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Hemorrhagic gastropathy in epidemic nephropathy
0016-5107/92/3804-0476$03.00 GASTROINTESTINAL ENDOSCOPY Copyright © 1992 by the American Society for Gastrointestinal Endoscopy
Hemorrhagic gastropathy in epidemic nephropathy H. Nuutinen, MD, M. Vuoristo, M. Farkkila, MD, A. Kahri, K. Seppala, MD, V. Valtonen, T. Joutsiniemi, MD, T. Miettinen,
MD MD MD MD
Helsinki, Finland
A patient with epidemic nephropathy (NE) and with gastrointestinal symptoms and hemorrhagic gastropathy prompted us to study further 10 consecutive patients with NE. Gastroscopy was carried out within 1 to 4 weeks after the beginning of the symptoms, and in every case a hemorrhagic gastropathy was observed. Hemorrhagic lesions were more marked, the shorter the elapsed time interval from the beginning of symptoms. Hemorrhagic changes were always more prominent in the proximal than in the distal part of the stomach. In 7 of 10 patients lesions were also observed in the duodenum. Colonoscopy was done in one patient and it showed similar spotty hemorrhages, suggesting that hemorrhagic lesions were not limited to the gastroduodenal mucosa only. Histological studies disclosed that the hemorrhagic lesions were associated with edema in the lamina propria, but without inflammatory changes. Follow-up gastroscopy in three patients 3 to 8 weeks later showed disappearance of hemorrhagic lesions in every patient. Thus, these results show for the first time that hemorrhagic gastropathy is a common finding in NE, and it may explain the abdominal symptoms and gastrointestinal bleeding in some of these patients. However, the mechanism of the hemorrhagic lesions needs further exploration. (Gastrointest Endosc 1992;38:476-480)
Nephropathia epidemica (NE) is the Scandinavian form of hemorrhagic fever with renal syndrome. NE was first described in 1934 in Swedish patients by Myhrman1,2 and Zetterholm. 3 Later, the disease was characterized as a viral Zoonosis in rodents, the bank vole being the natural host of the virus. 4 The hemorrhagic manifestations of NE are so mild that initially, as its name implies, NE was not considered as a hemorrhagic fever. The main endemic area for NE is Scandinavia, Western Europe, the Balkans, and the European regions ofthe Soviet Union. The occurrence clearly shows seasonal fluctuations with the largest proportion of cases occurring in winter from October to March, although there is also a smaller peak in Received December 11,1991. For revision January 8,1992. Accepted March 5, 1992. From the Second Department of Medicine, University Central Hospital of Helsinki, Department of Pathology, University of Helsinki, and the Deaconess Hospital, Helsinki, Finland. Reprint requests: Hannu Nuutinen, MD, Division of General Medical Sciences, Gastrointestinal Research Unit, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195. Presented in part at the XXIII Nordic Congress of Gastroenterology, Reykjavik, Iceland, June 14-16, 1990.
476
August. 5- 7 There are several hundred cases of NE patients hospitalized every year in Finland. However, there are at least 10 to 20 times more cases that are subclinical or undiagnosed, because the frequency of seropositivity for NE in the Finnish population of 5 million is 2 to 20%.7,8 NE is clinically, histologically, and epidemiologically similar to Korean hemorrhagic fever except that hemorrhagic manifestations are fewer and mortality is lower. 8 These two disorders are caused by two closely related viruses, Puumala virus and Hantaan virus, respectively.9-11 Although the clinical picture of NE is dominated by renal manifestations, most patients also have abdominal pain, nausea, vomiting, and diarrhea. 8 , 12-14 Minor hemorrhagic changes (epistaxis, petechiae, gross macroscopic hematuria, and metrorrhagia) have been reported in 5 to 40% of patients. 12- 15 Hematemesis and melena may also occur in some patients. 12 , 15 However, the reason for the abdominal symptoms of NE has remained obscure and to the best of our knowledge, no endoscopic reports of NE have been previously published. GASTROINTESTINAL ENDOSCOPY
Acute renal failure itself is of course one risk factor for gastrointestinal bleeding, particularly in intensive care units, and it may contribute to the hemorrhages observed in patients with NE. 16 However, in NE, the gastrointestinal symptoms frequently herald the onset of azotemia. Extensive retroperitoneal or peritoneal edema resulting from extravasation of plasma due to increased capillary permeability could be a factor that is responsible for the severe abdominal pain. 10 Because of our own experience with a patient with NE presenting with melena and hemorrhagic changes on gastroscopy, we decided to carry out a prospective endoscopic study in this disease. MATERIALS AND METHODS
This study consisted of 10 consecutive patients, 4 women and 6 men of 29 to 55 years old (mean, 35 years) with typical symptoms of NE (i.e., renal symptoms (10 of 10), acute onset of fever (10 of 10), headache (9 of 10), backache (7 of 10), myalgia (8 of 10), and blurred vision (7 of 10)). All except one (case 6) also had nausea and abdominal pain. Our first patient (case 1), whose endoscopic findings actually initiated this study, reported black stools 1 day before hospitalization and another patient (case 9) had hematemesis and melena. In one patient (case 8), blood pressure could not be measured on admission. After volume repletion, blood pressure increased to 100/60 mm Hg, and this patient also had the highest hemoconcentration. All other patients were normotensive on admission. Urinary protein and hemoglobin was positive in all our patients. The serum creatinine was between 116 and 1621 JLmoljliter (reference value <115), hemoglobin between 88 and 211 g/liter (women, 125 to 160 and men, 135 to 180), thrombocytes between 8 and 118 Eq/liter (140 to 320), Creactive protein between 40 and 201 mg/liter (0 to 10). In every case the diagnosis was confirmed by a positive serology for NE. l7 All patients underwent gastroscopic examination within 1 to 4 weeks after the beginning of symptoms. One of our patients (case 2) came to gastroscopy because of unknown fever and abdominal pain, and NE was diagnosed after hemorrhagic changes were seen during gastroscopy. Gastroscopic findings were graded as follows: 1. High grade: when over 60% of the epithelium was covered with hemorrhagic changes (as in Fig. 1, A and B).
2. Medium grade: when 20 to 60% of the epithelium was covered with hemorrhagic changes. 3. Low grade: less than 20% of the epithelium was covered with hemorrhagic changes. In three patients (cases 3, 4, and 9) a follow-up gastroscopy was done 1 and 2 months later and one patient (case 1) also underwent a colonoscopy. In eight patients, biopsies were taken from the descending duodenum, duodenal bulb, and gastric antral and body mucosa for histological analysis. In two patients (cases 9 and 10), biopsies were not taken because of marked thrombocytopenia at the time of gastroscopy. The gastroscopic biopsies were fixed in 10% formalin, blocked in paraffin, and stained with hematoxylin and eosin. A single observer (A. K), blinded to the clinical or endoscopic results of the patients, evaluated the histological changes. Histological changes were divided into three categories: 1. High grade: multiple hemorrhages and edema which involved more than 60% of the lamina propria (as in Fig. 3). 2. Medium grade: between high and low grade (20 to 60%). 3. Only a small portion of lamina propria «20%) showed hemorrhages, only slight or no edema. Pearson's correlation test was used in the calculations.
RESULTS Endoscopic
As seen in Table 1 and Figure 1, gastroscopy revealed different degrees of hemorrhagic gastropathy in every patient. In seven patients hemorrhages were also found in the first or second part of the duodenum, whereas the esophageal mucosa was normal in all patients. In every patient the hemorrhagic changes were more prominent in the proximal part of the stomach (Table 2 and Fig. 1). In three patients (cases 3,4, and 9) a second gastroscopy was done 4, 8, and 3 weeks later, respectively, and in every case macroscopic and microscopic hemorrhagic changes had disappeared. The endoscopic hemorrhagic score (Table 1) was higher in those patients in whom gastroscopy was done earlier in the course of the disease (Fig. 2). The endoscopic hemorrhagic score tended to be highest in the patients who had the lowest platelet levels (r = -0.624, p < 0.10) at the time of gastroscopy. Colon-
Table 1. Gastroscopy findings in 10 patients with nephropathia epidemica Case
Fundus Corpus Antrum Bulbus Duodenum Sum = score
1
2
3
4
5
6
7
8
9
10
++a ++ + + +
+++ +++ ++ ++ +
+ +
+++ +++ ++
+++ +++ ++ ++
++ ++ + +
+++ +++ + +
+++ +++ ++ +
+++ +++ ++ ++ ++
+++ +++ ++
7
11
2
8
10
6
8
9
12
8
a ++, Medium degree of hemorrhagic changes (as in Fig. lC); +++, high degree of hemorrhagic changes (as in Fig. 1, A and B); +, low degree of hemorrhagic changes.
VOLUME 38, NO.4, 1992
477
Figure 1. Typical gastroscopy finding in patients with nephropathia epidemica. A, Fundal part of stomach, patient 4. B, Proximal antrum, patient 4. C, Pyloric region, patient 4. 0, Duodenum, patient 2. Figure 3. Histological findings in patients with nephropathia epidemica. A, Corpus ventriculi, patient 2 subepithelial hemorrhage and extensive edema (lucent areas) (H&E; original magnification x250). B, Antrum, patient 2, extensive diffuse subepithelial hemorrhage, no inflammation (H&E; original magnification x250). C, Duodenum, patient 2, subepithelial hemorrhages in the duodenal mucosa (H&E; original magnification x50).
478
Table 2. Histological findings in eight patients with nephropathia epidemica
Patient
Corpus Antrum Bulbus Duodenum Sum = score
1
2
3
4
5
6
7
8
++a
+++ +++ ++ +
++
+ + +++
+++ +
+ +
+ + ++
+++ ++ +
+
+
+ + + +
7
9
2
5
3
4
4
6
a++, Medium degree of hemorrhagic changes; +++, high degree of hemorrhagic changes (as in Fig. 3); +, low degree of hemorrhagic changes. 15
~ 0 u
C/)
•
••
10
U
C. 0
.. U
C/)
0
'0«I
5
r = -0.8211 (p < 0.01)
• • •• • •
"
•
0L-..._ _......._ _......._ _.......
0-
5
10
15
-1
20
Gastroscopy day (from the beginning of symptoms)
2. Endoscopic hemorrhagic score from beginning of symptoms of nephropathia epidemica.
Figure
oscopy was done to the splenic flexure in one patient (case 10) and it showed similar high grade hemorrhagic changes in the entire descending colon and rectal mucosa. The mucosal blood vessels and light reflection of the colonic mucosa were normal. Histopathologic changes
All specimens from our patients showed variable amounts of hemorrhage and edema involving the lamina propria (Table 2 and Fig. 3). In three patients (cases 5, 6, and 10), there was also a mild chronic pangastritis associated with Helicobacter pylori infection. In one of these patients (case 5), there was also mild duodenal bulbitis with gastric metaplasia. In the other patients there was no gastritis. The colonic mucosa (case 10) also disclosed spotty hemorrhages and edema, but no inflammatory changes.
DISCUSSION
This study discloses for the first time that hemorrhagic gastropathy is a common finding in epidemic nephropathy. The reason for the distribution of hemVOLUME 38, NO.4, 1992
orrhages primarily in the upper part of the stomach remains obscure. However, mild hemorrhagic changes were also seen in the duodenum of seven patients, and in one patient colonoscopy showed similar changes in the large intestine. Consequently, hemorrhagic changes associated with NE may affect the entire gastrointestinal tract. As shown in this study, the endoscopic appearance is the result of intra-mucosal hemorrhage without inflammation, hence, the term hemorrhagic gastropathy rather than the older misnomer "hemorrhagic gastritis." We would like to make the point that much of what is called hemorrhagic gastritis in acute mucosal injury settings particularly in alcohol-induced as well as "stress"-type injury is in fact intra-mucosal hemorrhage without inflammation. 18 NE is usually a self-limited illness and symptoms usually subside within 1 to 3 weeks. 8 • 14 In this study hemorrhagic changes seemed to be more pronounced in those patients in whom gastroscopy was done during the first week after the onset of symptoms. Mucosal hemorrhages were absent in every patient who underwent a second gastroscopy 3 to 8 weeks later. Thus, the hemorrhagic changes of NE seem to be selflimited to the 2 to 3 months after the beginning of symptoms. Similar symptoms, i.e., gastrointestinal bleeding and acute renal failure and thrombocytopenia are produced by another condition, hemolytic-uremic syndrome, where the presentation is mainly that of intestinal and colonic involvement. 19,20 Hemorrhagic gastropathy has not been reported in hemolytic-uremic syndrome. In NE the virus itself might have a direct contribution to the capillary fragility and bleeding, with the virus being "gastrotopic." The mechanism(s) responsible for the mucosal hemorrhagic changes in NE is at present unknown. In the study presented here, the endoscopic hemorrhagic score tended to correlate inversely with the number of blood platelets, suggesting a close correlation between mucosal heplorrhages and thrombocytopenia. Previous studies suggest that thrombocytopenia may be caused by the virus itself or may be mediated by immune complexes. 21 Contributing to platelet dysfunction is likely to be the 479
acute renal insufficiency itself, i.e., uremic toxins are well known to affect platelet function, thus being additive to the hemorrhagic gastropathy.22 On the other hand, it is possible that the hemorrhagic lesions in various organs, including the gastrointestinal tract, may increase the consumption of blood platelets and thus worsen thrombocytopenia. Sternal marrow findings at the time of thrombocytopenia in NE suggest that peripheral consumption of platelets may be involved. 5 Hemorrhagic lesions ofNE were associated with edema in the lamina propria, particularly in the most severe cases, suggesting capillary damage. Extravasation of plasma and hemoconcentration during the early course of the disease may contribute to the observed mucosal hemorrhages and edema in patients with NE. Results of our study indicate that hemorrhagic gastropathy is a common finding in NE. It can be a reason for the hematemesis and melena seen in some of these patients. 12 ,15 NE should be considered as a possible cause of hemorrhagic lesions seen at gastroscopy, especially with fever of unknown origin or renal symptoms in patients from endemic areas.
REFERENCES 1. Myhrman G. En njursjukdom med egenartad symptombild (A renal disease with unusual symptomatology). Nord Med Tidsskr 1934;7:793-4. 2. Myhrman G. Nephropathia epidemica a new infectious disease in Northern Scandinavia. Acta Med Scand 1951;140:52-6. 3. Zetterholm SG. Akuta nefriter stimulerande akuta bukfall (Acute nephritis stimulating acute abdominal syndrome). Lakartidningen 1934;31:425-9. 4. Brummer-Korvenkontio M, Vaheri A, Hovi T, et al. Nephropathia epidemica: detection of antigen in bank voles and serologic diagnosis of human infection. J Infect Dis 1980;141:1314. 5. Lahdevirta J. Nephropathia epidemica in Finland: a clinical, histological and epidemiological study. Ann Clin Res
480
1971;3(suppI8):1-154. 6. Niklasson B, LeDuc JW. Epidemiology of nephropathia epidemica in Sweden. J Infect Dis 1987;155:269-76. 7. Brummer-Korvenkontio M, Henttonen H, Vaheri A. Hemorrhagic fever with renal syndrome in Finland: ecology and virology of nephropathia epidemica. Scand J Infect Dis 1982;suppl 36:88-91. 8. Lahdevirta J. The minor problem of hemorrhagic impairment in nephropathia epidemica, the mild Scandinavian form of hemorrhagic fever with renal syndrome. Rev Infect Dis 1989;11(suppI4):860S-3S. 9. Editorial. Hantavirus disease. Lancet 1990;336:407-8. 10. Lee HW, van der Groen G. Hemorrhagic fever with renal syndrome. Prog Med ViroI1989;36:62-102. 11. Svedmyr A, Lee P-W, Goldgaber D, et al. Antigenic differences between European and East Asian Strains of HFRS virus. Scand J Infect Dis 1982;suppI36:86-7. 12. Settergren B, Jato P, Trollfors B, Wadell G, Norrby SR. Hemorrhagic complications and other clinical findings in nephropathia epidemica in Sweden: a study of 355 serologically verified cases. J Infect Dis 1988;157:380-2. 13. Saari M, Alanko H, Jarvi J, Vetoniemi-Korhonen S-L, Rasanen O. Nephropathia epidemica, The Scandinavian form of hemorrhagic fever with renal syndrome. JAMA 1977;238:874-7. 14. Lahdevirta J, Savoia J, Brummer-Korvenkontio M, Berndt R, Illikainen R, Vaheri A. Clinical and serological diagnosis of nephropathia epidemica, the mild type of hemorrhagic fever with renal syndrome. J Infect 1984;9:230-8. 15. Settergren B, Jato P, Trollfors B, Wadell G, Norrby SR. Clinical characteristics of nephropathia epidemica in Sweden: prospective study of 74 cases. Rev Infect Dis 1989;11:921-7. 16. Zuckerman G, Cort D, Shuman R. Stress ulcer syndrome. J Intensive Care Med 1988;3:21-31. 17. Hedman K, Vaheri A, Brummer-Korvenkontio M. Rapid diagnosis of hantavirus disease with an IgG-avidity assay. Lancet 1991;2:1353-6. 18. Laine L, Weinstein WM. Histology of alcoholic hemorrhagic gastritis: a prospective evaluation. Gastroenterology 1988;94:1254-62. 19. Whitington P, Friedman A, Chesney R. Gastrointestinal disease in the hemolytic-uremic syndrome. Gastroenterology 1979;76:728-33. 20. Tzipori RS, Wachsmuth IK, Chapman C, et al. The pathogenesis of hemorrhagic colitis caused by Escherichia coli 0157:H7 in gnotobiotic piglets. J Infect Dis 1986;154:712-6. 21. Cosgriff TM. Virus and hemostasis. Rev Infect Dis 1989;11(suppI4):672S-88S. 22. Carvalho AC. Acquired platelet dysfunction in patients with uremia. Hematol Oncol Clin North Am 1990;4:129-43.
GASTROINTESTINAL ENDOSCOPY
Hemorrhagic gastropathy in epidemic nephropathy H. Nuutinen, MD, M. Vuoristo, M. Farkkila, MD, A. Kahri, K. Seppala, MD, V. Valtonen, T. Joutsiniemi, MD, T. Miettinen,
MD MD MD MD
Helsinki, Finland
A patient with epidemic nephropathy (NE) and with gastrointestinal symptoms and hemorrhagic gastropathy prompted us to study further 10 consecutive patients with NE. Gastroscopy was carried out within 1 to 4 weeks after the beginning of the symptoms, and in every case a hemorrhagic gastropathy was observed. Hemorrhagic lesions were more marked, the shorter the elapsed time interval from the beginning of symptoms. Hemorrhagic changes were always more prominent in the proximal than in the distal part of the stomach. In 7 of 10 patients lesions were also observed in the duodenum. Colonoscopy was done in one patient and it showed similar spotty hemorrhages, suggesting that hemorrhagic lesions were not limited to the gastroduodenal mucosa only. Histological studies disclosed that the hemorrhagic lesions were associated with edema in the lamina propria, but without inflammatory changes. Follow-up gastroscopy in three patients 3 to 8 weeks later showed disappearance of hemorrhagic lesions in every patient. Thus, these results show for the first time that hemorrhagic gastropathy is a common finding in NE, and it may explain the abdominal symptoms and gastrointestinal bleeding in some of these patients. However, the mechanism of the hemorrhagic lesions needs further exploration. (Gastrointest Endosc 1992;38:476-480)
Nephropathia epidemica (NE) is the Scandinavian form of hemorrhagic fever with renal syndrome. NE was first described in 1934 in Swedish patients by Myhrman1,2 and Zetterholm. 3 Later, the disease was characterized as a viral Zoonosis in rodents, the bank vole being the natural host of the virus. 4 The hemorrhagic manifestations of NE are so mild that initially, as its name implies, NE was not considered as a hemorrhagic fever. The main endemic area for NE is Scandinavia, Western Europe, the Balkans, and the European regions ofthe Soviet Union. The occurrence clearly shows seasonal fluctuations with the largest proportion of cases occurring in winter from October to March, although there is also a smaller peak in Received December 11,1991. For revision January 8,1992. Accepted March 5, 1992. From the Second Department of Medicine, University Central Hospital of Helsinki, Department of Pathology, University of Helsinki, and the Deaconess Hospital, Helsinki, Finland. Reprint requests: Hannu Nuutinen, MD, Division of General Medical Sciences, Gastrointestinal Research Unit, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195. Presented in part at the XXIII Nordic Congress of Gastroenterology, Reykjavik, Iceland, June 14-16, 1990.
476
August. 5- 7 There are several hundred cases of NE patients hospitalized every year in Finland. However, there are at least 10 to 20 times more cases that are subclinical or undiagnosed, because the frequency of seropositivity for NE in the Finnish population of 5 million is 2 to 20%.7,8 NE is clinically, histologically, and epidemiologically similar to Korean hemorrhagic fever except that hemorrhagic manifestations are fewer and mortality is lower. 8 These two disorders are caused by two closely related viruses, Puumala virus and Hantaan virus, respectively.9-11 Although the clinical picture of NE is dominated by renal manifestations, most patients also have abdominal pain, nausea, vomiting, and diarrhea. 8 , 12-14 Minor hemorrhagic changes (epistaxis, petechiae, gross macroscopic hematuria, and metrorrhagia) have been reported in 5 to 40% of patients. 12- 15 Hematemesis and melena may also occur in some patients. 12 , 15 However, the reason for the abdominal symptoms of NE has remained obscure and to the best of our knowledge, no endoscopic reports of NE have been previously published. GASTROINTESTINAL ENDOSCOPY
Acute renal failure itself is of course one risk factor for gastrointestinal bleeding, particularly in intensive care units, and it may contribute to the hemorrhages observed in patients with NE. 16 However, in NE, the gastrointestinal symptoms frequently herald the onset of azotemia. Extensive retroperitoneal or peritoneal edema resulting from extravasation of plasma due to increased capillary permeability could be a factor that is responsible for the severe abdominal pain. 10 Because of our own experience with a patient with NE presenting with melena and hemorrhagic changes on gastroscopy, we decided to carry out a prospective endoscopic study in this disease. MATERIALS AND METHODS
This study consisted of 10 consecutive patients, 4 women and 6 men of 29 to 55 years old (mean, 35 years) with typical symptoms of NE (i.e., renal symptoms (10 of 10), acute onset of fever (10 of 10), headache (9 of 10), backache (7 of 10), myalgia (8 of 10), and blurred vision (7 of 10)). All except one (case 6) also had nausea and abdominal pain. Our first patient (case 1), whose endoscopic findings actually initiated this study, reported black stools 1 day before hospitalization and another patient (case 9) had hematemesis and melena. In one patient (case 8), blood pressure could not be measured on admission. After volume repletion, blood pressure increased to 100/60 mm Hg, and this patient also had the highest hemoconcentration. All other patients were normotensive on admission. Urinary protein and hemoglobin was positive in all our patients. The serum creatinine was between 116 and 1621 JLmoljliter (reference value <115), hemoglobin between 88 and 211 g/liter (women, 125 to 160 and men, 135 to 180), thrombocytes between 8 and 118 Eq/liter (140 to 320), Creactive protein between 40 and 201 mg/liter (0 to 10). In every case the diagnosis was confirmed by a positive serology for NE. l7 All patients underwent gastroscopic examination within 1 to 4 weeks after the beginning of symptoms. One of our patients (case 2) came to gastroscopy because of unknown fever and abdominal pain, and NE was diagnosed after hemorrhagic changes were seen during gastroscopy. Gastroscopic findings were graded as follows: 1. High grade: when over 60% of the epithelium was covered with hemorrhagic changes (as in Fig. 1, A and B).
2. Medium grade: when 20 to 60% of the epithelium was covered with hemorrhagic changes. 3. Low grade: less than 20% of the epithelium was covered with hemorrhagic changes. In three patients (cases 3, 4, and 9) a follow-up gastroscopy was done 1 and 2 months later and one patient (case 1) also underwent a colonoscopy. In eight patients, biopsies were taken from the descending duodenum, duodenal bulb, and gastric antral and body mucosa for histological analysis. In two patients (cases 9 and 10), biopsies were not taken because of marked thrombocytopenia at the time of gastroscopy. The gastroscopic biopsies were fixed in 10% formalin, blocked in paraffin, and stained with hematoxylin and eosin. A single observer (A. K), blinded to the clinical or endoscopic results of the patients, evaluated the histological changes. Histological changes were divided into three categories: 1. High grade: multiple hemorrhages and edema which involved more than 60% of the lamina propria (as in Fig. 3). 2. Medium grade: between high and low grade (20 to 60%). 3. Only a small portion of lamina propria «20%) showed hemorrhages, only slight or no edema. Pearson's correlation test was used in the calculations.
RESULTS Endoscopic
As seen in Table 1 and Figure 1, gastroscopy revealed different degrees of hemorrhagic gastropathy in every patient. In seven patients hemorrhages were also found in the first or second part of the duodenum, whereas the esophageal mucosa was normal in all patients. In every patient the hemorrhagic changes were more prominent in the proximal part of the stomach (Table 2 and Fig. 1). In three patients (cases 3,4, and 9) a second gastroscopy was done 4, 8, and 3 weeks later, respectively, and in every case macroscopic and microscopic hemorrhagic changes had disappeared. The endoscopic hemorrhagic score (Table 1) was higher in those patients in whom gastroscopy was done earlier in the course of the disease (Fig. 2). The endoscopic hemorrhagic score tended to be highest in the patients who had the lowest platelet levels (r = -0.624, p < 0.10) at the time of gastroscopy. Colon-
Table 1. Gastroscopy findings in 10 patients with nephropathia epidemica Case
Fundus Corpus Antrum Bulbus Duodenum Sum = score
1
2
3
4
5
6
7
8
9
10
++a ++ + + +
+++ +++ ++ ++ +
+ +
+++ +++ ++
+++ +++ ++ ++
++ ++ + +
+++ +++ + +
+++ +++ ++ +
+++ +++ ++ ++ ++
+++ +++ ++
7
11
2
8
10
6
8
9
12
8
a ++, Medium degree of hemorrhagic changes (as in Fig. lC); +++, high degree of hemorrhagic changes (as in Fig. 1, A and B); +, low degree of hemorrhagic changes.
VOLUME 38, NO.4, 1992
477
Figure 1. Typical gastroscopy finding in patients with nephropathia epidemica. A, Fundal part of stomach, patient 4. B, Proximal antrum, patient 4. C, Pyloric region, patient 4. 0, Duodenum, patient 2. Figure 3. Histological findings in patients with nephropathia epidemica. A, Corpus ventriculi, patient 2 subepithelial hemorrhage and extensive edema (lucent areas) (H&E; original magnification x250). B, Antrum, patient 2, extensive diffuse subepithelial hemorrhage, no inflammation (H&E; original magnification x250). C, Duodenum, patient 2, subepithelial hemorrhages in the duodenal mucosa (H&E; original magnification x50).
478
Table 2. Histological findings in eight patients with nephropathia epidemica
Patient
Corpus Antrum Bulbus Duodenum Sum = score
1
2
3
4
5
6
7
8
++a
+++ +++ ++ +
++
+ + +++
+++ +
+ +
+ + ++
+++ ++ +
+
+
+ + + +
7
9
2
5
3
4
4
6
a++, Medium degree of hemorrhagic changes; +++, high degree of hemorrhagic changes (as in Fig. 3); +, low degree of hemorrhagic changes. 15
~ 0 u
C/)
•
••
10
U
C. 0
.. U
C/)
0
'0«I
5
r = -0.8211 (p < 0.01)
• • •• • •
"
•
0L-..._ _......._ _......._ _.......
0-
5
10
15
-1
20
Gastroscopy day (from the beginning of symptoms)
2. Endoscopic hemorrhagic score from beginning of symptoms of nephropathia epidemica.
Figure
oscopy was done to the splenic flexure in one patient (case 10) and it showed similar high grade hemorrhagic changes in the entire descending colon and rectal mucosa. The mucosal blood vessels and light reflection of the colonic mucosa were normal. Histopathologic changes
All specimens from our patients showed variable amounts of hemorrhage and edema involving the lamina propria (Table 2 and Fig. 3). In three patients (cases 5, 6, and 10), there was also a mild chronic pangastritis associated with Helicobacter pylori infection. In one of these patients (case 5), there was also mild duodenal bulbitis with gastric metaplasia. In the other patients there was no gastritis. The colonic mucosa (case 10) also disclosed spotty hemorrhages and edema, but no inflammatory changes.
DISCUSSION
This study discloses for the first time that hemorrhagic gastropathy is a common finding in epidemic nephropathy. The reason for the distribution of hemVOLUME 38, NO.4, 1992
orrhages primarily in the upper part of the stomach remains obscure. However, mild hemorrhagic changes were also seen in the duodenum of seven patients, and in one patient colonoscopy showed similar changes in the large intestine. Consequently, hemorrhagic changes associated with NE may affect the entire gastrointestinal tract. As shown in this study, the endoscopic appearance is the result of intra-mucosal hemorrhage without inflammation, hence, the term hemorrhagic gastropathy rather than the older misnomer "hemorrhagic gastritis." We would like to make the point that much of what is called hemorrhagic gastritis in acute mucosal injury settings particularly in alcohol-induced as well as "stress"-type injury is in fact intra-mucosal hemorrhage without inflammation. 18 NE is usually a self-limited illness and symptoms usually subside within 1 to 3 weeks. 8 • 14 In this study hemorrhagic changes seemed to be more pronounced in those patients in whom gastroscopy was done during the first week after the onset of symptoms. Mucosal hemorrhages were absent in every patient who underwent a second gastroscopy 3 to 8 weeks later. Thus, the hemorrhagic changes of NE seem to be selflimited to the 2 to 3 months after the beginning of symptoms. Similar symptoms, i.e., gastrointestinal bleeding and acute renal failure and thrombocytopenia are produced by another condition, hemolytic-uremic syndrome, where the presentation is mainly that of intestinal and colonic involvement. 19,20 Hemorrhagic gastropathy has not been reported in hemolytic-uremic syndrome. In NE the virus itself might have a direct contribution to the capillary fragility and bleeding, with the virus being "gastrotopic." The mechanism(s) responsible for the mucosal hemorrhagic changes in NE is at present unknown. In the study presented here, the endoscopic hemorrhagic score tended to correlate inversely with the number of blood platelets, suggesting a close correlation between mucosal heplorrhages and thrombocytopenia. Previous studies suggest that thrombocytopenia may be caused by the virus itself or may be mediated by immune complexes. 21 Contributing to platelet dysfunction is likely to be the 479
acute renal insufficiency itself, i.e., uremic toxins are well known to affect platelet function, thus being additive to the hemorrhagic gastropathy.22 On the other hand, it is possible that the hemorrhagic lesions in various organs, including the gastrointestinal tract, may increase the consumption of blood platelets and thus worsen thrombocytopenia. Sternal marrow findings at the time of thrombocytopenia in NE suggest that peripheral consumption of platelets may be involved. 5 Hemorrhagic lesions ofNE were associated with edema in the lamina propria, particularly in the most severe cases, suggesting capillary damage. Extravasation of plasma and hemoconcentration during the early course of the disease may contribute to the observed mucosal hemorrhages and edema in patients with NE. Results of our study indicate that hemorrhagic gastropathy is a common finding in NE. It can be a reason for the hematemesis and melena seen in some of these patients. 12 ,15 NE should be considered as a possible cause of hemorrhagic lesions seen at gastroscopy, especially with fever of unknown origin or renal symptoms in patients from endemic areas.
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GASTROINTESTINAL ENDOSCOPY