Liver Disease in the Differential Diagnosis of Coma

Liver Disease in the Differential Diagnosis of Coma WILLIAM V. McDERMOTT, JR., M.D., F.A.C.S.*

Liver disease has long been known to be associated with disturbances in central nervous system function, and over the past century various names such as hepatic coma, cholemia, and other ill-defined terms have been applied to this syndrome. Gradually, investigative work at the clinical and laboratory levels has led to the delineation in this overall syndrome of three major pathophysiological disorders: (1) acute yellow atrophy in which massive necrosis of liver cells occurs from either an infectious or a toxic agent and may frequently lead to deep unresponsive coma and death; (2) terminal stages of chronic liver disease in which progressive loss of hepatic reserve is attended by a very complex metabolic disorder associated with deterioration of most of the complex biochemical functions of the liver and clinically is manifested by deepening lethargy, coma, and ultimately complete liver failure and death; (3) portal-systemic shunting with intermittent encephalopathy. In the first two categories the metabolic changes associated with the progressive deterioration of hepatocellular function are so complex that no single biochemical disorder can be implicated alone as a cause of the obvious failure of brain function. In the clinical cases representing either of these two general groups there is usually no problem in differential diagnosis since the clinical and laboratory evidence of severe liver failure is sufficient to prevent any confusion with other causes of unconsciousness likely to be seen by the surgeon. On the other hand, the neuropsychiatric disorder associated with portal-systemic shunting may occur without any overt signs of disease of the liver or portal circulation and has, in fact, presented on innumerable occasions as a complex problem in differential diagnosis. It is, therefore, on this third category that this report will focus.

From the Department of Surgery, Harvard Medical School, and the Fifth (Harvard) Surgical Service and Sears Surgical Laboratory, Boston City Hospital, Boston, Massachusetts *Professor of Surgery, Harvard Medical School; Director, Fifth (Harvard) Surgical Service and Sears Surgical Laboratory, Boston City Hospital

Surgical Clinics of North America- Vol. 48, No. 2, April, 1968

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ENCEPHALOPATHY WITH HYPERAMMONIEMIA

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Figure 1.

Diagram of the factors involved in portal-systemic encephalopathy.

Perhaps the first recognition of this particular syndrome may be found in the report of Hahn and his colleagues,3 working in Pavlov's laboratory, when they described in 1893 some of the symptoms of what was referred to as meat intoxication in the Eck fistula dog. Over the subsequent decades innumerable investigators approached this problem with a view to establishing the specific biochemical disorder accounting for this phenomenon, and at the clinical level increasing recognition was given to the fact that the portal-systemic shunting which spontaneously develops in the presence of a portal bed block is an important factor in some of the cerebral manifestations seen in liver disease. An extensive review of the pertinent literature will not be given, but reference is made to a progress report 4 which contains references to most of the significant contributions. During the past decade an enor-

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mous amount of published material has appeared relative to this general area, stimulated by the reports of Phillips et al. 7 and Schwartz et al., 8 in which dietary protein was implicated in the genesis of hepatic coma, and by the report of McDermott and Adams 5 in which a syndrome of episodic stupor was described in a patient in whom a portal-systemic shunt had been constructed following resection of the portal vein in the presence of an invasive cancer of the pancreas. Although the specific biochemical defect or defects associated with this syndrome have not been completely clarified, it is clear at the present time that, in the presence of portal-systemic shunting, an increased nitrogenous load in the gastrointestinal tract results in the liberation of large amounts of ammonia by the enzymatic action of colonic micro-organisms, and a significant hyperammoniemia is manifested in the peripheral blood and accompanied by varying pattems of cerebral dysfunction (Fig. 1). While other substances released into the systemic circulation through the portal-systemic shunts may be factors in the disorder of cerebral metabolism, at the moment ammonia is the only substance which has been consistently implicated. The clinical manifestations of portal-systemic encephalopathy are so bizarre and varied that a familiarity with the protean manifestations of this syndrome is important to the clinician evaluating any case of stupor or coma of unknown etiology. A number of excellent descriptions of the neurological manifestations have been ·given and reference is made to these reports for descriptive detaiF· 2 • 9 · 10 Perhaps the simplest and yet the clearest is found in the report by Adams and Foley, 1 who described this syndrome as "a disorder of consciousness, i.e., a lack of awareness of stimuli and failure to respond accompanied by generalized disorder of movement. The derangement of consciousness presents first as mental confusion, with either increased or decreased psychomotor activity followed by stupor and coma."

DIAGNOSIS Clinical Findings Since overt signs of disease of the liver or portal circulation may be absent, it is well to consider the possibility of this syndrome as a cause of unexplained stupor or coma, particularly in any individual who has any degree of occult or obvious gastrointestinal bleeding. The possible existence of a portal-systemic shunt should be considered if a scar indicating right or left upper quadrant surgery is apparent in the comatose patient. It is important to re-emphasize, however, that spontaneous shunts can provide just as adequate a mechanism for portalsystemic encephalopathy as the surgically constructed channel. Obvious physical findings of hepatic disease need not be present, although splenomegaly is the most consistent abnormal physical finding in this syndrome. Careful search should be made for other stigmata of liver disease such as spider angiomata or liver palms, and particular attention should be given to the presence or absence of fetor hepaticus, the

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peculiar mousy odor on the breath which is almost invariably associated with this particular pathophysiological disorder. It is important to re-emphasize the difficulty in diagnosis, since cases have been seen in which occult gastrointestinal bleeding manifested only by a positive stool guaiac test has been the cause of deep coma, with not a single physical sign present to indicate hepatocellular disease.

Laboratory and Other Studies as an Aid in Differential Diagnosis LIVER TEsTs. The standard liver function tests will invariably show some degree of abnormality; perhaps the most important of these are the bilirubin levels, the prothrombin time, and the protein fractionation. Since a considerable segment of the population at large may show minor degree of hepatocellular damage by laboratory tests, attention will be directed in this report to studies which may be obtained rapidly and which taken together will provide the most consistent pertinent information in the evaluation of the presence or absence of portalsystemic encephalopathy. Whenever portal-systemic encephalopathy is suspected, bromsulphalein retention tests should be initiated and blood drawn for immediate measurement of ammonia nitrogen. Results of both of these tests should be available within an hour and in our studies they have proved to complement each other remarkably well. The bromsulphalein retention test is perhaps the most sensitive index of liver dysfunction, but its very sensitivity may be a source of confusion. In cases of decreased liver blood flow from any source such as upper gastrointestinal bleeding, there may be temporary derangements of a considerable degree in this test (Fig. 2). Nonetheless, if the test is normal, one can almost incontrovertibly rule out the presence of any disease of the liver or portal circulation. If one then looks at the applicability of the blood ammonia level (Fig. 2), one sees that in patients with a nitrogenous load such as blood in whom portal-systemic shunting exists, the blood ammonia level is invariably somewhat abnormal; and certainly, in patients with coma as a result of portal-systemic encephalopathy, it would be extremely unusual to find this test within the normal range. For more specific examples it may be helpful to refer specifically to certain cases numbered in Figure 2. Case 1 was the only apparent discrepancy in the diagnostic accuracy of blood ammonia under these circumstances, and in this instance the patient had been treated just prior to entry with a broad-spectrum antibiotic, thus neutralizing the enzymatic action of colon flora which are the source of the ammonia which is absorbed into the portal circulation. In Case 2 the patient was bleeding from a duodenal ulcer rather than varices, but this occurred after the construction of a portacaval shunt several years earlier and therefore the entire mechanism for this syndrome was present. Cases 4 and 5 represent patients who had known cirrhosis of the liver but had not developed portal hypertension; the blood ammonia levels were, therefore, within normal limits since there was no serious defect in urea synthesis and no portal-systemic shunting. Case 3 may be of particular interest because this patient had neither shunting nor liver

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disease in any form; the ammonia level was normal as might be expected, but apparently the severity of the hypovolemia was sufficient to cause a very significant increase in bromsulphalein retention. If the latter test had been used alone, one might have suspected liver disease with esophageal varices and shunting, but the normal ammonia level was a lead to a correct diagnosis. Perhaps undue emphasis has been given to these particular determinations, but the rapidity with which they can be obtained and the value of the two as related to each other is such that their importance cannot be overemphasized in the differential diagnosis of puzzling coma. ELECTROENCEPHALOGRAPHY. The electroencephalogram will invariably show some abnormality, usually characteristic, if portalsystemic encephalopathy is the cause of the coma. Detailed descriptions of the changes are available 6 but one could summarize these by stating that stupor or coma is associated with a diffuse slowing of the dominant rhythms from the alpha to the theta and delta ranges. Fast beta activity is occasionally seen and intermittent generalized slow rhythms with runs of normal activity may be encountered. If this diagnostic tool is available and can be easily obtained, it is of great importance since the changes described are so characteristic of portalsystemic encephalopathy. RoENTGEN STUDIES. A number of roentgenological techniques are available for the definition of portal-systemic shunting which, in certain particular instances, may be important in the differential diagnosis. The simplest of these is a barium swallow for the delineation of esophageal varices, but obviously this may not be practical in the type of patient BLEEDING ESOPHAGEAL VARICES

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encountered. Splenoportography will delineate portal-systemic shunts if a portal bed block exists to any degree, and selective celiac angiography may be of even more value since it defines very well the nature of the intrahepatic pathology and also in the venous phase will u'sually give evidence as to whether or not portal-systemic shunting exists. GUAIAC TEST ON THE STOOL. The importance of rectal examination and a guaiac test on the stool is certainly the simplest of all the laboratory determinations and may, in many instances, be the key to the correct diagnosis. In several instances of coma which came to our attention, the slow gastrointestinal bleeding which was the precipitating cause was manifested neither by hematemesis nor by melena, but the presence of a strongly positive guaiac test on the stool raised the index of suspicion and led to the correct diagnosis in these puzzling cases. In order to emphasize the possible obscurity of the diagnosis, I might state that one of these patients referred to was being prepared for a craniotomy, but fortunately the demonstration of occult blood diverted diagnostic efforts in the proper direction and led to the correct diagnosis of portal-systemic encephalopathy.

TREATMENT This report is to emphasize the role of liver disease in the differential diagnosis of coma. Only brief reference will be made to the appropriate therapy of this syndrome. It is imperative to remove nitrogenous material which is usually the precipitating cause of the metabolic disorder and, therefore, all oral protein is immediately restricted, attention is directed toward control of gastrointestinal bleeding if this exists, and a vigorous program of catharsis and enema is instituted in order to empty the colon of residual material which may be a source of ammonia. In addition, administration of large amounts of oral neomycin will alter the bacterial flora of the colon sufficiently to prevent further enzymatic activity on any residual nitrogenous material which has not been evacuated by the measures described above. Other methods which have been employed electively for the control of chronic recurrent portalsystemic encephalopathy are beyond the scope of this report.

SUMMARY Portal-systemic encephalopathy is a relatively frequent cause of stupor and coma. If overt signs of disease of the liver and portal circulation exist on physical examination, the diagnosis is usually not difficult. In a significant proportion of cases, however, physical signs are minimal or absent, an adequate history is not available, and the possibility of hepatic coma may not immediately occur to the examining physician. If one considers the syndrome in the differential diagnosis, however, its presence or absence may be rapidly established or excluded by a few simple diagnostic measures. Since the therapeutic measures briefly outlined above are usually so effective, the importance of quick recognition of this syndrome is particularly important.

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.REFERENCES 1. Adams, R. D., and Foley, J. M.: The neurological disorder associated with severe liver

disease. Proc. Res. Nerv. Dis., 32:198, 1953. 2. Davidson, E. A., and Summerskill, W. H. J.: Psychiatric aspects of liver disease. Postgrad. Med. J., 32:487-494, 1956. 3. Hahn, M., Massen, 0., Nencki, M., and Pawlow, J.: Die eck'sche Fistel zwischen der unteren Holivene und der Pfortader und ihre Folgen fiir den Organismus. Arch. f. exper. Path. u. Pharmakol., 32:161-210, 1893. 4. McDermott, W. V., Jr.: Metabolism and toxicity of ammonia. New Eng. J. Med., 257: 1076-1081, 1957. 5. McDermott, W. V., Jr., and Adams, R. D.: Episodic stupor associated with an Eck fistula in the human with particular reference to the metabolism of ammonia. J. Clin. Invest. 33:1-9, 1954. 6. Parsons-Smith, B. G., Summerskill, W. H. J., Dawson, A.M., and Sherlock, S.: The electroencephalograph in liver disease. Lancet, 1 :867-871, 1957. 7. Phillips, G. B., Schwartz, R., Gabuzda, G. J., Jr., and Davidson, C. S.: The syndrome of pending hepatic coma in patients with cirrhosis of the liver given certain nitrogenous substances. New Eng. J. Med.,247:239-246, 1952. 8. Schwartz, R., Phillips, G. B., Seegmiller, J. E., Gabuzda, G. J., Jr., and Davidson, C. S.: Dietary protein in the genesis of hepatic coma. New Eng. J. Med., 251:685-690, 1954. 9. Summerskill, W. H. J., Davidson, E. A., Sherlock, S., and Steiner, R. E.: The neuropsychiatric syndrome associated with hepatic cirrhosis and an extensive portal collateral circulation. Quart. J. Med., 25:245-266, 1956. 10. Walshe, J. M.: Hepatic coma. Postgrad. Med. J., 32:467-472, 1956. 818 Harrison Avenue Boston, Massachusetts 02118