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Developing a World view toward acute liver failure
Developing a World View Toward Acute Liver Failure More often than not, Western physicians assume that what is true about a disease in the Western hemisphere must be universal; that is, if a certain disease is described in Europe, the United Kingdom, or North America, that description must apply to the rest of the world. We know a priori that this may not be true, and yet we make this assumption repeatedly in texts and review articles in regard to any number of topics. The article by Acharya et al.1 in the June 1996 issue of HEPATOLOGY describing acute liver failure (ALF) on the Indian subcontinent challenges that assumption and, in doing so, sheds new insight into the impact geography makes on disease characteristics. The authors review an extensive experience in 423 cases of ALF seen over a 6.5-year period in New Delhi. The resulting survey identifies some striking differences between East and West (or perhaps between tropical countries and northern ‘‘climes,’’ as the authors put it). In Northern India, hepatitis A, B, and D viruses made up 33% of cases of ALF, which was not surprising; however, 62% were considered to be non-A, non-B disease (viral markers negative, no other etiology apparent). A sample of the non-A, non-B group tested for hepatitis E virus (HEV) RNA revealed 40% with HEV RNA alone, 14% with hepatitis C virus (HCV) RNA alone, and 22% with both HEV and HCV RNA in their serum samples. In all, nearly 90% of all cases were thought to be caused by viral hepatitis, based on the numbers and assumptions mentioned above. Only 5% of the entire series were thought to be drug-induced, and all these were ingesting isoniazid and rifampicin at the time of onset of illness. Thus, no acetaminophen cases were seen, nor were there the large number of drug-induced cases commonly seen in Western series, such as non-steroidal anti-inflammatory drugs, antibiotics, and anticonvulsants. Can these striking differences in etiology of ALF be ascribed to differences in culture or drug availability, or are these cases, for some reason, not referred to an urban center such as the All India Institute where the study was conducted? The authors do not address this question. A second difference apparent between East and West is the very short interval between the onset of symptoms and the onset of encephalopathy observed in the present study. Although a criterion for inclusion of an interval of less than 8 weeks between onset of symptoms and onset of encephalopathy was used, all patients demonstrated intervals shorter than 3 weeks, and thus no intermediate cases between acute and subacute hepatic failure were included. The authors make the point that no difference was observed between survivors and nonsurvivors in terms of the interval between onset of symptoms and encephalopathy or onset of icterus and encephalopathy. Thus, there was no more favorable outcome observed in those with hyperacute (less than 7 days) disease than in the slower-onset cases, as has been suggested by O’Grady et al.2 This finding may
Abbreviations: ALF, acute liver failure; HEV, hepatitis E virus; HCV, hepatitis C virus. Received June 3, 1996; accepted June 3, 1996. Address reprint requests to: William M. Lee, M.D., University of Texas SW Medical Center at Dallas–Mail Code 8887, Department of Internal Medicine, Liver Unit, 5323 Harry Hines Blvd., Dallas, TX 75235-8887. Copyright q 1996 by the American Association for the Study of Liver Diseases. 0270-9139/96/2401-0043$3.00/0
simply reflect the almost complete absence of etiologies other than viral, or a difference in the severity of illness observed in this series. Not only were there very few drugs implicated, but there were apparently no cases of Wilson’s disease, mushroom toxicity, fatty liver of pregnancy, cancer, or circulatory collapse. This seems surprising, but may simply reflect a more advanced stage of disease at presentation. The mean survival following admission was less than 2 days, and virtually all patients were dead within the first hospital week. Referral patterns may be different as well, thus limiting, for example, the transfer of pregnant patients to a tertiary care facility. However, overall survival did not differ significantly from what we would expect. A 34% survival is excellent and somewhat better than pretransplant American series,3 possibly reflecting the dominance of viral etiologies that may carry a better survival when compared with idiosyncratic drug reactions. A striking difference that emerged from the Indian experience is that, although 25% of the women admitted for acute liver failure were pregnant, their survival was not different from that observed for the nonpregnant women. This seems surprising because we have always understood that hepatitis E, and perhaps A as well, is more severe during pregnancy and that the fatality rate for hepatitis E during pregnancy approaches 70% based on previous reports principally from India. It is unfortunate that the authors did not do a more detailed analysis of the pregnant patient group, because it remains unclear based on their experience whether the established maxim that hepatitis in pregnancy is associated with decreased survival is still viable. The authors examined the overall mortality rates, which were essentially similar for all etiologies. If 25% of the women were pregnant, and there was no predilection to increased fatalities in the third trimester as the authors state, then viral hepatitis itself and not pregnancy per se is the culprit. However, the authors’ own data demonstrated a marked increase in the acquisition rate of hepatitis in the pregnant versus the nonpregnant woman. These data would logically lead to the conclusion that pregnancy is associated with an increased chance of death from hepatitis when compared with not being pregnant (with its reduced risk of acquiring viral hepatitis). Their point is valid, but their reasoning is somewhat tautologic. Finally, the authors apply their own unique set of criteria for predicting survival based on regression analysis. The index derived from their data set is different than those employed in the West4 and more likely reflects its bias toward Third-World countries, where the etiologies of ALF are overwhelmingly viral. Age, bilirubin, and prothrombin time are used, but in addition, a high value is placed on cerebral edema as a criterion for distinguishing survivors. More than 70% of patients succumbed to cerebral edema rather than to conditions such as sepsis or gastrointestinal bleeding. Nearly all patients died within 48 hours, including most of those who had cerebral edema on admission. This further emphasizes the severity of the liver failure observed in this study. Are there others who don’t make it to the hospital? One could argue that the criteria used for identifying cerebral edema were not con-
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WBS: Hepatology
HEPATOLOGY Vol. 24, No. 1, 1996
LEE AND SORRELL
firmed by objective, diagnostic methods; in particular, the use of pulse and blood pressure readings is suspect, because these values are dependent on so many other variables.5,6 However, these efforts seem worthwhile in an attempt to make sense out of bedside observations in a setting where access to modern technology is restricted. Once again, the criteria used here will help confirm the clinical diagnosis of cerebral edema where intracranial monitoring is not available. What can we glean from this interesting and puzzling study? First, an increased awareness that practice in other parts of the world truly is different and many of the rules of the West are just that — local rules. This is particularly true where acetaminophen is a prominent part of the picture as it is in the United Kingdom and the United States. Of interest, acetaminophen toxicity is much less commonly seen in France and certainly doesn’t appear to play any role in India. Can we conclude that prognostic indicators are also country-specific? Yes, but we knew previously that different etiologies carried different survival statistics. The present study simply exemplifies this fact to the nth degree.
AID
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5P10$$1021
06-21-96 16:59:34
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WILLIAM M. LEE, M.D. University of Texas Southwestern Medical School Dallas, TX MICHAEL F. SORRELL, M.D. University of Nebraska Medical Center Omaha, NE REFERENCES 1. Acharya SK, Dasarathy S, Kumer TL, Sushma S, Uma Prasarna KS, Tandon A, Speenivas V, et al. Fulminant hepatitis in a tropical population: clinical course, cause, and early predictors of outcome. HEPATOLOGY 1996; 23:1448-1455. 2. O’Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet 1993;342:273-275. 3. Rakela J, Lange SM, Ludwig J, Baldus WP. Fulminant hepatitis; Mayo Clinic experience with 34 cases. Mayo Clin Proc 1985;60:289-292. 4. O’Grady JG, Alexander GJM, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989;97:439-445. 5. Ede RJ, Williams R. Hepatic encephalopathy and cerebral oedema. Semin Liver Dis 1986;6:107-108. 6. Blei AT. Cerebral edema and intracranial hypertension in acute liver failure: distinct aspects of the same problem. HEPATOLOGY 1991;13:376-378.
hptas
WBS: Hepatology
Abbreviations: ALF, acute liver failure; HEV, hepatitis E virus; HCV, hepatitis C virus. Received June 3, 1996; accepted June 3, 1996. Address reprint requests to: William M. Lee, M.D., University of Texas SW Medical Center at Dallas–Mail Code 8887, Department of Internal Medicine, Liver Unit, 5323 Harry Hines Blvd., Dallas, TX 75235-8887. Copyright q 1996 by the American Association for the Study of Liver Diseases. 0270-9139/96/2401-0043$3.00/0
simply reflect the almost complete absence of etiologies other than viral, or a difference in the severity of illness observed in this series. Not only were there very few drugs implicated, but there were apparently no cases of Wilson’s disease, mushroom toxicity, fatty liver of pregnancy, cancer, or circulatory collapse. This seems surprising, but may simply reflect a more advanced stage of disease at presentation. The mean survival following admission was less than 2 days, and virtually all patients were dead within the first hospital week. Referral patterns may be different as well, thus limiting, for example, the transfer of pregnant patients to a tertiary care facility. However, overall survival did not differ significantly from what we would expect. A 34% survival is excellent and somewhat better than pretransplant American series,3 possibly reflecting the dominance of viral etiologies that may carry a better survival when compared with idiosyncratic drug reactions. A striking difference that emerged from the Indian experience is that, although 25% of the women admitted for acute liver failure were pregnant, their survival was not different from that observed for the nonpregnant women. This seems surprising because we have always understood that hepatitis E, and perhaps A as well, is more severe during pregnancy and that the fatality rate for hepatitis E during pregnancy approaches 70% based on previous reports principally from India. It is unfortunate that the authors did not do a more detailed analysis of the pregnant patient group, because it remains unclear based on their experience whether the established maxim that hepatitis in pregnancy is associated with decreased survival is still viable. The authors examined the overall mortality rates, which were essentially similar for all etiologies. If 25% of the women were pregnant, and there was no predilection to increased fatalities in the third trimester as the authors state, then viral hepatitis itself and not pregnancy per se is the culprit. However, the authors’ own data demonstrated a marked increase in the acquisition rate of hepatitis in the pregnant versus the nonpregnant woman. These data would logically lead to the conclusion that pregnancy is associated with an increased chance of death from hepatitis when compared with not being pregnant (with its reduced risk of acquiring viral hepatitis). Their point is valid, but their reasoning is somewhat tautologic. Finally, the authors apply their own unique set of criteria for predicting survival based on regression analysis. The index derived from their data set is different than those employed in the West4 and more likely reflects its bias toward Third-World countries, where the etiologies of ALF are overwhelmingly viral. Age, bilirubin, and prothrombin time are used, but in addition, a high value is placed on cerebral edema as a criterion for distinguishing survivors. More than 70% of patients succumbed to cerebral edema rather than to conditions such as sepsis or gastrointestinal bleeding. Nearly all patients died within 48 hours, including most of those who had cerebral edema on admission. This further emphasizes the severity of the liver failure observed in this study. Are there others who don’t make it to the hospital? One could argue that the criteria used for identifying cerebral edema were not con-
270
AID
Hepa 0052
/
5P10$$1021
06-21-96 16:59:34
hptas
WBS: Hepatology
HEPATOLOGY Vol. 24, No. 1, 1996
LEE AND SORRELL
firmed by objective, diagnostic methods; in particular, the use of pulse and blood pressure readings is suspect, because these values are dependent on so many other variables.5,6 However, these efforts seem worthwhile in an attempt to make sense out of bedside observations in a setting where access to modern technology is restricted. Once again, the criteria used here will help confirm the clinical diagnosis of cerebral edema where intracranial monitoring is not available. What can we glean from this interesting and puzzling study? First, an increased awareness that practice in other parts of the world truly is different and many of the rules of the West are just that — local rules. This is particularly true where acetaminophen is a prominent part of the picture as it is in the United Kingdom and the United States. Of interest, acetaminophen toxicity is much less commonly seen in France and certainly doesn’t appear to play any role in India. Can we conclude that prognostic indicators are also country-specific? Yes, but we knew previously that different etiologies carried different survival statistics. The present study simply exemplifies this fact to the nth degree.
AID
Hepa 0052
/
5P10$$1021
06-21-96 16:59:34
271
WILLIAM M. LEE, M.D. University of Texas Southwestern Medical School Dallas, TX MICHAEL F. SORRELL, M.D. University of Nebraska Medical Center Omaha, NE REFERENCES 1. Acharya SK, Dasarathy S, Kumer TL, Sushma S, Uma Prasarna KS, Tandon A, Speenivas V, et al. Fulminant hepatitis in a tropical population: clinical course, cause, and early predictors of outcome. HEPATOLOGY 1996; 23:1448-1455. 2. O’Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet 1993;342:273-275. 3. Rakela J, Lange SM, Ludwig J, Baldus WP. Fulminant hepatitis; Mayo Clinic experience with 34 cases. Mayo Clin Proc 1985;60:289-292. 4. O’Grady JG, Alexander GJM, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989;97:439-445. 5. Ede RJ, Williams R. Hepatic encephalopathy and cerebral oedema. Semin Liver Dis 1986;6:107-108. 6. Blei AT. Cerebral edema and intracranial hypertension in acute liver failure: distinct aspects of the same problem. HEPATOLOGY 1991;13:376-378.
hptas
WBS: Hepatology