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Liver damage in heatstroke and its regression
LIVER DAMAGE IN HEATSTROKE AND ITS REGRESSION A Biopsy Study Leonard Bianchi, lVI.D. ,'"
Helmut Ohnacker, M.D., t
*
Kurt Beck, M.D., and May Zimmerli-Ning, M.D .§
Abstract Two cases of heatstroke occurring simultaneously with biochemical features resembling' viral hepatitis are presented. Histologic changes are documented in a sequential manner up to the period of one year. Severe centrilobular zonal necrosis, marked hydropic swelling, and extensive cholestasis with leucocytic "ch ola ngiolitis" were striking features. The similarity to viral hepatitis with confluent necrosis is noted. There was complete recovery, and the hepatic lesions disappeared in both patients. "Cholangiolitis" has hitherto not been reported in heatstroke.
Liver damage from heatstroke has been repeatedly described since Saffert's report in 1937,1 The adverse effects of heat on the liver have been documented by various observers on autopsy material in the mid thirties and forties when therapeutic hyperpyrexia was widely used.v" Detailed studies of pathologic changes, however, are lacking. Austin and Berry" published a report of 100 cases of heatstroke but without histologic examination of the liver. Morphologic changes previ-
ously reported are based on a single liver biopsy," :" Recently Kew et al." described hepatocellular damage in Bantu gold miners as evidenced in biopsy studies. However, the histologic changes were not followed up. The purpose of this paper is to describe the evolution of liver damage by serial biopsies in two cases of heatstroke occurring simultaneously with severe hepatocellular damage and complete recovery after one year.
"Professor of Pathology. University of Basel. Basel. Switzerland. tHead. Division of Pediatric Pathology, Un iversity of Basel, Basel, Switzerland. :j:l'rofessor of Medicine. Department of Castroenterology, Deutsche Klinik filr Diagnostik, Wiesbaden, West Germany. §Assistant in Medicine, University of Basel, Basel, Switzerland.
237
liUMAN PATI/O!O(;Y - VOLUME 3, NUMBER 2 June 1972 CASE REPORTS
Two patients suffered from heatstroke during the course of a cross country foot race on a summer day with high humidity in the air. Patient A was a 23 year old healthy male who was brought to the hospital after he had collapsed at this race. He was unconscious for one hour, without recordable blood pressure. Patient B was a 26 year old health student tak-
ing part in the same race who also collapsed. His blood pressure was not measurable on admission, and he was unconscious for 10 hours, after which a value of 105/70 mm. Hg was recordecl. Both patients became icteric on the third day. They denied any drug intake or alcoholism and, similarly, any malaise or fever prior to the race. The clinical and biochemical data are represented in Figure 1. Serial liver biopsies were taken.
COLLAPSE 1* HOUR
22 20
PATIENT
18 16 14 12 10
A
23
cJ
8
6 4
2
A COLLAPSE 10 ~HOURS
24 22
20 18 16 14 12
PATIENT
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10 8 6 4 2
~~:;::::;::::;~~~~~ 30 40
0 2 4 6 8 101214161820
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238
Figure 1.
oc.
~~ 36~::::=======------------
Clinical and biochemical data
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two patients with heatstroke occurring simultaneously.
LI VER DAMAGE I N HEATSTROKE AND ITS REGR ESSIO N- B rANc HI
ET AL.
Figure 2. Biopsy I (n ine days afte r heats trok e) in p atient s A and B, showing centr ilobular n ecrosis , exten sive hydropic swelling of liver cells, and sma ll pa renchymal rim of fairly norma l liver ce lls sur r ounding por tal tract (~ ) . (Hema to xylin and eosin stain. X 140.)
BIOPSY FINDINGS
First Biopsy (Da y 9 after Heatstroke) Biopsy I in both patient s showed centr ilobular necrosis, involving u p to o ne-thir d of the lobule; the liver cells in th ese areas had disappeared (Fig. 2). At the pe riphery of these necrotic zones hydropic swelli ng of the hepatocytes was conspicuous (Figs. 2. 4). No signi-
fican t fatt y change was present. There was pronou nced nuclear pol ymorphism and m itoses wer e frequent. Widespread cholestasis with man y bile th rombi was an outstanding fea tur e . The seve r ity of the parenchymal alteration s. especially hydropic swelling. d e creased with incre asin g distance fro m the cen tr a l are a ; a sma ll parenchymal rim sur roundi ng portal tracts appeared nearly unaltered (Fig. 2). Areas of spotty eosinophilic single cell ne crosis, however, were scattered throughou t the lobule.
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HUMAN P,\.THOLOC;Y - VOLUl'vlE 3, NUMBER 2 June 1972
Figure 3. Biopsy I (nine days after heatstroke) from patient B, showing cholestasis with bile thrombi. A large eosinophilic ovoid cytoplasmic inclusion body, which is PAS negative, is seen in the center of the field. (PAS stain after diastase digestion. x 625,)
Within and bordering the areas of zonal necrosis mesenchymal cells had conspicuously proliferated and were swollen; some of them contained brown pigment, such as PAS positive lipofuscin (ceroid) and t.races of siderin. This reaction was intermixed with neutrophils, the latter often locat.ed around bile t.hrombi. Intra-
240
lobular cholangioles in the neighborhood of necrotic zones were prominent and often dilated (Fig. 4). Neutrophils were present in large numbers within and around these d uctules (Fig. 'I). Portal tracts were somewhat. edematous and only slightly infiltrated by a few neutro-
Figure 4. Biopsy I (nine days after heatstroke) from patient A. showing dilated cholangiole with neutrophilic invasion and central necrosis (lower left). Note marked hydropic swelling of hepatocytes. (Hematoxylin and eosin stain. x ,100.)
LIVER DAMAGE IN HEATSTROKE AND ITS REGRESSION-BIANCHI
ET AL.
Figure 5. Biopsy I (nine days after heatstroke) from patient E, showing' intact reticulin framework. Arrow indicates central areas. (Cornori stain. X 140.)
phils, lymphocytes, and histiocytes. The centrilobular reticulin framework was still intact (Fig. 5); only a few fibers had collapsed, but no collagenation was seen. Centrilobular sinusoids in both patients appeared somewhat dilated and engorged with erythrocytes (Fig. 2). There was some blood pooling in patient A (Fig. 2). Fibrin thrombi (intravascular coagulation) were absent. The similarity of the histologic picture in both patients was striking, the extent of the lesion being somewhat greater in patient A. Neutrophilic "cholangiolitis" was also more prominent in patient A, but cholestasis was slightly more pronounced in patient B. In addition, unusual large, eosinophilic, round or ovoid cytoplasmic inclusion bodies were seen within some hepatocytes in patient B (Fig. 3).
Second Biopsy (Day 13 after Heatstroke) At the time of the second biopsy centrilobular necrosis was still prominent in both patients (Fig. 6). I-l ydropic degeneration and polymorphism of cells and nuclei were less pronounced than before. A few large fat droplets appeared adjacent .to the area of central
necrosis. Cholestasis and invasion of cholangioles by segmented leukocytes were less conspicuous. The same was true for the mesenchymal reaction, but pigment deposition was the same as in the first biopsy. Infiltration of the portal tracts and the centrilobular reticulin pattern were unchanged. Centrilobular sinusoids were still slightly dilated. No signs of intravascular coagulation were seen.
Third Biopsy (Four Weeks after Heatstroke) The parenchyma was almost fully restored in both patients (Fig. 7). Newly formed hepaiocytes had almost entirely repopulated the central zones of previous necrosis. Binucleated liver cells appeared in great numbers. Cholestasis had dirninuishcd, in case A more than in B. The bile thrombi were often phagocytosed by Kupffer cells. Leucocytic "cholangiolitis" and portal inflammation were less pronounced. Fat droplets were scattered throughout the lobule. The faintly eosinophilic, PAS-negative cytoplasmic inclusion bodies in patient B could still be seen. In this third biopsy in both patients many clusters of pigment laden macrophages, pre-
241
l-IUMAN PATHOLOGY - VOLUME 3. NUMBER 2 JUlie 1972
Figure 6. Biopsy II (13 days after heatstroke) from patient B. Ccntrilobular necrosis (top left) is still predominant. Hydropic degeneration and polymorphism of hepatocytes are less pronounced. Portal tracts (-» are only slightly infiltrated. (Chromotrope aniline blue stain. x lAO.)
Figure 7. Biopsy III (four weeks after heatstroke) from patient A, showing almost complete restoration of parenchyma. Note clusters of pigment laden, swollen Kupffer cells. (PAS stain after diastase digestion. x 80.)
242
LIVER DAMAGE IN HEATSTROKE AND ITS REGRESSION-BIANCHI
ET
AL.
Figure 8. Biopsy IV (two months after heatstroke) in paticnt. A, showing complete restoration of parenchyma; dusters of pigment laden Kupffer cells are still present. Arrow indicates central area. (PAS stain after diastase digestion. x 200.)
dominantly in central and midzonal areas and within portal tracts, were an outstanding feature (Fig. 7). The amount of siderin was increased. The histologic picture in both patients was remarkably similar.
Fourth Biopsy (Two Months after Heatstroke) The parenchyma was entirely restored (Fig. 8). Clusters of scavenger cells loaded with brown pigment, i.e., ceroid and siderin, were still present but were less pronounced than in the previous biopsy. Cholestasis was absent in patient A; a few residual bile thrombi were found within swollen Kupffer cells in the specimen from patient B. Binucleated hepatocyt.es were less abundant. Leucocytic "cholangiolitis" had disappeared. Fatty change had slightly increased. The minor central reticulin collapse seen in the previous biopsies had disappeared without sequelae (Fig. 9).
Fifth Biopsy (Eleven and Twelve Months after Heatstroke) Both specimens showed normal liver tissue except for a few swollen and pigment laden
intralobular scavenger cells (Fig. 10). The pigment was now iron negative and PAS positive. No reticulin collapse or fibrosis and no signs of inflammation were noted (Fig. 11). A slight fatty change was present in the biopsy in patient B. Histologic parameters, namely, hydropic and eosinophilic degeneration, bile thrombi, binculeatcd hepatocytes, and mitotic figures, were quantitated per 1000 liver cells in a sequential manner on four of the histologic specimens of both patients (Fig. 12). A marked decrease in hydropic degeneration, bile thrombi, and eosinophilic degeneration was thus demonstrated during the course of recovery.
DISCUSSION Hepatic alterations nine days after heatstroke consist of centrilobular zonal necrosis, conspicuous hydropic change at the border of necrotic areas, extensive cholestasis, proliferation of intralobular bile ductules with leucocytic "cholangiolitis," and an inflammatory mesenchymal response.
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HUMAN PATHOLOGY - VOLUME 3, NUMBER 2 JUlie 1972
Figure 9. Biopsy IV (two months after heatstroke) from patient B, showing normal reticulin framework. Central areas are in the upper part of the figure. (Gomori stain. X 200.)
Figure 10. Biopsy V (II months after heatstroke) in patient A. showing normal liver parenchyma. A few pigment laden Kupffcr cells are still present in the neighborhood of the central vein. (PAS stain after diastase digestion. x 140,)
244
LI VER DAMA G E IN HEATSTROKE AND ITS REGRESSIO N-BIANCHI ET
A I. .
Figure 11. Biopsy V ( 12 mo n ths a fte r heatstroke) in pati en t E , showing normal live r parenchyma. No fibro sis is see n. (Chromouo pe aniline blue stain, x 140. )
Centrilobular liver cell necrosis in heatstroke has been d escribed in several autopsy specimens.": 9 -11 Kew et al." mentioned centril obular liver cell necrosis an d widen ing of cen tr al veins and adjacent sin usoids. Cholestasis was seen in only one case . Vescia an d Peck" also o bse rved cen trilobular ne cros is co ns isting of occasional g rou ps of two to th ree liver cells and sligh t ch o lestasis. Howeve r , cen tral ne cros is reported in patients who surv ive d ep isodes of he atstroke was o nly mild and ne ver reached the ex te n t of that in the two patien ts presented here, H yalin e bodies as see n in pat ient B ha ve been reponed in au to psy cases of heatstroke by Br agdon " and Gore and Isa acson ." Sim ilar inclusion bodies have been produ ce d experi me n ta lly in cats su bj ected to anoxia. I:! The nature of these inclusions remai ns unknown. Hepatic changes in o u r cases were such as to raise qu estions of differential diagnosis.
Viral Hepatitis T he biochemical constellation suggeste d the diagnosis of viral h e patitis , and both patien ts were reported as suc h t.o th e Regis try of Epidemics b y the clinician . T he h istologic fea tures of ce nuilob ul ar con flue n t necr os is, exte nsive h yd ropic swelling, spotty sing le ce ll ne crosi s, cho les tasis with "ch o langio litis," an d mesen chymal re sponse at fir st gla nce are highly suggestive of acute vir al h epatitis with confluent necrosis!' o r subacute hepatic nec rosis. In Vescia and Peck" in the bio psy of their case o f heatstroke also considere d viral hepatitis in the dill eren tial diagnosis. H oweve r, several findings in our cases a re not consisten t wit h viral hepatitis. The zon al ne crosis observed is strictly cent ri lobu la r , the portal infla m ma tion is only minimal, and the int ral obular mesenchymal reaction is less pronounced than is generally the case in viral h epatitis.
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HUMA N P ATHOLOGY- VOLUME 3, N UM BER 2 J une 1972 PER 1000 HEPATOCYTES 120
100
PAT A HYDROPIC SWELLING EOSINOPHILIC NECROSIS 81LE THROMBI 81NUCLEATED CELLS MITOSES
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In addition, th at both patients suffered from heatstroke on the same occasion and that both presented identical clinical and morphologic changes over a comparable period of time make viral hepatitis an unlikely diagnosis.
Drug-induced Hepatic Injury The histologic pattern we have described would be consistent with both the h ypersensitivity or viral hepatitis-like type (halothane, monoamine oxidase inhibitors) and the direct toxic typ e of liver injury (carbon tetrachloride, mushroom po ison ing). The hepatitic type of drug-induced liver damage can be ruled out for the same reasons as those stated fOT viral hepatitis. In contrast to the direct toxic liver lesion , hydropic swellin g in our cases was too extensive, and no fatty change was evident. In addition, no history of drug intake could be obtained by careful inquiry of both patients. Shock
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27
57
DAYS
Quantitative alterations in morphologic features in the evoluti on of liver damage in heatstroke.
Central necrosis from shock of different etiologies is common. I 6 - 20 In our experience with liver biopsies in shock, no
or only minimal hydropic change was observed. Slight to moderate cholestasis has been reported in shock.IS Centrilobular necrosis and mesenchymal reaction in our heatstroke cases therefore may be a response to shock. In our experience, however, shock-induced hydropic change, particularly cholestasis, is never as extensive as that seen in the present cases. In ad dition , "cholangiolitis" and ductular proliferation have not been observed in liver damage by shock alone. The pathogenesis of hepatic damage in heatstroke is still controversial. Hypoxia ma y be an important factor and may explain some of the histologic features, su ch as central necrosis and po ssibly cholestasis. I 3 In addition, direct injury by heat may play a role. The possible pathogenetic mechanisms are discussed in many reports of autopsy cases of liver damage by hyperthermia alon e.s- 3 Leucocytic "cho langiolitis," as in our cases of heatstroke, has not been found in the cases reported in literature. This morphologic alteration in heatstroke is a further example demonstrating that this finding, often considered helpful in the diagnosis of extrahepatic biliary obstruction, may occur in the absence of this disorder.
LIVER DAMAGE IN HEATSTROKE AND ITS REGRESSION-BIANCHI
Concomitant leucocytic "cholangiolitis" accompanies a variety of intrahepatic liver cell lesions, such as viral hepatitis, especially the variation with confluent necrosis':' and drug induced hepatitis.t! Leucocytic "cholangiolitis" therefore has to be considered a nonspecific phenomenon. The pathogenesis of such leucocytic "cholangiolitis" is still poorly understood and many authors have discussed it,13, 22-26 Histologic regression of the hepatic lesions in heatstroke is morphologically and with regard to the speed of evolution similar to the healing pattern of viral hepatitis.vv " In the first biopsy, nine days after the heatstroke, degenerative alterations were already accompanied by signs of regeneration. The appearance of mitoses in considerable number, followed by an increase in binucleated cells, is a well known sequence in regeneration after cell damage of different etiology. In the case of Vescia and Peck" the biopsy was also taken on the ninth day and few mitoses were observed. The regenerative process has been confirmed to be nonspecific. . Cholestasis decreased rapidly until day 13. However, it was st.ill det.ectable after four weeks when liver cell necrosis had disappeared. The persistence of cholestasis after acute liver damage is observed similarly in viral hepatitis. "Cholangiolitis" together with cholestasis gradually subsided in our patients. A mesenchymal reaction with the accumulation of brown pigment-already present in the first biopsy - had its peak after four weeks and two months, respectively (third and fourth biopsies). This response parallels the evolution of the mesenchymal reaction in the late stage of viral hepatitis." Whereas the parenchyma was completely restored after one year (fifth biopsy), a few pigment laden Kupffer cells remained, indicating prior hepatocyric damage. The lack of fibrosis in the central area, despite the extensive central necrosis and some previous reticulin collapse, lis remarkable. This is in contrast to the sequelae of viral hepatitis in which confluent necrosis of the extent seen in the present cases as a rule results in centrilobular fibrosis. This difference may be explained by the fact that in heatstroke a
ET
AL.
single attack produces central necrosis, allowing the regenerating parenchyma immediately to grow between the reticulin fibers devoided of liver cells, and therefore preventing larger areas of collapse. In viral hepatitis, possibly more than one step of necrosis occurs. Recurrent liver cell death in viral hepatitis therefore may lead to collapse of the reticulin framework and subsequent fibrosis despite active regeneration. A similar sequence of events, i.e., stepwise repeated cell death followed by fibrosis, is even better demonstrated in alcoholic hepatitis in which the offending agent acts repeatedly and central fibrosis usually results.F REFERENCES I. Saffert, C. A.: Heat hyperpyrexia. Minn. Med.,
77:106,1937. 2. Hartman, F. W., and Major, R. C.: Pathological changes resulting from accurately controlled artificial fever therapy. Amer. J. Clin, Path., 5:392, 1935. 3. Gore, 1., and Isaacson, N. H.: The pathology of hyperpyrexia, observation at autopsy in 17 cases of fever therapy. Amer.]. Path., 25: 1029, 1949. 4. Wilbur, E. L., and Stevens.}. B.: Morbid anatomic changes following artificial fever with report of autopsies. South. Meel. j., 30:286, 1937 ..· 5. Austin, M. G., and Berry, J. W.: Observation on 100 cases of heatstroke . .J.A.M.A., 161:1525, 1956. 6. Vescia, F. G., and Peck, O. G.: Liver diseases from heat stroke. Gastroenterology, 43:340, 1962. 7. Herman, R., and Sullivan, B.: Heat stroke and jaundice. Amer. J. Meel., 27:154, 1959. 8. Kew, M., Bersohn, 1., Sefrer, H., and Kent, G;: Liver damage in heat stroke. Amer, ]. Med., 49: 192, 1970. 9. Malamud, N., Haymaker, W., and Custer, P.: Heatstroke-a clinical pathological study of 125 fatal cases. Milit. Surg., 99: 397, 1946. 10. Baxter, C. R., and Teschan, P. E.: Atypical heat stroke with hypernatremia, acute renal failure, and fulminating potassium intoxication. Arch. Int. Med., 101:1040, 1958. 11. Coburn, J. W., and Reba, R. C.: Potassium depletion in heatstroke, a possible etiological factor. Milit. Mee!., 131 :678, 1966. 12. Bragdon, J.: The hepatitis of hyperthermia, report ofa fatal case. New Eng.J. Meet. 237:765, 1947. 13. Altmann, H. W.: Ueber Leberveranderungen bei allgemeinern Sauerstoffrnangel nach Unterdruckexperimenten an Katzen. Frankfurt Z. Path., 60:376, 1949. 14. An International Group: Morphological criteria in viral hepatitis. Lancet, i:333. 1971. 15. Boyer,]. 1.., and Klatskin, G.: Pattern of necrosis
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16.
17. 18. 19.
20.
21.
in acute viral hepatitis. Prognostic value of bridging (subacute hepatic necrosis). New Eng. I. Med., 283: 1063, 1970. Beneke, G.: Veranderungen del' Leber im Schock. In Horatz, K. (Editor): Leber- und Pankreas-schaden durch Schock und Narkose. Stuttgart, Georg Thieme Verlag, 1970, p. 2. Clarke, W. T. W.: Centrilobular hepatic necrosis following cardiac infarction. Amer. J. Path., 26:249, 1950. Ellenberg, M., and Ossermann, K. E.: The role of shock in the production of central liver cell necrosis. Amer, J. Med., 11:170, 1951. Korb, G., MUlier, R., Gedigk, P., and Hellwig, K.: Ueber die Entstehung lind Abheilung von Lebernekrosen nach einem einmaligen Schock. Virchows Arch. (Path. Anat.), 348:374, 1969. Scheuer, P.: Liver Biopsy Interpretation. London, Baillierc, Tindall & Cassell, Ltd., 1968, p. 82. Popper, H., and Schaffner, F.: Drug-induced hepatic injury. Ann. Int. Med., 5/: 12:~O, 1959.
22. Watson, C. J., and Hoffbauer, F. W.: The problem of prolonged hepatitis with particular reference to the cholangiolitic type and to the development of cholangiolitic cirrhosis of the liver. Ann. Int. Med .. 25: 195. 1946. 23. Gall, E. A., and Braunstein, H.: Hepatitis with manifestations simulating bile duct obstruction (so-called "cholangiolitic hepatitis"). Amer. J. Clin. Path., 25:1113,1955. 24. Popper, H.: Cholestasis. Ann. Rev. Med .. 19:39, 1968. 25. Bianchi, L.: Punkrat-Morphologie und Differenrialdiagnose del' Hepatitis. Berne, Hans Huber Medical Publisher, 1967, p. 62. 26. Popper, H., and Schaffner, F.: Pathophysiology of cholestasis. Ham. Path., 1: I, 1970. 27. Peters, R, L., Reynolds, T. E., and Kuzma, O. T.: Sclerosing hyaline necrosis of the liver in the chronic alcoholic; a recognizable clinical syndrome. Ann. Int. Med., 59:646, 1963. Department of Pathology University of Basel Schoenbeinstrasse 40 CH-4000 Basel, Switzerland (Dr. Bianchi)
248
Helmut Ohnacker, M.D., t
*
Kurt Beck, M.D., and May Zimmerli-Ning, M.D .§
Abstract Two cases of heatstroke occurring simultaneously with biochemical features resembling' viral hepatitis are presented. Histologic changes are documented in a sequential manner up to the period of one year. Severe centrilobular zonal necrosis, marked hydropic swelling, and extensive cholestasis with leucocytic "ch ola ngiolitis" were striking features. The similarity to viral hepatitis with confluent necrosis is noted. There was complete recovery, and the hepatic lesions disappeared in both patients. "Cholangiolitis" has hitherto not been reported in heatstroke.
Liver damage from heatstroke has been repeatedly described since Saffert's report in 1937,1 The adverse effects of heat on the liver have been documented by various observers on autopsy material in the mid thirties and forties when therapeutic hyperpyrexia was widely used.v" Detailed studies of pathologic changes, however, are lacking. Austin and Berry" published a report of 100 cases of heatstroke but without histologic examination of the liver. Morphologic changes previ-
ously reported are based on a single liver biopsy," :" Recently Kew et al." described hepatocellular damage in Bantu gold miners as evidenced in biopsy studies. However, the histologic changes were not followed up. The purpose of this paper is to describe the evolution of liver damage by serial biopsies in two cases of heatstroke occurring simultaneously with severe hepatocellular damage and complete recovery after one year.
"Professor of Pathology. University of Basel. Basel. Switzerland. tHead. Division of Pediatric Pathology, Un iversity of Basel, Basel, Switzerland. :j:l'rofessor of Medicine. Department of Castroenterology, Deutsche Klinik filr Diagnostik, Wiesbaden, West Germany. §Assistant in Medicine, University of Basel, Basel, Switzerland.
237
liUMAN PATI/O!O(;Y - VOLUME 3, NUMBER 2 June 1972 CASE REPORTS
Two patients suffered from heatstroke during the course of a cross country foot race on a summer day with high humidity in the air. Patient A was a 23 year old healthy male who was brought to the hospital after he had collapsed at this race. He was unconscious for one hour, without recordable blood pressure. Patient B was a 26 year old health student tak-
ing part in the same race who also collapsed. His blood pressure was not measurable on admission, and he was unconscious for 10 hours, after which a value of 105/70 mm. Hg was recordecl. Both patients became icteric on the third day. They denied any drug intake or alcoholism and, similarly, any malaise or fever prior to the race. The clinical and biochemical data are represented in Figure 1. Serial liver biopsies were taken.
COLLAPSE 1* HOUR
22 20
PATIENT
18 16 14 12 10
A
23
cJ
8
6 4
2
A COLLAPSE 10 ~HOURS
24 22
20 18 16 14 12
PATIENT
B
26
cJ
10 8 6 4 2
~~:;::::;::::;~~~~~ 30 40
0 2 4 6 8 101214161820
TEMP.
B
238
Figure 1.
oc.
~~ 36~::::=======------------
Clinical and biochemical data
1'1'0111
two patients with heatstroke occurring simultaneously.
LI VER DAMAGE I N HEATSTROKE AND ITS REGR ESSIO N- B rANc HI
ET AL.
Figure 2. Biopsy I (n ine days afte r heats trok e) in p atient s A and B, showing centr ilobular n ecrosis , exten sive hydropic swelling of liver cells, and sma ll pa renchymal rim of fairly norma l liver ce lls sur r ounding por tal tract (~ ) . (Hema to xylin and eosin stain. X 140.)
BIOPSY FINDINGS
First Biopsy (Da y 9 after Heatstroke) Biopsy I in both patient s showed centr ilobular necrosis, involving u p to o ne-thir d of the lobule; the liver cells in th ese areas had disappeared (Fig. 2). At the pe riphery of these necrotic zones hydropic swelli ng of the hepatocytes was conspicuous (Figs. 2. 4). No signi-
fican t fatt y change was present. There was pronou nced nuclear pol ymorphism and m itoses wer e frequent. Widespread cholestasis with man y bile th rombi was an outstanding fea tur e . The seve r ity of the parenchymal alteration s. especially hydropic swelling. d e creased with incre asin g distance fro m the cen tr a l are a ; a sma ll parenchymal rim sur roundi ng portal tracts appeared nearly unaltered (Fig. 2). Areas of spotty eosinophilic single cell ne crosis, however, were scattered throughou t the lobule.
239
HUMAN P,\.THOLOC;Y - VOLUl'vlE 3, NUMBER 2 June 1972
Figure 3. Biopsy I (nine days after heatstroke) from patient B, showing cholestasis with bile thrombi. A large eosinophilic ovoid cytoplasmic inclusion body, which is PAS negative, is seen in the center of the field. (PAS stain after diastase digestion. x 625,)
Within and bordering the areas of zonal necrosis mesenchymal cells had conspicuously proliferated and were swollen; some of them contained brown pigment, such as PAS positive lipofuscin (ceroid) and t.races of siderin. This reaction was intermixed with neutrophils, the latter often locat.ed around bile t.hrombi. Intra-
240
lobular cholangioles in the neighborhood of necrotic zones were prominent and often dilated (Fig. 4). Neutrophils were present in large numbers within and around these d uctules (Fig. 'I). Portal tracts were somewhat. edematous and only slightly infiltrated by a few neutro-
Figure 4. Biopsy I (nine days after heatstroke) from patient A. showing dilated cholangiole with neutrophilic invasion and central necrosis (lower left). Note marked hydropic swelling of hepatocytes. (Hematoxylin and eosin stain. x ,100.)
LIVER DAMAGE IN HEATSTROKE AND ITS REGRESSION-BIANCHI
ET AL.
Figure 5. Biopsy I (nine days after heatstroke) from patient E, showing' intact reticulin framework. Arrow indicates central areas. (Cornori stain. X 140.)
phils, lymphocytes, and histiocytes. The centrilobular reticulin framework was still intact (Fig. 5); only a few fibers had collapsed, but no collagenation was seen. Centrilobular sinusoids in both patients appeared somewhat dilated and engorged with erythrocytes (Fig. 2). There was some blood pooling in patient A (Fig. 2). Fibrin thrombi (intravascular coagulation) were absent. The similarity of the histologic picture in both patients was striking, the extent of the lesion being somewhat greater in patient A. Neutrophilic "cholangiolitis" was also more prominent in patient A, but cholestasis was slightly more pronounced in patient B. In addition, unusual large, eosinophilic, round or ovoid cytoplasmic inclusion bodies were seen within some hepatocytes in patient B (Fig. 3).
Second Biopsy (Day 13 after Heatstroke) At the time of the second biopsy centrilobular necrosis was still prominent in both patients (Fig. 6). I-l ydropic degeneration and polymorphism of cells and nuclei were less pronounced than before. A few large fat droplets appeared adjacent .to the area of central
necrosis. Cholestasis and invasion of cholangioles by segmented leukocytes were less conspicuous. The same was true for the mesenchymal reaction, but pigment deposition was the same as in the first biopsy. Infiltration of the portal tracts and the centrilobular reticulin pattern were unchanged. Centrilobular sinusoids were still slightly dilated. No signs of intravascular coagulation were seen.
Third Biopsy (Four Weeks after Heatstroke) The parenchyma was almost fully restored in both patients (Fig. 7). Newly formed hepaiocytes had almost entirely repopulated the central zones of previous necrosis. Binucleated liver cells appeared in great numbers. Cholestasis had dirninuishcd, in case A more than in B. The bile thrombi were often phagocytosed by Kupffer cells. Leucocytic "cholangiolitis" and portal inflammation were less pronounced. Fat droplets were scattered throughout the lobule. The faintly eosinophilic, PAS-negative cytoplasmic inclusion bodies in patient B could still be seen. In this third biopsy in both patients many clusters of pigment laden macrophages, pre-
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l-IUMAN PATHOLOGY - VOLUME 3. NUMBER 2 JUlie 1972
Figure 6. Biopsy II (13 days after heatstroke) from patient B. Ccntrilobular necrosis (top left) is still predominant. Hydropic degeneration and polymorphism of hepatocytes are less pronounced. Portal tracts (-» are only slightly infiltrated. (Chromotrope aniline blue stain. x lAO.)
Figure 7. Biopsy III (four weeks after heatstroke) from patient A, showing almost complete restoration of parenchyma. Note clusters of pigment laden, swollen Kupffer cells. (PAS stain after diastase digestion. x 80.)
242
LIVER DAMAGE IN HEATSTROKE AND ITS REGRESSION-BIANCHI
ET
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Figure 8. Biopsy IV (two months after heatstroke) in paticnt. A, showing complete restoration of parenchyma; dusters of pigment laden Kupffer cells are still present. Arrow indicates central area. (PAS stain after diastase digestion. x 200.)
dominantly in central and midzonal areas and within portal tracts, were an outstanding feature (Fig. 7). The amount of siderin was increased. The histologic picture in both patients was remarkably similar.
Fourth Biopsy (Two Months after Heatstroke) The parenchyma was entirely restored (Fig. 8). Clusters of scavenger cells loaded with brown pigment, i.e., ceroid and siderin, were still present but were less pronounced than in the previous biopsy. Cholestasis was absent in patient A; a few residual bile thrombi were found within swollen Kupffer cells in the specimen from patient B. Binucleated hepatocyt.es were less abundant. Leucocytic "cholangiolitis" had disappeared. Fatty change had slightly increased. The minor central reticulin collapse seen in the previous biopsies had disappeared without sequelae (Fig. 9).
Fifth Biopsy (Eleven and Twelve Months after Heatstroke) Both specimens showed normal liver tissue except for a few swollen and pigment laden
intralobular scavenger cells (Fig. 10). The pigment was now iron negative and PAS positive. No reticulin collapse or fibrosis and no signs of inflammation were noted (Fig. 11). A slight fatty change was present in the biopsy in patient B. Histologic parameters, namely, hydropic and eosinophilic degeneration, bile thrombi, binculeatcd hepatocytes, and mitotic figures, were quantitated per 1000 liver cells in a sequential manner on four of the histologic specimens of both patients (Fig. 12). A marked decrease in hydropic degeneration, bile thrombi, and eosinophilic degeneration was thus demonstrated during the course of recovery.
DISCUSSION Hepatic alterations nine days after heatstroke consist of centrilobular zonal necrosis, conspicuous hydropic change at the border of necrotic areas, extensive cholestasis, proliferation of intralobular bile ductules with leucocytic "cholangiolitis," and an inflammatory mesenchymal response.
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HUMAN PATHOLOGY - VOLUME 3, NUMBER 2 JUlie 1972
Figure 9. Biopsy IV (two months after heatstroke) from patient B, showing normal reticulin framework. Central areas are in the upper part of the figure. (Gomori stain. X 200.)
Figure 10. Biopsy V (II months after heatstroke) in patient A. showing normal liver parenchyma. A few pigment laden Kupffcr cells are still present in the neighborhood of the central vein. (PAS stain after diastase digestion. x 140,)
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LI VER DAMA G E IN HEATSTROKE AND ITS REGRESSIO N-BIANCHI ET
A I. .
Figure 11. Biopsy V ( 12 mo n ths a fte r heatstroke) in pati en t E , showing normal live r parenchyma. No fibro sis is see n. (Chromouo pe aniline blue stain, x 140. )
Centrilobular liver cell necrosis in heatstroke has been d escribed in several autopsy specimens.": 9 -11 Kew et al." mentioned centril obular liver cell necrosis an d widen ing of cen tr al veins and adjacent sin usoids. Cholestasis was seen in only one case . Vescia an d Peck" also o bse rved cen trilobular ne cros is co ns isting of occasional g rou ps of two to th ree liver cells and sligh t ch o lestasis. Howeve r , cen tral ne cros is reported in patients who surv ive d ep isodes of he atstroke was o nly mild and ne ver reached the ex te n t of that in the two patien ts presented here, H yalin e bodies as see n in pat ient B ha ve been reponed in au to psy cases of heatstroke by Br agdon " and Gore and Isa acson ." Sim ilar inclusion bodies have been produ ce d experi me n ta lly in cats su bj ected to anoxia. I:! The nature of these inclusions remai ns unknown. Hepatic changes in o u r cases were such as to raise qu estions of differential diagnosis.
Viral Hepatitis T he biochemical constellation suggeste d the diagnosis of viral h e patitis , and both patien ts were reported as suc h t.o th e Regis try of Epidemics b y the clinician . T he h istologic fea tures of ce nuilob ul ar con flue n t necr os is, exte nsive h yd ropic swelling, spotty sing le ce ll ne crosi s, cho les tasis with "ch o langio litis," an d mesen chymal re sponse at fir st gla nce are highly suggestive of acute vir al h epatitis with confluent necrosis!' o r subacute hepatic nec rosis. In Vescia and Peck" in the bio psy of their case o f heatstroke also considere d viral hepatitis in the dill eren tial diagnosis. H oweve r, several findings in our cases a re not consisten t wit h viral hepatitis. The zon al ne crosis observed is strictly cent ri lobu la r , the portal infla m ma tion is only minimal, and the int ral obular mesenchymal reaction is less pronounced than is generally the case in viral h epatitis.
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HUMA N P ATHOLOGY- VOLUME 3, N UM BER 2 J une 1972 PER 1000 HEPATOCYTES 120
100
PAT A HYDROPIC SWELLING EOSINOPHILIC NECROSIS 81LE THROMBI 81NUCLEATED CELLS MITOSES
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80
110
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Figure 12.
13
In addition, th at both patients suffered from heatstroke on the same occasion and that both presented identical clinical and morphologic changes over a comparable period of time make viral hepatitis an unlikely diagnosis.
Drug-induced Hepatic Injury The histologic pattern we have described would be consistent with both the h ypersensitivity or viral hepatitis-like type (halothane, monoamine oxidase inhibitors) and the direct toxic typ e of liver injury (carbon tetrachloride, mushroom po ison ing). The hepatitic type of drug-induced liver damage can be ruled out for the same reasons as those stated fOT viral hepatitis. In contrast to the direct toxic liver lesion , hydropic swellin g in our cases was too extensive, and no fatty change was evident. In addition, no history of drug intake could be obtained by careful inquiry of both patients. Shock
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27
57
DAYS
Quantitative alterations in morphologic features in the evoluti on of liver damage in heatstroke.
Central necrosis from shock of different etiologies is common. I 6 - 20 In our experience with liver biopsies in shock, no
or only minimal hydropic change was observed. Slight to moderate cholestasis has been reported in shock.IS Centrilobular necrosis and mesenchymal reaction in our heatstroke cases therefore may be a response to shock. In our experience, however, shock-induced hydropic change, particularly cholestasis, is never as extensive as that seen in the present cases. In ad dition , "cholangiolitis" and ductular proliferation have not been observed in liver damage by shock alone. The pathogenesis of hepatic damage in heatstroke is still controversial. Hypoxia ma y be an important factor and may explain some of the histologic features, su ch as central necrosis and po ssibly cholestasis. I 3 In addition, direct injury by heat may play a role. The possible pathogenetic mechanisms are discussed in many reports of autopsy cases of liver damage by hyperthermia alon e.s- 3 Leucocytic "cho langiolitis," as in our cases of heatstroke, has not been found in the cases reported in literature. This morphologic alteration in heatstroke is a further example demonstrating that this finding, often considered helpful in the diagnosis of extrahepatic biliary obstruction, may occur in the absence of this disorder.
LIVER DAMAGE IN HEATSTROKE AND ITS REGRESSION-BIANCHI
Concomitant leucocytic "cholangiolitis" accompanies a variety of intrahepatic liver cell lesions, such as viral hepatitis, especially the variation with confluent necrosis':' and drug induced hepatitis.t! Leucocytic "cholangiolitis" therefore has to be considered a nonspecific phenomenon. The pathogenesis of such leucocytic "cholangiolitis" is still poorly understood and many authors have discussed it,13, 22-26 Histologic regression of the hepatic lesions in heatstroke is morphologically and with regard to the speed of evolution similar to the healing pattern of viral hepatitis.vv " In the first biopsy, nine days after the heatstroke, degenerative alterations were already accompanied by signs of regeneration. The appearance of mitoses in considerable number, followed by an increase in binucleated cells, is a well known sequence in regeneration after cell damage of different etiology. In the case of Vescia and Peck" the biopsy was also taken on the ninth day and few mitoses were observed. The regenerative process has been confirmed to be nonspecific. . Cholestasis decreased rapidly until day 13. However, it was st.ill det.ectable after four weeks when liver cell necrosis had disappeared. The persistence of cholestasis after acute liver damage is observed similarly in viral hepatitis. "Cholangiolitis" together with cholestasis gradually subsided in our patients. A mesenchymal reaction with the accumulation of brown pigment-already present in the first biopsy - had its peak after four weeks and two months, respectively (third and fourth biopsies). This response parallels the evolution of the mesenchymal reaction in the late stage of viral hepatitis." Whereas the parenchyma was completely restored after one year (fifth biopsy), a few pigment laden Kupffer cells remained, indicating prior hepatocyric damage. The lack of fibrosis in the central area, despite the extensive central necrosis and some previous reticulin collapse, lis remarkable. This is in contrast to the sequelae of viral hepatitis in which confluent necrosis of the extent seen in the present cases as a rule results in centrilobular fibrosis. This difference may be explained by the fact that in heatstroke a
ET
AL.
single attack produces central necrosis, allowing the regenerating parenchyma immediately to grow between the reticulin fibers devoided of liver cells, and therefore preventing larger areas of collapse. In viral hepatitis, possibly more than one step of necrosis occurs. Recurrent liver cell death in viral hepatitis therefore may lead to collapse of the reticulin framework and subsequent fibrosis despite active regeneration. A similar sequence of events, i.e., stepwise repeated cell death followed by fibrosis, is even better demonstrated in alcoholic hepatitis in which the offending agent acts repeatedly and central fibrosis usually results.F REFERENCES I. Saffert, C. A.: Heat hyperpyrexia. Minn. Med.,
77:106,1937. 2. Hartman, F. W., and Major, R. C.: Pathological changes resulting from accurately controlled artificial fever therapy. Amer. J. Clin, Path., 5:392, 1935. 3. Gore, 1., and Isaacson, N. H.: The pathology of hyperpyrexia, observation at autopsy in 17 cases of fever therapy. Amer.]. Path., 25: 1029, 1949. 4. Wilbur, E. L., and Stevens.}. B.: Morbid anatomic changes following artificial fever with report of autopsies. South. Meel. j., 30:286, 1937 ..· 5. Austin, M. G., and Berry, J. W.: Observation on 100 cases of heatstroke . .J.A.M.A., 161:1525, 1956. 6. Vescia, F. G., and Peck, O. G.: Liver diseases from heat stroke. Gastroenterology, 43:340, 1962. 7. Herman, R., and Sullivan, B.: Heat stroke and jaundice. Amer. J. Meel., 27:154, 1959. 8. Kew, M., Bersohn, 1., Sefrer, H., and Kent, G;: Liver damage in heat stroke. Amer, ]. Med., 49: 192, 1970. 9. Malamud, N., Haymaker, W., and Custer, P.: Heatstroke-a clinical pathological study of 125 fatal cases. Milit. Surg., 99: 397, 1946. 10. Baxter, C. R., and Teschan, P. E.: Atypical heat stroke with hypernatremia, acute renal failure, and fulminating potassium intoxication. Arch. Int. Med., 101:1040, 1958. 11. Coburn, J. W., and Reba, R. C.: Potassium depletion in heatstroke, a possible etiological factor. Milit. Mee!., 131 :678, 1966. 12. Bragdon, J.: The hepatitis of hyperthermia, report ofa fatal case. New Eng.J. Meet. 237:765, 1947. 13. Altmann, H. W.: Ueber Leberveranderungen bei allgemeinern Sauerstoffrnangel nach Unterdruckexperimenten an Katzen. Frankfurt Z. Path., 60:376, 1949. 14. An International Group: Morphological criteria in viral hepatitis. Lancet, i:333. 1971. 15. Boyer,]. 1.., and Klatskin, G.: Pattern of necrosis
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16.
17. 18. 19.
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in acute viral hepatitis. Prognostic value of bridging (subacute hepatic necrosis). New Eng. I. Med., 283: 1063, 1970. Beneke, G.: Veranderungen del' Leber im Schock. In Horatz, K. (Editor): Leber- und Pankreas-schaden durch Schock und Narkose. Stuttgart, Georg Thieme Verlag, 1970, p. 2. Clarke, W. T. W.: Centrilobular hepatic necrosis following cardiac infarction. Amer. J. Path., 26:249, 1950. Ellenberg, M., and Ossermann, K. E.: The role of shock in the production of central liver cell necrosis. Amer, J. Med., 11:170, 1951. Korb, G., MUlier, R., Gedigk, P., and Hellwig, K.: Ueber die Entstehung lind Abheilung von Lebernekrosen nach einem einmaligen Schock. Virchows Arch. (Path. Anat.), 348:374, 1969. Scheuer, P.: Liver Biopsy Interpretation. London, Baillierc, Tindall & Cassell, Ltd., 1968, p. 82. Popper, H., and Schaffner, F.: Drug-induced hepatic injury. Ann. Int. Med., 5/: 12:~O, 1959.
22. Watson, C. J., and Hoffbauer, F. W.: The problem of prolonged hepatitis with particular reference to the cholangiolitic type and to the development of cholangiolitic cirrhosis of the liver. Ann. Int. Med .. 25: 195. 1946. 23. Gall, E. A., and Braunstein, H.: Hepatitis with manifestations simulating bile duct obstruction (so-called "cholangiolitic hepatitis"). Amer. J. Clin. Path., 25:1113,1955. 24. Popper, H.: Cholestasis. Ann. Rev. Med .. 19:39, 1968. 25. Bianchi, L.: Punkrat-Morphologie und Differenrialdiagnose del' Hepatitis. Berne, Hans Huber Medical Publisher, 1967, p. 62. 26. Popper, H., and Schaffner, F.: Pathophysiology of cholestasis. Ham. Path., 1: I, 1970. 27. Peters, R, L., Reynolds, T. E., and Kuzma, O. T.: Sclerosing hyaline necrosis of the liver in the chronic alcoholic; a recognizable clinical syndrome. Ann. Int. Med., 59:646, 1963. Department of Pathology University of Basel Schoenbeinstrasse 40 CH-4000 Basel, Switzerland (Dr. Bianchi)
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