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Portal hypertension in systemic mastocytosis
00165085/78/7403-0595$02.99/o GMTBOENTEROLOGY 74595-597, 1978 Copyright0 1978by the AmericanGastroenterological Association
PORTAL HYPERTENSION
Vol. 74, No. 3 Printed in USA.
IN SYSTEMIC MASTOCYTOSIS
JEAN-PIERRE CAPRON, M.D.,
DIDIER LEBREC, M.D.,
DOMINIQUE CHIVRAC, M.D.,
BRUNO COEVOET, M.D.,
CLAUDE DEGOTT,
M.D.,
AND JACQUES DELOBEL, M.D.
Clinique Mkdicale A, Laboratorie d’Ht+natologie, Centre Hospitalier Universitaire, Amiens, and the Unit6 de Recherches de Physiopathologie HPpatique (INSERM), Laboratoire Central d’Anatomie et Cytologie Pathologiques, H6pital Beaujon, Clichy, France
We report the case of a 66-year-old male patient with portal hypertension related to systemic mastocytosis. The liver was enlarged; microscopic examination showed portal mast cell infiltration and fibrosis. Portal hypertension was evidenced by splenomegaly, esophageal varices, and increased wedged-free hepatic venous pressure gradient. Arteriography showed that portal vein was patent. Portal hypertension could be the consequence of intrahepatic block due to mast cell infiltration and/or fibrosis of the liver. Systemic mastocytosis is characterized by proliferation of mast cells in skin, bones, lymph nodes, and parenchymal organs. l-3 Enlargement of the liver is present in nearly 70% of patients with systemic mastocytosis.3 The hepatic lesions are represented by mild to moderate fibrosis in 13 to 38%, and mast cell proliferation, as a diffise infiltrate or in well defined masses, in 38 to 57%.3,4 We report the case of a patient suffering from systemic mastocytosis with portal hypertension, a complication which has not been hitherto described in this disease. Case Report In a 66-year-old non alcoholic man, systemic mastocytosis was proved by typical skin changes (urticaria pigmentosa), generalized bone changes on roentgenograms (osteosclerosis and osteoporosis), mast cell infiltration of the skin, bone marrow, and gastric mucosa, and hyperhistaminuria (452 pg per 24 hr; normal, less than 50 pg per 24 hr) with normal fasting serum histamine (0.013 pg per ml; normal, 0.040 to 0.0090 pg per ml). The liver was 17 cm on the midclavicular line; its surface was smooth and its consistance was firm. Splenomegaly was palpable 5 cm below the costal margin. Total serum bilirubin was 0.8 mg per 100 ml; serum alanine amino-transferase was 13 IU (normal, less than 15 U); serum alkaline phosphatase was 246 IU (normal, less than 170 U); 5’-nucleotidase was 25 IU (normal, less than 10 U); serum albumin was 4.5 g per 100 ml and y-globulin was 0.9 per 100 ml; prothrombin was 80% of normal; cholesterol was 0.18 g per 100 ml; fractional clearance of bromosulfophthalein was 0.138 min-’ (normal range, 0.110 to 0.160). Hepatitis B surface antigen was undetectable. Clinical examination showed abdominal collateral circulation. No ascites was found. Endoscopy showed esophageal varices. Celiac and superior mesenteric angiography demon-
strated that the splenic and portal veins were patent. A hepatic vein catheterization was carried out with a radioopaque catheter under fluoroscopic control: wedged and free hepatic venous pressures were 22 and 6 mm Hg, respectively; wedging was demonstrated by injection into the catheter of radioopaque dye. The gradient between wedged and free hepatic venous pressures was 16 mm Hg with normal range from 2 to 4 mm Hg.5 During this procedure, a transvenous liver biopsy was performed.” The liver specimen consisted of a tissue cylinder 2 cm long and 0.1 cm in diameter, which was placed in Bouin’s fixative. The portal tracts were enlarged with extensive fibrosis and abundant infiltration by polymorphonuclear cells (fig. 1). The trabecular architecture remained normal. No liver cell necrosis was observed. A great number of mast cells were seen within portal areas and along the sinusoids. In fibrotic areas some lymphocytes and histiocytes were visualized. On hematoxylin and eosin stain, these cells appeared polygonal and smaller than hepatic cells. With Giemsa stain, mast cells contained intracytoplasmic deep blue granules. With metachromatic stains, such as toluidine blue, the granules were reddish blue (fig. 2).
Discussion
In our patient the diagnosis of systemic mastocytosis was established on the following arguments: urticaria pigmentosa, radiological osteocondensation and osteosclerosis, large numbers of mast cells in the skin, bone marrow, and gastric mucosa, and hyperhistaminuria. Liver involvement is a frequent finding in systemic mastocytosis.3,4 Hepatomegaly, often associated with splenomegaly, is usually asymptomatic; however, ascites has been described in some patients79 8 Liver function tests are usually normal even if the liver is markedly enlarged. However, in a few patients, increased alkaline phosphatase level and decreased bromosulfophthalein clearance have been reported.7*s, lo The hepatic cells are preserved and the architectural ReceivedJuly 11, 1977. AcceptedOctober18, 1977. Address requests for reprints to: Dr. J. P. Capron, Clinique pattern of the liver is generally unaltered, although it MedicaleA, CentreHospitalierUniversitaire,Place Victor Pauchet, may be distorted by a massive mast cell infiltrate.” A mild to moderate portal and periportal fibrosis is pres80030 Amiens CBdex, France. ent in 13 to 38% of cases3*4 Mast cells, which are absent The authors wish to thank Professor J. P. Benhamou for his or scanty in the parenchyma of the normal human advice and criticism during the preparation of this manuscript. 595
596
CASE REPORTS
Vol. 74, No. 3
F‘IG. 1. Enlarged portal tract with extensive fibrosis and polymorphous cellular infiltration. Normal trabecular architecture (H & E 9X 85).
FIG. 2. Numerous mast cells with intracytoplasmic reddish blue granules (arrows) (Toluidine blue, x 840).
live!r,l* are easily demonstrated by Giemsa staining in the portal and periportal areas,13or in the walls and/or lunien of the sinusoids,‘, I1 in the form of diffuse infiltralte14or well defined masses.8
In our case portal hypertension is the consequence of intrahepatic block owing to mast cell infiltratioh Ol; fibrosis, or both. Dense cellular ifiltration of the porlLal areas, such as in cases of myeloproliferative SyndroIne
March 1978
CASE REPORTS
or reticulosis, could be the cause of portal hypertension; however, in these cases, the gradient between wedged and free hepatic venous pressures is usually norma1.15 Portal hypertension is presumably secondary to portal fibrosis. High gradient between wedged and free hepatic venous pressures in the absence of regenerative nodules has been reported in several types of liver disease, such as primary biliary cirrhosis,16congenital hepatic fibrosis,” and liver schistosomiasis. l* Connective tissue stimulation and fibrosis are remarkable features of mast cell disease.” 2 A close relationship of the mast cell to the formation of the collagen fibrils has been suggested. The mast cell is known to participate in production or storage of pharmacologically active substances such as heparin, histamine, and possibly hyaluronic acid. lgAddition of heparin to a solution of collagen results in the formation of collagen fibrils.20 Increased histamine synthesis is demonstrated in many tissues undergoing rapid growth or repair.” In systemic mastocytosis the heparin and the histamine contents in the liver are increased.*, l**22Our case suggests that mast cell disease would be another rare example of new fibre formation in the absence of liver cell necrosis.23 REFERENCES 1. Sweda JA, Abraham JP, Fine G, et al: Systemic mast cell
2. 3. 4. 5.
6.
disease. A review and report of three cases. Am J Med 32:227239, 1962 Demis DJ: The mastocytosis syndrome: clinical and biological studies. Ann Intern Med 59194-206, 1963 Sagher F, Even-Paz Z: Mastocytosis and the mast cell. Chicago, Year Book Medical Publishers Inc, 1967 Lennert K: Zur pathologischen Anatomie von Urticaria pigmentosa and Mastzellen-reticulose. Klin Wochenschr 40:61-72, 1962 Benhamou JP, Girond C, Guillemot R, et al: Etudes sur I’hemodynamique hepatique. VI. Pressions auriculaire droite, cave inferieure, sus-hepatique libre, sus-hepatique bloquee et intrasplenique au tours des cirrhoses. Rev Fr Etud Clin Biol 7:397-405, 1962 Lebrec D, Degott C, Rueff B, et al: Transvenous (transjugular)
597
liver biopsy. An experience based on 100 biopsies. Am J Dig Dis (in press), 1977 7. Zak FG, Covey JA, Shodgrass JJ: Osseous lesions in u&aria pigmentosa. N Engl J Med 256%-62,1957 8. Bloom G, Franzen S, Siren M: Malignant systemic mast cell disease (mastocytoma) in man. Acta Med Stand 168:95-102, 1960 9. Havard CWH, Scott RB: Urticaria pigmentosa with visceral and skeletal lesions. Q J Med 28:459-470,1959 10. Stutzman L, Zsoldos S, Ambrus JL, et al: Systemic mast cell disease. Physiologic considerations and report of a patient treated with nitrogen mustard. Am J Med 29894-901, 1960 11. Waters XJ, Lacson PS: Mast cell leukemia presenting as urticaria pigmentosa. Report of a case. Pediatrics 19:1033-1042, 1957 12. Michels NA: The mast cells. In Handbook of Hematology. Edited by H Downey. New York, Hoeber, 1938, p 231 13. Gonnella JS, Lipsey AI: Mastocytosis manifested by hepatosplenomegaly. N Engl J Med 271:533-535, 1964 14. Ellis JM: Urticaria pigmentosa: report of a case with autopsy. Arch Path01 48: 426-435, 1949 15. Shaldon S, Sherlock S: Portal hypertension in the myeloproliferative syndrome and the reticuloses. Am J Med 32:758-764, 1962 16. Lebrec D, Sicot C, Degott C, et al: Portal hypertension and primary biliary cirrhosis. Digestion 14:220-226, 1976 17. Clermont RJ, Maillard JN, Benhamou JP, et al: Fibrose hepatique congenitale. Can Med Assoc J 97:1272-1278, 1967 18. Paes Alves CA, Alves AR, Abreu WN, et al: Hepatic artery hypertrophy and sinusoidal hypertension in advanced schistosomiasis. Gastroenterology 72:126-128, 1977 19. Riley JF: Functional significance of histamine and heparin in tissue mast cells. Ann NY Acad Sci 103:151-163, 1963 20. Morrione TC: Formation of collagen fibers by action of heparin on soluble collagen; electron microscope study. J Exp Med 96:107-113,1952 21. Kahlson G, Rosengren E: New approaches to the physiology of histamine. Physiol Rev 48:155-196,1968 22. Brodeur G, Gardner LI: Urticaria pigmentosa as a problem in diagnosis (report of two cases, one with systemic involvement). N Engl J Med 254:1165-1168, 1956 23. Popper H, Kent G: Fibrosis in chronic liver disease. In Clinics in Gastroenterology. Edited by H Popper. London, Philadelphia, Toronto, WB Saunders Co, 1975, p 315-332
PORTAL HYPERTENSION
Vol. 74, No. 3 Printed in USA.
IN SYSTEMIC MASTOCYTOSIS
JEAN-PIERRE CAPRON, M.D.,
DIDIER LEBREC, M.D.,
DOMINIQUE CHIVRAC, M.D.,
BRUNO COEVOET, M.D.,
CLAUDE DEGOTT,
M.D.,
AND JACQUES DELOBEL, M.D.
Clinique Mkdicale A, Laboratorie d’Ht+natologie, Centre Hospitalier Universitaire, Amiens, and the Unit6 de Recherches de Physiopathologie HPpatique (INSERM), Laboratoire Central d’Anatomie et Cytologie Pathologiques, H6pital Beaujon, Clichy, France
We report the case of a 66-year-old male patient with portal hypertension related to systemic mastocytosis. The liver was enlarged; microscopic examination showed portal mast cell infiltration and fibrosis. Portal hypertension was evidenced by splenomegaly, esophageal varices, and increased wedged-free hepatic venous pressure gradient. Arteriography showed that portal vein was patent. Portal hypertension could be the consequence of intrahepatic block due to mast cell infiltration and/or fibrosis of the liver. Systemic mastocytosis is characterized by proliferation of mast cells in skin, bones, lymph nodes, and parenchymal organs. l-3 Enlargement of the liver is present in nearly 70% of patients with systemic mastocytosis.3 The hepatic lesions are represented by mild to moderate fibrosis in 13 to 38%, and mast cell proliferation, as a diffise infiltrate or in well defined masses, in 38 to 57%.3,4 We report the case of a patient suffering from systemic mastocytosis with portal hypertension, a complication which has not been hitherto described in this disease. Case Report In a 66-year-old non alcoholic man, systemic mastocytosis was proved by typical skin changes (urticaria pigmentosa), generalized bone changes on roentgenograms (osteosclerosis and osteoporosis), mast cell infiltration of the skin, bone marrow, and gastric mucosa, and hyperhistaminuria (452 pg per 24 hr; normal, less than 50 pg per 24 hr) with normal fasting serum histamine (0.013 pg per ml; normal, 0.040 to 0.0090 pg per ml). The liver was 17 cm on the midclavicular line; its surface was smooth and its consistance was firm. Splenomegaly was palpable 5 cm below the costal margin. Total serum bilirubin was 0.8 mg per 100 ml; serum alanine amino-transferase was 13 IU (normal, less than 15 U); serum alkaline phosphatase was 246 IU (normal, less than 170 U); 5’-nucleotidase was 25 IU (normal, less than 10 U); serum albumin was 4.5 g per 100 ml and y-globulin was 0.9 per 100 ml; prothrombin was 80% of normal; cholesterol was 0.18 g per 100 ml; fractional clearance of bromosulfophthalein was 0.138 min-’ (normal range, 0.110 to 0.160). Hepatitis B surface antigen was undetectable. Clinical examination showed abdominal collateral circulation. No ascites was found. Endoscopy showed esophageal varices. Celiac and superior mesenteric angiography demon-
strated that the splenic and portal veins were patent. A hepatic vein catheterization was carried out with a radioopaque catheter under fluoroscopic control: wedged and free hepatic venous pressures were 22 and 6 mm Hg, respectively; wedging was demonstrated by injection into the catheter of radioopaque dye. The gradient between wedged and free hepatic venous pressures was 16 mm Hg with normal range from 2 to 4 mm Hg.5 During this procedure, a transvenous liver biopsy was performed.” The liver specimen consisted of a tissue cylinder 2 cm long and 0.1 cm in diameter, which was placed in Bouin’s fixative. The portal tracts were enlarged with extensive fibrosis and abundant infiltration by polymorphonuclear cells (fig. 1). The trabecular architecture remained normal. No liver cell necrosis was observed. A great number of mast cells were seen within portal areas and along the sinusoids. In fibrotic areas some lymphocytes and histiocytes were visualized. On hematoxylin and eosin stain, these cells appeared polygonal and smaller than hepatic cells. With Giemsa stain, mast cells contained intracytoplasmic deep blue granules. With metachromatic stains, such as toluidine blue, the granules were reddish blue (fig. 2).
Discussion
In our patient the diagnosis of systemic mastocytosis was established on the following arguments: urticaria pigmentosa, radiological osteocondensation and osteosclerosis, large numbers of mast cells in the skin, bone marrow, and gastric mucosa, and hyperhistaminuria. Liver involvement is a frequent finding in systemic mastocytosis.3,4 Hepatomegaly, often associated with splenomegaly, is usually asymptomatic; however, ascites has been described in some patients79 8 Liver function tests are usually normal even if the liver is markedly enlarged. However, in a few patients, increased alkaline phosphatase level and decreased bromosulfophthalein clearance have been reported.7*s, lo The hepatic cells are preserved and the architectural ReceivedJuly 11, 1977. AcceptedOctober18, 1977. Address requests for reprints to: Dr. J. P. Capron, Clinique pattern of the liver is generally unaltered, although it MedicaleA, CentreHospitalierUniversitaire,Place Victor Pauchet, may be distorted by a massive mast cell infiltrate.” A mild to moderate portal and periportal fibrosis is pres80030 Amiens CBdex, France. ent in 13 to 38% of cases3*4 Mast cells, which are absent The authors wish to thank Professor J. P. Benhamou for his or scanty in the parenchyma of the normal human advice and criticism during the preparation of this manuscript. 595
596
CASE REPORTS
Vol. 74, No. 3
F‘IG. 1. Enlarged portal tract with extensive fibrosis and polymorphous cellular infiltration. Normal trabecular architecture (H & E 9X 85).
FIG. 2. Numerous mast cells with intracytoplasmic reddish blue granules (arrows) (Toluidine blue, x 840).
live!r,l* are easily demonstrated by Giemsa staining in the portal and periportal areas,13or in the walls and/or lunien of the sinusoids,‘, I1 in the form of diffuse infiltralte14or well defined masses.8
In our case portal hypertension is the consequence of intrahepatic block owing to mast cell infiltratioh Ol; fibrosis, or both. Dense cellular ifiltration of the porlLal areas, such as in cases of myeloproliferative SyndroIne
March 1978
CASE REPORTS
or reticulosis, could be the cause of portal hypertension; however, in these cases, the gradient between wedged and free hepatic venous pressures is usually norma1.15 Portal hypertension is presumably secondary to portal fibrosis. High gradient between wedged and free hepatic venous pressures in the absence of regenerative nodules has been reported in several types of liver disease, such as primary biliary cirrhosis,16congenital hepatic fibrosis,” and liver schistosomiasis. l* Connective tissue stimulation and fibrosis are remarkable features of mast cell disease.” 2 A close relationship of the mast cell to the formation of the collagen fibrils has been suggested. The mast cell is known to participate in production or storage of pharmacologically active substances such as heparin, histamine, and possibly hyaluronic acid. lgAddition of heparin to a solution of collagen results in the formation of collagen fibrils.20 Increased histamine synthesis is demonstrated in many tissues undergoing rapid growth or repair.” In systemic mastocytosis the heparin and the histamine contents in the liver are increased.*, l**22Our case suggests that mast cell disease would be another rare example of new fibre formation in the absence of liver cell necrosis.23 REFERENCES 1. Sweda JA, Abraham JP, Fine G, et al: Systemic mast cell
2. 3. 4. 5.
6.
disease. A review and report of three cases. Am J Med 32:227239, 1962 Demis DJ: The mastocytosis syndrome: clinical and biological studies. Ann Intern Med 59194-206, 1963 Sagher F, Even-Paz Z: Mastocytosis and the mast cell. Chicago, Year Book Medical Publishers Inc, 1967 Lennert K: Zur pathologischen Anatomie von Urticaria pigmentosa and Mastzellen-reticulose. Klin Wochenschr 40:61-72, 1962 Benhamou JP, Girond C, Guillemot R, et al: Etudes sur I’hemodynamique hepatique. VI. Pressions auriculaire droite, cave inferieure, sus-hepatique libre, sus-hepatique bloquee et intrasplenique au tours des cirrhoses. Rev Fr Etud Clin Biol 7:397-405, 1962 Lebrec D, Degott C, Rueff B, et al: Transvenous (transjugular)
597
liver biopsy. An experience based on 100 biopsies. Am J Dig Dis (in press), 1977 7. Zak FG, Covey JA, Shodgrass JJ: Osseous lesions in u&aria pigmentosa. N Engl J Med 256%-62,1957 8. Bloom G, Franzen S, Siren M: Malignant systemic mast cell disease (mastocytoma) in man. Acta Med Stand 168:95-102, 1960 9. Havard CWH, Scott RB: Urticaria pigmentosa with visceral and skeletal lesions. Q J Med 28:459-470,1959 10. Stutzman L, Zsoldos S, Ambrus JL, et al: Systemic mast cell disease. Physiologic considerations and report of a patient treated with nitrogen mustard. Am J Med 29894-901, 1960 11. Waters XJ, Lacson PS: Mast cell leukemia presenting as urticaria pigmentosa. Report of a case. Pediatrics 19:1033-1042, 1957 12. Michels NA: The mast cells. In Handbook of Hematology. Edited by H Downey. New York, Hoeber, 1938, p 231 13. Gonnella JS, Lipsey AI: Mastocytosis manifested by hepatosplenomegaly. N Engl J Med 271:533-535, 1964 14. Ellis JM: Urticaria pigmentosa: report of a case with autopsy. Arch Path01 48: 426-435, 1949 15. Shaldon S, Sherlock S: Portal hypertension in the myeloproliferative syndrome and the reticuloses. Am J Med 32:758-764, 1962 16. Lebrec D, Sicot C, Degott C, et al: Portal hypertension and primary biliary cirrhosis. Digestion 14:220-226, 1976 17. Clermont RJ, Maillard JN, Benhamou JP, et al: Fibrose hepatique congenitale. Can Med Assoc J 97:1272-1278, 1967 18. Paes Alves CA, Alves AR, Abreu WN, et al: Hepatic artery hypertrophy and sinusoidal hypertension in advanced schistosomiasis. Gastroenterology 72:126-128, 1977 19. Riley JF: Functional significance of histamine and heparin in tissue mast cells. Ann NY Acad Sci 103:151-163, 1963 20. Morrione TC: Formation of collagen fibers by action of heparin on soluble collagen; electron microscope study. J Exp Med 96:107-113,1952 21. Kahlson G, Rosengren E: New approaches to the physiology of histamine. Physiol Rev 48:155-196,1968 22. Brodeur G, Gardner LI: Urticaria pigmentosa as a problem in diagnosis (report of two cases, one with systemic involvement). N Engl J Med 254:1165-1168, 1956 23. Popper H, Kent G: Fibrosis in chronic liver disease. In Clinics in Gastroenterology. Edited by H Popper. London, Philadelphia, Toronto, WB Saunders Co, 1975, p 315-332