessment of hepatic blood flow In 41/48 patients in the low cardiac output/no H H and in 20/20 patients in the low cardiac output/HH group, high blood flow was measured for the 12 h following diagnosis of low cardiac output syndrome, using the well-established and easily performed method of galactose clearance at low concentrations as described by Henderson and coworkers in 1980 (10,11). At low concentrations, galactose is eliminated almost exclusively by the liver during the first passage. Body clearance approximates hepatic clearance very closely and corresponds to hepatic blood flow. The systemic galactose clearance may overestimate liver blood flow, probably because of a small, but significant extrahepatic galactose elimination. So far, renal
HYPOXIC HEPATITIS AND CARDIAC FAILURE
clearance and red cell metabolism have been shown to contribute approx. 5-8% to clearance (11,12).
Validation of the method h7 vivo Hepatic blood flow was estimated in 13 control patients. It is doubtful whether patients with gastrointestinal hemorrhage (8 cases) and attempted suicide (3 cases) are good controls, however, since their hemodynamic status had stabilized. N o information is given on the severity of the hemorrhage and the mode of attempted suicide (drugs?). These factors may influence extrahepatic galactose elimination. The method was also evaluated in seven additional control patients and in five patients with HH. The five patients with HH were used as controls to assess the value of portal systemic collaterals and/or impaired hepatocellular activity. The goal of the investigators with these particular patients was to assess and validate the hepatic galactose extraction fraction by measuring the galactose concentration in the right and left hepatic veins. Thus, the study appears to be based on valuable control data. Validation of galactose clearance remains, however, quite tricky, irrespective of the fact that others have used well-established control methods like indocyanine green concentration measurements (according to Fick's principle) (13) or volumetric assessments (as in liver transplant patients) (12). The paper by Henrion and coworkers shows that patients with HH exhibit an increased central venous pressure (passive hepatic venous congestion) and a reduced hepatic blood flow. Yet, the pathophysiological mechanisms of HH remain insufficiently understood and need further investigations.
695
References
1. Gibson P, Dudley E Ischemic, hepatitis: clinical features, diagnosis and prognosis. Aust N Z J Med 1984; 14: 822-5. 2. Henrion J, Luwaert R, Colin L, Schmitz A, Schapira A, Heller FR. H6patite hypoxique: 6tude prospective, clinique et h~modynamique de 45 ~pisodes. Gastro~nterol Clin Biol 1990; 14: 836-41. 3. Ratcliff NB, Hackel DB, Mikat E The effect of hyperbaric oxygen on the myocardial lesions of hemorrhagic shock in dogs. Am J Pathol 1967; 51: 341-9. 4. Hickman PE, Potter JM. Mortality associated with ischemic hepatitis. Aust N Z J Med 1990; 20: 32~.. 5. Potter JM, Hickman PE. Cardiodepressant drugs and the high mortality rate associated with ischemic hepatitis. Crit Care Med 1992; 20: 474-8. 6. Wolke AM, Brooks KM, Schauffauer E The liver in congestive heart failure. Primary Cardiol 1982; 8: 130. 7. Henrion J, Descamps O, Luwaert R. Schapira M, Parfonry A, Heller E Hypoxic hepatitis in patients with cardiac failure: incidence in a coronary care unit and measurement of hepatic blood flow. J Hepatol [994; 21: 696-703. 8. Kantrowitz A, Cardona RR, Au J, Freed PS. Intraaortic balloon pumping in congestiveheart failure. In: Hosenpud JD, Greenberg BH eds. Congestive Heart Failure. New York: Springer, 1994; 534. 9. Graudins A. Hawker E Ischemic Hepatitis. Proceedings of the 9th NSW ANZICS Meeting, Sydney, Australia, 1992. 10. Henderson JM, Vales FW. Continuous flow fluorometry of low galactose concentration in blood or plasma. Clin Chem 1980;26: 282-5. 11. Henderson JM, Kumer MH, Bain RE First-order clearance of plasma galactose: the effect of liver disease. Gastroenterology 1982; 83: 1090-6. 12. Henderson JM, Mackay GJ, Kutner MH, Noe B. Volumetricand functional liver blood flow are both increased in the human transplanted liver. J Hepatol 1993; 17: 204-7. 13. Keiding S. Galactose clearance measurements and liver blood flow. Gastroenterology 1988; 94: 477-81. 14. Demetris AJ. Ischemic cholangitis (Editorial). Mayo Clin Proc June 1992; 67: 601-2. 15. Hawker E Critical care management. The Liver. Philadelphia: W. B. Saunders, 1993: 310-23.