ANNUAL REVIEWS
Further
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Copyright 1975. All rights reserved
Annu. Rev. Med. 1975.26:143-157. Downloaded from www.annualreviews.org Access provided by University of Waterloo on 02/03/15. For personal use only.
PATHOGENESIS OF HEPATIC
+7138
COMA Leslie Zieve, MD. and Demetre M Nicoloff, MD., Ph.D. Departments of Medicine and Surgery, Minneapolis Veterans Hospital, University of
Minnesota, Minneapolis, Minnesota 55417
Hepatic coma is a complex pathophysiologic state that is multifactorial in origin. Incomplete and uncontrolled but significant observations in patients have offered clues for experimental study. Unfortunately the body of solid experimental data is small, and the amount of uninhibited speculation excessive. To compound this problem there has been confusion between correlation and causation. Hepatic en cephalopathy has many associated alterations, some of which are noncausal corre lated changes and some consequences of the encephalopathy. Seen after the fact, these two types of alterations cannot be differentiated from causal factors. This has often been forgotten in this field where everyone is primarily interested in etiology, and claims have been made that do not withstand careful inspection. Several previous reviews offer broad perspectives on the whole subject (1-3). In 1966 we (4) reviewed the subject of pathogenesis in detail, and we will assume acquaintance with that material for purposes of the present review. In addition to the known metabolic abnormalities, which will again be summarized and brought up to date, that article provided a brief discussion of the clinical picture, the role of precipitating factors, and the contribution of electrolyte and acid-base abnormali ties. Since then Zimmon (5, 6) has shown that the well-known shift to the right in the in vivo oxyhemoglobin dissociation curve, when more than minimal, is asso ciated with the presence of hepatic encephalopathy and is due to an unidentified small molecular weight acidic plasma factor. When the hepatic encephalopathy disappears, the shift to the right is reversed. Such reversal has been observed following suppression of gut bacteria.
KNOWN METABOLIC ABNORMALITIES Brain Oxygen Consumption and Glucose Utilization Are Decreased
In acute hepatic coma of less than 24 hr duration brain oxygen consumption and glucose utilization are essentially normal (7). Therefore the onset of acute hepatic 143
Annu. Rev. Med. 1975.26:143-157. Downloaded from www.annualreviews.org Access provided by University of Waterloo on 02/03/15. For personal use only.
144
ZIEVE & NICOLOFF
coma cannot be attributed to depression of brain energy metabolism. Beyond 24 hr of coma, oxygen consumption and glucose utilization decrease, the average reduc tion of each in samples of such patients being approximately 50% (7, 8). The correlation between the cerebral metabolic rate and the degree of neuropsychiatric involvement is poor (7). In some patients the mental state and the oxygen consump tion may be influenced favorably by induction of metabolic alkalosis with sodium bicarbonate (9). The reason for this arou5al effect is unknown. Decreased utilization of oxygen characterizes all nonconvulsive (or preconvul sive) coma states (10). This is not due to lack of oxygen, but a reduced demand for oxygen. The adenylate energy charge, ([ATP] + 1h[ADP])/ ([ATP] + [ADP] + [AMP]), was found to be normal in acute experimental hepatic coma and in other coma states due to fatty acids, mercaptans, barbiturates, or ether (11). It was also normal in rats made hyperammonemic with portacaval shunts (12). Thus these coma states do not disrupt the balance between production and utilization of energy in the brain. Oxidation is coupled normally to phosphorylation in acute experimen tal hepatic coma and other coma states (U). Therefore the reduced demand for oxygen must reflect decreased utilization cf ATP. Ammonia Is Increased in the Blood, c.nd Ammonia and Glutamine Are Increased in Muscle. Brain. and Spinal Fluid
From clinical inconsistencies and from extensive experimental observations it seems clear that hepatic coma cannot be due simply to an excess of ammonia (13). We concluded previously that disturbed ammonia metabolism is in some way basic to the syndrome of hepatic coma, but that it is not the only etiologic abnormality (4). The primary disposition of ammonia in the brain is by the formation of glutamine. In rats with portacaval shunts a high correlation (0.92) was observed between blood ammonia and the brain content of glutamine (14). In man, Moore and associates (15) observed a high correlation (r = 080) between arterial and spinal fluid am monia, but patients in hepatic coma cou\----O N= 13
Sedation ('Z4hrs.) N=4
N�r=��l -+-
SUBSTRATES
0-----0
:t 5EM
160
'c + c: � -.
Further
Quick links to online content
Copyright 1975. All rights reserved
Annu. Rev. Med. 1975.26:143-157. Downloaded from www.annualreviews.org Access provided by University of Waterloo on 02/03/15. For personal use only.
PATHOGENESIS OF HEPATIC
+7138
COMA Leslie Zieve, MD. and Demetre M Nicoloff, MD., Ph.D. Departments of Medicine and Surgery, Minneapolis Veterans Hospital, University of
Minnesota, Minneapolis, Minnesota 55417
Hepatic coma is a complex pathophysiologic state that is multifactorial in origin. Incomplete and uncontrolled but significant observations in patients have offered clues for experimental study. Unfortunately the body of solid experimental data is small, and the amount of uninhibited speculation excessive. To compound this problem there has been confusion between correlation and causation. Hepatic en cephalopathy has many associated alterations, some of which are noncausal corre lated changes and some consequences of the encephalopathy. Seen after the fact, these two types of alterations cannot be differentiated from causal factors. This has often been forgotten in this field where everyone is primarily interested in etiology, and claims have been made that do not withstand careful inspection. Several previous reviews offer broad perspectives on the whole subject (1-3). In 1966 we (4) reviewed the subject of pathogenesis in detail, and we will assume acquaintance with that material for purposes of the present review. In addition to the known metabolic abnormalities, which will again be summarized and brought up to date, that article provided a brief discussion of the clinical picture, the role of precipitating factors, and the contribution of electrolyte and acid-base abnormali ties. Since then Zimmon (5, 6) has shown that the well-known shift to the right in the in vivo oxyhemoglobin dissociation curve, when more than minimal, is asso ciated with the presence of hepatic encephalopathy and is due to an unidentified small molecular weight acidic plasma factor. When the hepatic encephalopathy disappears, the shift to the right is reversed. Such reversal has been observed following suppression of gut bacteria.
KNOWN METABOLIC ABNORMALITIES Brain Oxygen Consumption and Glucose Utilization Are Decreased
In acute hepatic coma of less than 24 hr duration brain oxygen consumption and glucose utilization are essentially normal (7). Therefore the onset of acute hepatic 143
Annu. Rev. Med. 1975.26:143-157. Downloaded from www.annualreviews.org Access provided by University of Waterloo on 02/03/15. For personal use only.
144
ZIEVE & NICOLOFF
coma cannot be attributed to depression of brain energy metabolism. Beyond 24 hr of coma, oxygen consumption and glucose utilization decrease, the average reduc tion of each in samples of such patients being approximately 50% (7, 8). The correlation between the cerebral metabolic rate and the degree of neuropsychiatric involvement is poor (7). In some patients the mental state and the oxygen consump tion may be influenced favorably by induction of metabolic alkalosis with sodium bicarbonate (9). The reason for this arou5al effect is unknown. Decreased utilization of oxygen characterizes all nonconvulsive (or preconvul sive) coma states (10). This is not due to lack of oxygen, but a reduced demand for oxygen. The adenylate energy charge, ([ATP] + 1h[ADP])/ ([ATP] + [ADP] + [AMP]), was found to be normal in acute experimental hepatic coma and in other coma states due to fatty acids, mercaptans, barbiturates, or ether (11). It was also normal in rats made hyperammonemic with portacaval shunts (12). Thus these coma states do not disrupt the balance between production and utilization of energy in the brain. Oxidation is coupled normally to phosphorylation in acute experimen tal hepatic coma and other coma states (U). Therefore the reduced demand for oxygen must reflect decreased utilization cf ATP. Ammonia Is Increased in the Blood, c.nd Ammonia and Glutamine Are Increased in Muscle. Brain. and Spinal Fluid
From clinical inconsistencies and from extensive experimental observations it seems clear that hepatic coma cannot be due simply to an excess of ammonia (13). We concluded previously that disturbed ammonia metabolism is in some way basic to the syndrome of hepatic coma, but that it is not the only etiologic abnormality (4). The primary disposition of ammonia in the brain is by the formation of glutamine. In rats with portacaval shunts a high correlation (0.92) was observed between blood ammonia and the brain content of glutamine (14). In man, Moore and associates (15) observed a high correlation (r = 080) between arterial and spinal fluid am monia, but patients in hepatic coma cou\----O N= 13
Sedation ('Z4hrs.) N=4
N�r=��l -+-
SUBSTRATES
0-----0
:t 5EM
160
'c + c: � -.
