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Hepatic Veno-Occlusive Disease Originating in Ecuador
GASTROENTEROLOGY 70:105-108, 1976 Copyright © 1976 by The Williams & Wilkins Co.
Vol. 70, No.1 Printed in U.S.A.
CASE REPORTS HEPATIC VENO-OCCLUSIVE DISEASE ORIGINATING IN ECUADOR L. LYFORD, M.D., F.A.C.P.
CHARLES
M.D., GERARDO G. VERGARA, M.D., AND DONALD D. MOELLER,
University of Kansas Medical Center and Trinity Luthemn Hospital, Kansas City, Missouri
A case of hepatic veno-occlusive disease manifested by massive ascites is described in a 35-year-old female. She had consumed an herbal tea containing a Crotalaria plant species for 6 months prior to evaluation. Inferior vena cava and hepatic veins were patent by angiography. Liver biopsy showed histological changes typical of hepatic veno-occlusive disease, consisting of centrilobular congestion and sublobular hepatic vein obstruction. Complete clinical, biochemical, and histological recovery was documented 1 year after ingestion of the brew was discontinued. This is the first case known to be reported from Ecuador and the first to be diagnosed in the United States. Veno-occlusive disease of the liver (VOD) is a diffuse occlusive primary endophlebitis of the central and sublobular veins associated with congestion, hemorrhage, and hepatocellular necrosis. I, 2 Acutely, it presents clinically with hepatomegaly, ascites, and edema. 3 It may progress to cirrhosis, indistinguishable from cirrhosis of other causes, massive esophageal bleeding, or it may resolve completely. 1,4, 5 Plant-induced venoocclusive disease in man is widely distributed with cases reported predominantly from the West Indies, Africa, India, South America, and the Middle East. 6 To the best of our knowledge, human hepatic venoocclusive disease induced by plant toxin has not previously been reported to originate from Ecuador, nor has the diagnosis of this disorder previously been made in the United States. The reservoir for this disease is great and may be more frequent than clinically suspected. The purpose of this report is to describe a patient with toxin-induced hepatic veno-occlusive disease and to review the literature briefly. Case Report A 35-year-old female citizen of Quito, Ecuador experienced arthralgias for 3 years for which she sought medical advice and received treatment with indomethacin and phenylbutazone. Upon consulting an herbologist in ~uito in March 1973, she received 7 containers, each with leaves of local plants. Names of all the plants were obtained and included that of Crotalaria juncea. For 6 weeks she consumed 2 liters, and subsequently 1 liter daily of a tea made from these leaves. In June 1973, nausea and epigastric discomfort were noted, and in August 1973, Received January 28, 1975. Accepted July 8, 1975. Address communications to: Charles L. Lyford, M.D., 167 So. Conwell, Casper, Wyoming 82601. Appreciation is expressed to Dr. Peter J. Scheuer of The Royal Free Hospital, London, for assisting in interpretation of histological materials, and to Dr. Constantine Arvanitakis of the University of Kansas Medical Center for manuscript review. 105
abdominal distention occurred. At that time hospitalization in Ecuador revealed portal hypertension due to liver cirrhosis. She was transferred to Trinity Lutheran Hospital, Kansas City, Missouri, in September 1973, 7 months after beginning ingestion of the tea. Physical examination revealed marked ascites with prominent superficial abdominal veins and hepatomegaly without splenomegaly. Uterine enlargement and a positive pregnancy test indicated that the patient was pregnant. Pertinent laboratory findings were: serum albumin, 2.2 g per 100 ml; globulin, 2.6 g per 100 ml; alkaline phosphatase, 122 mU per ml (normal 45 to 85); cholesterol, 60 mg per 100 ml; bilirubin, 0.6 mg per 100 ml; SGOT, 37 mU per ml; LDH, 185 mU per m!. Prothrombin time was 15.4 sec (11.2 sec, control). Abdominal paracentesis showed that ascitic fluid was a transudate without malignant cells. Right heart catheterization revealed normal right heart, superior and inferior venocaval pressures, and a hepatic wedge pressure fo 28 mm Hg (normal, up to 10 mm Hg). Hepatic venography and inferior venocavogram showed patent main hepatic veins and inferior vena cava. Exploratory laparotomy revealed voluminous ascites, but no abdominal malignancy or major vein occlusion. Portal vein pressure was 28 cm of water (normal less than 20 cm) and the liver appeared large and congested. A side-to-side portocaval shunt, wedge liver biopsy, and therapeutic abortion were carried out. Postoperative recovery occurred slowly with albumin infusion, diuretics, and dietary sodium and protein restriction. Eight weeks postoperatively she returned to Ecuador and remained free of ascites. One year later she returned to the United States with no complaints, and normal physical and laboratory examination. A percutaneous liver biopsy showed complete resoiution of pathological changes.
Pathology The first percutaneous liver biopsy showed centrilobular congestion and marked red cell extravasation between hepatocytes and into Disse's space, suggesting hepatic vein occlusion (fig. 1). The wedge biopsy specimen obtained at laparotomy showed the congestion of blood surrounding the central spaces with portal areas remaining uninvolved (fig. 2). Several sublobular veins disclosed partial to complete obliteration of the
106
Vol. 70, No.1
CASE REPORTS
FIG. 1. Red cell extravasation between hepatocytes (arrow) and into Disse's space (S, Sinusoid) (H & E, x 560).
FIG. 2. Wedge liver biopsy showing congestion of blood surrounding central spaces with sparing of portal triad areas (P, portal triad) (H & E, x 30).
lumen by edema and subendothelial connective tissue (fig. 3). Occasional hepatic vein radicles showed recanalization. Thrombi or inflammation were not evident. These changes were consistent with the diagnosis of hepatic veno-occlusive disease.
Discussion The case reported here has all the characteristics of veno-occlusive liver disease. A history of ingestion of brew containing Crotalaria, clinical findings, and the
January 1976
CASE REPORTS
107
FIG. 3. Wedge liver biopsy showing partial to complete luminal obliteration of two sublobular veins by edema and subendothelial connective tissue (reticulin stain, x 110).
typical histological findings of sublobular hepatic vein occlusion with extensive centrilobular congestion were diagnostic of hepatic veno-occlusive disease. This diagnosis is further confirmed by findings of increased hepatic vein wedge pressure and portal pressure in the absence of right heart failure or main hepatic vein occlusion. In addition, this case illustrates the clinical and histological reversibility of hepatic veno-occlusive disease. Hepatic veno-occlusive disease is caused by ingestion of certain species of plants belonging to the genera Senecio, Crotalaria, Heliotropium, and Cynoglossum. 7 The common characteristic of these plants is the presence of pyrrolizidine alkaloids. The hepatic pathology consists of liver degeneration, necrosis, and cirrhosis. Cushny 8 and Watt 9 documented cirrhosis in livestock secondary to Senecio ingestion and produced the characteristic histopathological changes in experimental animals after administration of senecifolin and sencifolidine, extracted from Senecio latifolus. Will mot and Robertson lO reported the first cases in persons consuming bread made from flour contaminated by Senecio ilicifolius and Senecio burchelli. A number of similar cases were later reported l l-l 3 but Selzer and Parker l4 subsequently described Senecio poisoning, labeling it as Chiari's syndrome. Bras, Jelliffe, and Stuart l5 first coined the term veno-occlusive disease in Jamaican children consuming "bush tea", thus implicating plants which contain pyrrolizidine radicles as a cause of human disease. Clinically, the entity has been divided into acute, subacute, and chronic stages with the natural
history of the disease ranging from complete clinical recovery to fatal esophageal variceal bleeding and hepatic failure. 14 Although in most cases pyrrolizidine alkaloids were implicated, Scott et al. 16 described the same entity in a man receiving hepatic irradiation and alkylating agents for metastatic seminoma. The primary histopathological lesion was at first considered to be deposition of thrombi in the centrilobular, sublobular, and medium-sized hepatic veins. Stirling, Bras, and Urguhart,17 however, failed to show staining characteristics of newly formed thrombus in immunofluorescent staining studies. The typical early lesions consisted of delicate fibers which appeared to arise from cells, staining for collagen and fibrin. These fibers were related to thickening of vein walls. The thickened, disorganized vein wall, along with fibrin deposits surrounding the veins and collapse of the reticulin framework in the centrilobular zones, caused obstruction of blood flow from the sinusoids. Oral, intravenous, or intraperitoneal administration of pyrrolizidine alkaloids to experimental animals resulted in the typical liver lesions. IS Mattocks l9 demonstrated that the parent pyrrolizidine alkaloids are converted to pyrrole derivatives by liver tissue. Butler et al. 20 noted that the pyrrole alkaloids produced changes in structures primarily exposed, such as alveolar edema and alveolar wall thickening with intravenous administration, portal vein necrosis, and thrombosis with mesenteric vein administration. These studies suggest that hepatocellular enzymatic conversion of the relatively nontoxic pyrrolizidine alkaloids to the pyrrole derivatives yields
108
CASE REPORTS
Vol. 70, No.1
of the hepatic cirrhosis of cattle (Pictou, Molteno, or Winton toxic substances which in turn result in a postsinusoid disease). J Pharmacol Exp Ther 2:531-548, 1910-1911 obstruction. The obliterative lesion may be the result of direct injury to the vein wall with subsequent deposition 9. Watt HE: The alkaloids of Senecio latifolius. J Chern Soc 95:466-477, 1909 of collagen and reticular tissue, or centrilobular cell 10. Willmot FC, Robertson GW: Senecio disease or cirrhosis of the injury resulting in the formation of blood lakes and liver due to Senecio poisoning. Lancet 2:848-489, 1920 occlusion of the vessel wall. 11. McFarlane AL, Branday WJ: Hepatic enlargement with ascites in REFERENCES 1. Jelliffe DB, Bras G, Stuart KL: The clinical picture ofveno-occlusive disease of the liver in Jamacian children. Ann Trop Med Parasitol 48:386-396, 1954 2. Bras G, Jelliffe DB, Stuart KL: Veno-occlusive disease ofliver with non portal type of cirrhosis, occurring in Jamaican. Arch Pathol 57:285-300, 1954 3. Bras G: Aspects of hepatic vascular lesions. International Academy of Pathology Monograph. The Liver. Edited by EA Gall, FK Mostofi. Baltimore, The Williams & Wilkins Company, 1973, p 412-430 4. Brooks SEH, Miller CG, McKenzick K, et al: Acute veno-occlusive disease of the liver. Fine structure in Jamaican children. Arch Pathol 89:507-520, 1970 5. Stuart KL, Bras G: Veno-occlusive disease of the liver. Q J Med 26:291-315, 1957 6. Hill KR: The world-wide distribution of Seneciosis in man and animals. Proc R Soc Med 53:281-283, 1960 7. Bull LB, Culvenor CCJ, Dick AT: The Pyrrolizidine Alkaloids. Their chemistry, pathogenicity and other biochemical properties. New York, American Elsevier Publishing Company, Inc. 8. Cushny AR: On the action of Senecio alkaloids and the causation
children. Br Med J 2:838-840, 1945 12. Hill KR, Rhodes K, Stafford JL, et al: Serous hepatosis: A pathogenesis of hepatic fibrosis in Jamaican children-preliminary report. Br Med J 1:117-122, 1953 13. Teilum G: Endophlebitis hepatica obliterans. Acta Pathol MicrobioI Scand 26:157-166,1949 14. Selzer G, Parker RGF: Senecio poisoning exhibiting as Chiari's syndrome. A report of twelve cases. Am J PathoI27:885-900, 1951 15. Bras, G, Jelliffe DB, Stuart KL: Histologic observations on hepatic disease in Jamaican infants and children. Doc Med Geog et Trop 6:43-60, 1954 16. Scott RB, Budinger JM, Prendergast RAM, et al: Hepatic venoocclusive syndrome in an American adult. Gastroenterology 42:631-636, 1962 17. Stirling GA, Bras G, Urquhart AE: The early lesions in veno-occlusive disease of the liver. Arch Dis Child 37:535-538, 1962 18. McLean EK: The toxic actions ofpyrrolizidine (Senecio) alkaloids. Pharmacol Rev 22:429-483, 1970 19. Mattocks AR: Dihydropyrrolizine derivatives from unsaturated pyrrolizidine alkaloids. J Chern Soc 8:1155-1162, 1969 20. Butler WH, Mattocks AR, Barnes JM: Lesions in the liver and lungs of rats given pyrrole derivatives of pyrrolizidine alkaloids. J Pathol 100:169-175, 1970
Vol. 70, No.1 Printed in U.S.A.
CASE REPORTS HEPATIC VENO-OCCLUSIVE DISEASE ORIGINATING IN ECUADOR L. LYFORD, M.D., F.A.C.P.
CHARLES
M.D., GERARDO G. VERGARA, M.D., AND DONALD D. MOELLER,
University of Kansas Medical Center and Trinity Luthemn Hospital, Kansas City, Missouri
A case of hepatic veno-occlusive disease manifested by massive ascites is described in a 35-year-old female. She had consumed an herbal tea containing a Crotalaria plant species for 6 months prior to evaluation. Inferior vena cava and hepatic veins were patent by angiography. Liver biopsy showed histological changes typical of hepatic veno-occlusive disease, consisting of centrilobular congestion and sublobular hepatic vein obstruction. Complete clinical, biochemical, and histological recovery was documented 1 year after ingestion of the brew was discontinued. This is the first case known to be reported from Ecuador and the first to be diagnosed in the United States. Veno-occlusive disease of the liver (VOD) is a diffuse occlusive primary endophlebitis of the central and sublobular veins associated with congestion, hemorrhage, and hepatocellular necrosis. I, 2 Acutely, it presents clinically with hepatomegaly, ascites, and edema. 3 It may progress to cirrhosis, indistinguishable from cirrhosis of other causes, massive esophageal bleeding, or it may resolve completely. 1,4, 5 Plant-induced venoocclusive disease in man is widely distributed with cases reported predominantly from the West Indies, Africa, India, South America, and the Middle East. 6 To the best of our knowledge, human hepatic venoocclusive disease induced by plant toxin has not previously been reported to originate from Ecuador, nor has the diagnosis of this disorder previously been made in the United States. The reservoir for this disease is great and may be more frequent than clinically suspected. The purpose of this report is to describe a patient with toxin-induced hepatic veno-occlusive disease and to review the literature briefly. Case Report A 35-year-old female citizen of Quito, Ecuador experienced arthralgias for 3 years for which she sought medical advice and received treatment with indomethacin and phenylbutazone. Upon consulting an herbologist in ~uito in March 1973, she received 7 containers, each with leaves of local plants. Names of all the plants were obtained and included that of Crotalaria juncea. For 6 weeks she consumed 2 liters, and subsequently 1 liter daily of a tea made from these leaves. In June 1973, nausea and epigastric discomfort were noted, and in August 1973, Received January 28, 1975. Accepted July 8, 1975. Address communications to: Charles L. Lyford, M.D., 167 So. Conwell, Casper, Wyoming 82601. Appreciation is expressed to Dr. Peter J. Scheuer of The Royal Free Hospital, London, for assisting in interpretation of histological materials, and to Dr. Constantine Arvanitakis of the University of Kansas Medical Center for manuscript review. 105
abdominal distention occurred. At that time hospitalization in Ecuador revealed portal hypertension due to liver cirrhosis. She was transferred to Trinity Lutheran Hospital, Kansas City, Missouri, in September 1973, 7 months after beginning ingestion of the tea. Physical examination revealed marked ascites with prominent superficial abdominal veins and hepatomegaly without splenomegaly. Uterine enlargement and a positive pregnancy test indicated that the patient was pregnant. Pertinent laboratory findings were: serum albumin, 2.2 g per 100 ml; globulin, 2.6 g per 100 ml; alkaline phosphatase, 122 mU per ml (normal 45 to 85); cholesterol, 60 mg per 100 ml; bilirubin, 0.6 mg per 100 ml; SGOT, 37 mU per ml; LDH, 185 mU per m!. Prothrombin time was 15.4 sec (11.2 sec, control). Abdominal paracentesis showed that ascitic fluid was a transudate without malignant cells. Right heart catheterization revealed normal right heart, superior and inferior venocaval pressures, and a hepatic wedge pressure fo 28 mm Hg (normal, up to 10 mm Hg). Hepatic venography and inferior venocavogram showed patent main hepatic veins and inferior vena cava. Exploratory laparotomy revealed voluminous ascites, but no abdominal malignancy or major vein occlusion. Portal vein pressure was 28 cm of water (normal less than 20 cm) and the liver appeared large and congested. A side-to-side portocaval shunt, wedge liver biopsy, and therapeutic abortion were carried out. Postoperative recovery occurred slowly with albumin infusion, diuretics, and dietary sodium and protein restriction. Eight weeks postoperatively she returned to Ecuador and remained free of ascites. One year later she returned to the United States with no complaints, and normal physical and laboratory examination. A percutaneous liver biopsy showed complete resoiution of pathological changes.
Pathology The first percutaneous liver biopsy showed centrilobular congestion and marked red cell extravasation between hepatocytes and into Disse's space, suggesting hepatic vein occlusion (fig. 1). The wedge biopsy specimen obtained at laparotomy showed the congestion of blood surrounding the central spaces with portal areas remaining uninvolved (fig. 2). Several sublobular veins disclosed partial to complete obliteration of the
106
Vol. 70, No.1
CASE REPORTS
FIG. 1. Red cell extravasation between hepatocytes (arrow) and into Disse's space (S, Sinusoid) (H & E, x 560).
FIG. 2. Wedge liver biopsy showing congestion of blood surrounding central spaces with sparing of portal triad areas (P, portal triad) (H & E, x 30).
lumen by edema and subendothelial connective tissue (fig. 3). Occasional hepatic vein radicles showed recanalization. Thrombi or inflammation were not evident. These changes were consistent with the diagnosis of hepatic veno-occlusive disease.
Discussion The case reported here has all the characteristics of veno-occlusive liver disease. A history of ingestion of brew containing Crotalaria, clinical findings, and the
January 1976
CASE REPORTS
107
FIG. 3. Wedge liver biopsy showing partial to complete luminal obliteration of two sublobular veins by edema and subendothelial connective tissue (reticulin stain, x 110).
typical histological findings of sublobular hepatic vein occlusion with extensive centrilobular congestion were diagnostic of hepatic veno-occlusive disease. This diagnosis is further confirmed by findings of increased hepatic vein wedge pressure and portal pressure in the absence of right heart failure or main hepatic vein occlusion. In addition, this case illustrates the clinical and histological reversibility of hepatic veno-occlusive disease. Hepatic veno-occlusive disease is caused by ingestion of certain species of plants belonging to the genera Senecio, Crotalaria, Heliotropium, and Cynoglossum. 7 The common characteristic of these plants is the presence of pyrrolizidine alkaloids. The hepatic pathology consists of liver degeneration, necrosis, and cirrhosis. Cushny 8 and Watt 9 documented cirrhosis in livestock secondary to Senecio ingestion and produced the characteristic histopathological changes in experimental animals after administration of senecifolin and sencifolidine, extracted from Senecio latifolus. Will mot and Robertson lO reported the first cases in persons consuming bread made from flour contaminated by Senecio ilicifolius and Senecio burchelli. A number of similar cases were later reported l l-l 3 but Selzer and Parker l4 subsequently described Senecio poisoning, labeling it as Chiari's syndrome. Bras, Jelliffe, and Stuart l5 first coined the term veno-occlusive disease in Jamaican children consuming "bush tea", thus implicating plants which contain pyrrolizidine radicles as a cause of human disease. Clinically, the entity has been divided into acute, subacute, and chronic stages with the natural
history of the disease ranging from complete clinical recovery to fatal esophageal variceal bleeding and hepatic failure. 14 Although in most cases pyrrolizidine alkaloids were implicated, Scott et al. 16 described the same entity in a man receiving hepatic irradiation and alkylating agents for metastatic seminoma. The primary histopathological lesion was at first considered to be deposition of thrombi in the centrilobular, sublobular, and medium-sized hepatic veins. Stirling, Bras, and Urguhart,17 however, failed to show staining characteristics of newly formed thrombus in immunofluorescent staining studies. The typical early lesions consisted of delicate fibers which appeared to arise from cells, staining for collagen and fibrin. These fibers were related to thickening of vein walls. The thickened, disorganized vein wall, along with fibrin deposits surrounding the veins and collapse of the reticulin framework in the centrilobular zones, caused obstruction of blood flow from the sinusoids. Oral, intravenous, or intraperitoneal administration of pyrrolizidine alkaloids to experimental animals resulted in the typical liver lesions. IS Mattocks l9 demonstrated that the parent pyrrolizidine alkaloids are converted to pyrrole derivatives by liver tissue. Butler et al. 20 noted that the pyrrole alkaloids produced changes in structures primarily exposed, such as alveolar edema and alveolar wall thickening with intravenous administration, portal vein necrosis, and thrombosis with mesenteric vein administration. These studies suggest that hepatocellular enzymatic conversion of the relatively nontoxic pyrrolizidine alkaloids to the pyrrole derivatives yields
108
CASE REPORTS
Vol. 70, No.1
of the hepatic cirrhosis of cattle (Pictou, Molteno, or Winton toxic substances which in turn result in a postsinusoid disease). J Pharmacol Exp Ther 2:531-548, 1910-1911 obstruction. The obliterative lesion may be the result of direct injury to the vein wall with subsequent deposition 9. Watt HE: The alkaloids of Senecio latifolius. J Chern Soc 95:466-477, 1909 of collagen and reticular tissue, or centrilobular cell 10. Willmot FC, Robertson GW: Senecio disease or cirrhosis of the injury resulting in the formation of blood lakes and liver due to Senecio poisoning. Lancet 2:848-489, 1920 occlusion of the vessel wall. 11. McFarlane AL, Branday WJ: Hepatic enlargement with ascites in REFERENCES 1. Jelliffe DB, Bras G, Stuart KL: The clinical picture ofveno-occlusive disease of the liver in Jamacian children. Ann Trop Med Parasitol 48:386-396, 1954 2. Bras G, Jelliffe DB, Stuart KL: Veno-occlusive disease ofliver with non portal type of cirrhosis, occurring in Jamaican. Arch Pathol 57:285-300, 1954 3. Bras G: Aspects of hepatic vascular lesions. International Academy of Pathology Monograph. The Liver. Edited by EA Gall, FK Mostofi. Baltimore, The Williams & Wilkins Company, 1973, p 412-430 4. Brooks SEH, Miller CG, McKenzick K, et al: Acute veno-occlusive disease of the liver. Fine structure in Jamaican children. Arch Pathol 89:507-520, 1970 5. Stuart KL, Bras G: Veno-occlusive disease of the liver. Q J Med 26:291-315, 1957 6. Hill KR: The world-wide distribution of Seneciosis in man and animals. Proc R Soc Med 53:281-283, 1960 7. Bull LB, Culvenor CCJ, Dick AT: The Pyrrolizidine Alkaloids. Their chemistry, pathogenicity and other biochemical properties. New York, American Elsevier Publishing Company, Inc. 8. Cushny AR: On the action of Senecio alkaloids and the causation
children. Br Med J 2:838-840, 1945 12. Hill KR, Rhodes K, Stafford JL, et al: Serous hepatosis: A pathogenesis of hepatic fibrosis in Jamaican children-preliminary report. Br Med J 1:117-122, 1953 13. Teilum G: Endophlebitis hepatica obliterans. Acta Pathol MicrobioI Scand 26:157-166,1949 14. Selzer G, Parker RGF: Senecio poisoning exhibiting as Chiari's syndrome. A report of twelve cases. Am J PathoI27:885-900, 1951 15. Bras, G, Jelliffe DB, Stuart KL: Histologic observations on hepatic disease in Jamaican infants and children. Doc Med Geog et Trop 6:43-60, 1954 16. Scott RB, Budinger JM, Prendergast RAM, et al: Hepatic venoocclusive syndrome in an American adult. Gastroenterology 42:631-636, 1962 17. Stirling GA, Bras G, Urquhart AE: The early lesions in veno-occlusive disease of the liver. Arch Dis Child 37:535-538, 1962 18. McLean EK: The toxic actions ofpyrrolizidine (Senecio) alkaloids. Pharmacol Rev 22:429-483, 1970 19. Mattocks AR: Dihydropyrrolizine derivatives from unsaturated pyrrolizidine alkaloids. J Chern Soc 8:1155-1162, 1969 20. Butler WH, Mattocks AR, Barnes JM: Lesions in the liver and lungs of rats given pyrrole derivatives of pyrrolizidine alkaloids. J Pathol 100:169-175, 1970