Some conditions affecting the hepatic vasculature are extrahepatic, such as congestive heart failure and systemic hypotension. Abnormalities of the vascular system can also be seen in the liver biopsy; examples are Budd-Chiari syndrome and venoocclusive disease (VOD), as well as peliosis hepatis and endothelialitis of liver allograft rejection (Table 19.1).
HEPATIC ARTERY
The hepatic artery rarely is a cause of clinical or morphologic liver disease, since the major blood flow to the liver is via the portal vein. Ischemic liver disease based on the hepatic artery is often a function of decreased hepatic artery blood flow rather than reduction of lumen size, as in heart failure.
Atherosclerosis
Atherosclerosis affects the hepatic artery just as it does the rest of the arterial system, and atherosclerotic changes of the hepatic artery branches can sometimes be observed in portal tracts in liver biopsies (e-Fig. 19.1); atherosclerotic liver disease, however, in and of itself, does not occur. The liver is remarkably resistant to anoxia. Significant hepatic artery atherosclerosis will not affect the liver unless the portal or hepatic vein system is compromised.
Hepatic Ischemia
With hepatic ischemia, biochemical changes suggest hepatitis, with significant and rapid elevations in the serum aminotransferase values (20). Ischemic hepatitis occurs with myocardial infarction, cardiac arrhythmias, or hypotension. The morphologic features are characteristic and virtually diagnostic, consisting of zone 3 (centrolobular) hepatocytic coagulative necrosis (5,54). A relatively sharp demarcation can be seen (Fig. 19.1, e-Fig. 19.2). Nuclear pyknosis, karyorrhexis, and eosinophilic necrosis occurs, usually with sparing of sinusoidal cells. With severe and prolonged ischemia, zone 2 can also be involved (14). However, it should be remembered that both zone 2 and zone 3 arc from the portal tracts (see Chapter 2). Necrosis in the midportion of the limiting plate, at the interface between the portal tract and the hepatocytes, is common as a reflection of predominantly zone 3 necrosis and is not necessarily representative of diffuse hepatic necrosis (Fig. 19.2).
|
TABLE 19.1 Vascular Disorders of the Liver in Terms of Their Localization in the Liver Biopsy |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|
FIGURE 19.1 Zone 3 (centrolobular) ischemic necrosis in a chronically ill patient with intermittent hypotension in whom biopsy was performed to exclude the possibility of concurrent viral hepatitis. There is a relatively sharp line of demarcation between the ischemic zone and the viable zone 2 (hematoxylin-eosin, original magnification ×200). |
Phagocytosed cell material in Kupffer cells can be demonstrated after a few days with diastase-periodic acid-Schiff (dPAS) reaction. Other changes include canalicular cholestasis adjacent to the necrosis, and eosinophilic hyaline globules, resembling those of α1-antitrypsin deficiency (32) as well as mild steatosis and early regenerative changes. With right-sided heart failure, sinusoids are dilated and congested. Uncommonly, a picture similar to that of hepatic vein obstruction (Budd-Chiari), with red blood cells filling the liver cord in place of the removed hepatocytes, is seen and the biopsyderived diagnosis may be misleading. In patients who recover, the histologic structure is restored. Sometimes perivenular fibrosis remains, particularly with recurrent or prolonged heart failure, and there may be associated calcification.
|
|
|
FIGURE 19.2 Ischemic necrosis in a patient with cardiogenic shock showing involvement of the central, zone 3 portion of the limiting plate (hematoxylin-eosin, original magnification ×200). |
Hepatic artery thrombosis, involving the extrahepatic portion of the hepatic artery, can occur after trauma, including that related to surgery and catheterization. Rarely, arteritis, embolization or tumor invasion occurs. Trauma can also lead to hepatic artery aneurysm. Infusion of chemotherapeutic agents can also cause hepatic artery thrombosis. Oral contraceptives have also been implicated as causal, with intrahepatic arterial branch intimal hyperplasia (43).
Intrahepatic thrombi can be seen in association with disseminated intravascular coagulopathy (DIC) or thrombotic thrombocytopenic purpura (TTP). Patients with these conditions, and indeed most thrombotic disorders, however, are rarely, if ever, subject to liver biopsy.
Hepatic Infarction
Hepatic infarction is uncommon and exceedingly rare in liver biopsy samples (23,52). Extensive coagulative necrosis affects one or more lobules (e-Fig. 19.2).
Vasculitis
The systemic arteritides, including periarteritis nodosa (e-Fig. 19.3), systemic lupus erythematosus (53), rheumatoid arthritis, and others, as well as drug-induced vasculitis, can potentially, but rarely, affect the liver (19,65). Liver biopsy helps identify concurrent or complicating conditions. A form of vasculitis affecting the portal vein and its tributaries is characteristic of acute allograft rejection and is discussed in Chapter 25.
Amyloidosis
Amyloidosis is discussed in Chapter 21.
PORTAL VEIN
Luminal obstruction is the basis of most portal vein disorders, occurring at any level of the portal vein system. Consequences depend on site and extent. With an intact hepatic artery system, portal vein obstruction may not have significant clinical or morphologic manifestations. Instead, prehepatic portal vein obstruction with portal hypertension may ensue.
Prehepatic Portal Vein Obstruction
The effects on the liver are variable and often minor (12). There are no consistent liver biopsy patterns (25). Indeed, the liver may not show any changes with portal vein compromise. In elderly patients, however, with advanced atherosclerosis, hepatic ischemia, particularly affecting zone 3, will be seen after portal vein thrombosis. Similarly, associated heart failure or mechanical hepatic vein obstruction causes zone 3 necrosis. Prehepatic portal vein obstruction can be (a) congenital; (b) caused by intra-abdominal inflammatory disorders causing pylephlebitis (27); (c) seen with hypercoagulable states; (d) hormone related, including pregnancy and oral contraceptive pill usage; (e) associated with myeloproliferative disorders (50,62); (f) after trauma, including surgery; (g) with cirrhosis; (h) with neoplasm, particularly hepatocellular carcinoma; (i) from mass compression effect, generally from tumors; and (j) as a sequel to hepatic vein outflow obstruction (7).
Intrahepatic Portal Vein Obstruction
Intrahepatic portal vein obstruction may be associated with the same long list of conditions as prehepatic portal vein obstruction. In addition, intrahepatic portal vein obstruction can follow intrahepatic abscess formation, sarcoidosis, schistosomiasis, and other less common conditions. Often, the cause cannot be established. The clinical diagnosis may be quite difficult to establish, and venous flow studies may be required (6).
Thrombi are seen in portal vein tributaries. Because of the irregular distribution of changes, biopsy is often not helpful. Septic thrombi occur with acute pylephlebitis. Nodular hyperplasia can follow occlusion of intrahepatic portal vein branches and may be seen in the liver biopsy without evidence of the causative thrombus (41,53,54,61) (see Chapter 4). Inflammatory change of the intrahepatic portal vein, as seen in acute allograft rejection and graft versus host disease, is generally not associated with thrombosis (38).
Hepatoportal Sclerosis
Hepatoportal sclerosis is a rare and distinct clinicopathologic entity characterized by sclerosis of the intrahepatic portal veins that causes noncirrhotic portal hypertension (23,33,37) (see Chapter 20).
The intrahepatic portal venous system can have degrees of fibrosis and occlusion, leading to presinusoidal obstruction. The fibrosis can also affect the prehepatic portal vein, which generally does not become completely occluded (43). The changes are irregularly distributed and vary from mild intimal thickening to complete occlusion, with or without thrombus formation. Some portal vein sclerosis is seen with aging.
Zahn Infarcts
Zahn infarcts are best recognized macroscopically and typically in autopsy material, as a sequel to a space-occupying lesion, most often metastatic carcinoma. Mild to moderate liver cell plate atrophy with associated sinusoidal dilatation is seen, without necrosis (22). This is only rarely seen in liver biopsy material (e-Fig. 19.4).
Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Disease)
This autosomal dominant condition rarely affects the liver, with clinical liver disease uncommon (34). Dilated vascular channels in the portal tract and periportal region are seen (e-Fig. 19.5). There may be varying degrees of portal and periportal fibrosis, and fibrous septa can form, usually without regenerative nodules.
SINUSOIDS
Sinusoidal Dilatation
Sinusoidal dilatation occurs with or without accompanying liver plate atrophy, in various conditions. Most often zone 3 (centrolobular) congestion is seen (Fig. 19.3). This is typical in venous outflow obstruction, whether it is a result of congestive heart failure (e-Fig. 19.6), Budd-Chiari syndrome, or venoocclusive disease. Drugs can also cause zone 3 sinusoidal dilatation; it is not uncommon in transplant patients treated with azathioprine. Zone 2 (midzonal) sinusoidal dilatation has been documented as a paraneoplastic phenomenon (1).
Zone 1 (periportal) sinusoidal dilatation can be seen with long-term oral contraceptive pill usage (4,65). It is characteristic of eclampsia and preeclampsia (12,47) in which sinusoidal fibrin thrombi (2) and ischemic necrosis may also be seen, and also typical of DIC (55).
|
|
|
FIGURE 19.3 Zone 3 (centrolobular) congestion in a patient with congestive heart failure in whom serum aminotransferase values were elevated. Zone 3 sinusoids are dilated, and the terminal hepatic venule (central vein) is filled with blood (hematoxylin-eosin, original magnification ×200). |
Sinusoidal dilatation, generally irregularly distributed, has been seen after exposure to agents that also cause hepatic angiosarcoma, such as arsenic, vinyl chloride, and thorium dioxide (Thorotrast), and can also be seen in the vicinity of a space-occupying lesion (e-Fig. 19.7). The liver biopsy in acquired immunodeficiency syndrome can also show irregular sinusoidal dilatation. In pregnancy the sinusoidal dilatation may be predominantly periportal (17).
Sinusoidal dilatation is typically seen in sickle cell disease, in which the sinusoids are packed with the characteristic sickled erythrocytes (e-Fig. 19.8) (38,44). There is also marked enlargement of Kupffer cells, with siderosis and erythrophagocytosis. In Hodgkin lymphoma, sinusoidal dilatation may be prominent, although not diagnostic (8,9).
Peliosis Hepatis
The sinusoids are dilated and transformed into cystlike, blood-filled spaces (e-Figs. 19.9, 19.10) (60,64). Peliosis hepatis was first recognized in association with chronic debilitating conditions such as tuberculosis and malignancy. Many medications have been implicated, including oral contraceptives, anabolic steroids (3), corticosteroids, tamoxifen, danazol, azathioprine, as well as arsenic, vinyl chloride, and thorium dioxide (29,39,65,66). Peliosis can be scattered throughout the liver, and there is often nonpeliotic sinusoidal dilatation associated, with communications between the sinusoidal dilatation and the peliosis demonstrable. Bacillary angiomatosis strongly resembles peliosis hepatis (58).
Sinusoidal Thrombosis
Fibrin thrombi may form in sinusoids in DIC, in sickle cell disease, and in eclampsia (48).
Outflow Venous Disease
TERMINAL HEPATIC VENULES (CENTRAL VEINS)
Right Heart Failure
The hallmark of acute congestive heart failure is zone 3 (centrolobular) sinusoidal dilatation and congestion (e-Fig. 19.6) (15). Hepatocyte necrosis generally does not occur unless there is coincident left heart failure with systemic hypotension. With sustained heart failure, liver cell atrophy ensues and the Disse space becomes easily seen. In long-standing disease, zone 3 perivenular fibrosis develops with eventual linking of central areas by vascular fibrous septa (cardiac cirrhosis) (e-Fig. 19.11). True cirrhosis, with regenerative nodules and central-portal as well as central-central septa (see Chapter 20), is now uncommon. The terminal hepatic venules have thickened fibrotic walls and may show complete luminal obliteration (42).
Left Heart Failure and Systemic Hypotension
The hallmark of systemic hypotension (shock) is zone 3 (centrolobular) necrosis, which, if prolonged or severe, can involve zone 2 (e-Fig. 19.2) (5,30). Portal tracts and zone 1 hepatocytes usually are unremarkable, and there is usually little or no inflammation at first, with accumulations of polymorphonuclear leukocytes after a few days. There may be cholestasis.
Hepatic Venous Outflow Obstruction
Venous outflow may be impeded by congestive heart failure and primary and secondary neoplasms affecting the right heart. This section will concentrate on disorders of the hepatic vein and hepatic vein branches that contribute to impaired hepatic venous outflow.
BUDD-CHIARI SYNDROME. Budd-Chiari syndrome is a distinctive clinicopathologic entity characterized by narrowing or occlusion of the hepatic veins (16,32,35,45) as a result of thrombus formation or nonthrombotic causes. Budd-Chiari is associated with (a) myeloproliferative disorders, such as polycythemia vera (63,64); (b) disorders of coagulation, including protein C deficiency; (c) several medications, including oral contraceptives (31); (d) pregnancy (26); and (e) neoplasms, either from direct invasion, as occurs with hepatocellular carcinoma, renal cell carcinoma, and adrenal cortical carcinoma, or from external compression. Uncommonly fibrous webs or membranes obstruct the hepatic vein (21,24). Uncommon causes include trauma, connective tissue disorders, and the use of cancer chemotherapeutic agents, as well as conditions affecting the heart primarily, such as constrictive pericarditis (59).
The classic clinical triad is of hepatomegaly, right upper quadrant abdominal pain, and ascites, with an insidious onset that may take many months to fully develop. Rarely, the onset may be acute (46).
Pathology. Variable changes can be seen (e-Figs. 19.12-19.23). Zone 3 sinusoidal congestion and dilatation may be the only finding in early Budd-Chiari (Fig. 19.4). Sometimes red blood cells appear to have replaced zone 1 hepatocytes within the liver cord (Fig. 19.4). Zone 3 hepatocytes then begin to atrophy (Fig. 19.5). With more severe and prolonged obstruction, hepatocytes may disappear completely with no inflammatory response. Occasionally true ischemic necrosis is seen. Thrombi can be seen in terminal hepatic venules, and, ultimately, there may be fibrous obliteration. Changes are not uniform throughout the liver, and areas of more severe and advanced change can alternate with relatively mildly affected regions.
After many weeks the centrolobular regions become fibrotic and central-central septa form. Fibrous obliteration of terminal hepatic venules, indistinguishable from the changes of VOD, can be seen. Liver plates can be thickened, and there may be associated nodular hyperplasia. True cirrhosis is rare and may be related to secondary thrombosis of the portal vein. It may be exceedingly difficult, solely on the basis of a single liver biopsy, to distinguish early Budd-Chiari syndrome from other causes of hepatic venous outflow obstruction.
|
|
|
FIGURE 19.4 Budd-Chiari syndrome, early stage, showing zone 3 sinusoidal dilatation and early necrosis with red blood cells in liver cords (hematoxylin-eosin, original magnification ×200). |
VENOOCLUSIVE DISEASE. Budd-Chiari involves hepatic vein segments between the liver and the inferior vena cava. VOD, in contrast, affects smaller, intrahepatic portions of the hepatic vein system and the terminal hepatic venules (Fig. 19.6). The veins are occluded by fibrous tissue (e-Figs. 19.24-19.28) (49). This can be identified in biopsy samples, although it is generally not uniformly distributed throughout the liver and any one biopsy may not be helpful.
|
|
|
FIGURE 19.5 Budd-Chiari syndrome, late stage, showing atrophy of zone 2 and 3 hepatocytes (hematoxylin-eosin, original magnification ×100). |
|
|
|
FIGURE 19.6 Venoocclusive disease, showing complete obliteration of hepatic vein lumen (trichrome, original magnification ×200). |
VOD is caused by (a) ingestion of pyrrolizidine alkaloids, which can be found in various herbal remedies; (b) several chemotherapeutic agents, including azathioprine and 6-mercaptopurine (4); (c) alkylating agents, particularly in bone marrow transplantation (36,56,57,64); (d) hepatic radiation (51); (e) hypervitaminosis A; (f) arsenic (28); and (g) thorium dioxide (13).
Pathology. Terminal hepatic venules show proliferation of loose connective tissue in the subintima leading to luminal narrowing (18). Connective tissue stains are particularly helpful. Surrounding liver shows changes of acute venous outflow obstruction, similar to Budd-Chiari syndrome and right heart failure, with congestion of zone 3 sinusoids and atrophy of hepatocytes. Thrombi are generally not seen, and inflammation is not prominent.
The subintimal lesions eventually become fibrotic, and perivenular fibrosis and central-central septa formation follow. Nodular hyperplasia and true regenerative nodules can occur, and cirrhosis may be the end result.
Fibrous obliteration of terminal hepatic venules can also be seen in alcoholic liver injury (10,11,40) (see Chapter 13) and in cirrhosis from almost any cause. The diagnosis of VOD should be based on both the vein changes and the histologic appearance of the zone 3 hepatocytes and sinusoids, as well as appropriate clinical factors.
REFERENCES
1. Aoyagi T, Mori I, Ueyma Y, et al. Sinusoidal dilatation of the liver as a paraneoplastic manifestation of renal cell carcinoma. Hum Pathol 1989;20:1193-1197.
2. Arias F, Mancilla-Jiminez R. Hepatic fibrinogen deposits in pre-eclampsia. N Engl J Med 1976;295:578-582.
3. Bagheri SA, Boyer JL. Peliosis hepatis associated with androgenic-anabolic steroid therapy. A severe form of hepatic injury. Ann Intern Med 1974;81:610-618.
4. Balás M. Sinusoidal dilatation of the liver in patients on oral contraceptives: electron microscopic study of 14 cases. Exp Pathol 1988;35:231-237.
5. Birgens HS, Henriksen J, Marzen P, et al. The shock liver. Clinical and biochemical findings in patients with centrolobular liver necrosis following cardiogenic shock. Acta Med Scand 1978;204:417-421.
6. Boyer JL, Hales MR, Klatskin G. “Idiopathic” portal hypertension due to occlusion of intrahepatic portal veins by organized thrombi. Medicine 1974;53:77-91.
7. Brown KM, Kaplan MM, Donowitz M. Extrahepatic portal venous thrombosis: frequent recognition of associated diseases. J Clin Gastroenterol 1985;7:153-159.
8. Bruguera M, Aranguibel F, Ros E, et al. Incidence and clinical significance of sinusoidal dilatation in liver biopsies. Gastroenterology 1978;75:474-478.
9. Bruguera M, Caballero T, Carreras E, et al. Hepatic sinusoidal dilatation in Hodgkin's disease. Liver 1987;7:76-80.
10. Burt AD, MacSween RNM. Hepatic vein lesions in alcoholic liver diseases: retrospective biopsy and necropsy study. J Clin Pathol 1986;39:63-67.
11. Caulet S, Fabre M, Schoevart D, et al. Quantitative study of centrolobular hepatic fibrosis in alcoholic disease before cirrhosis. Virchows Arch A Pathol Anat Histopathol 1989; 416:11-17.
12. Cohen J, Edelman RR, Chopra S. Portal vein thrombosis: a review. Am J Med 1992;92: 173-182.
13. Dejgaard A, Krogsgaard K, Jacobsen M. Veno-occlusive disease and peliosis of the liver after thorotrast administration. Virchows Arch A Pathol Anat Histopathol 1984;403: 87-94.
14. de la Monte S, Arcidi JM, Moore GW, et al. Midzonal necrosis as a pattern of hepatocellular injury after shock. Gastroenterology 1984;86:627-631.
15. Dunn GD, Hayes P, Breen KJ, et al. The liver in congestive heart failure: a review. Am J Med Sci 1973;265:174-189.
16. Farah S, Uthman S, Abyad A. Budd-Chiari syndrome: a review of ten cases. J Intern Med Res 1997;25:171-174.
17. Fisher MR, Neiman HL. Periportal sinusoidal dilatation associated with pregnancy. Cardiovasc Int Radiol 1984;7:299-302.
18. Goodman ZD, Ishak KG. Occlusive venous lesions in alcoholic liver disease. A study of 200 cases. Gastroenterology 1982;83:786-796.
19. Goritsas CP, Repanti M, Papadaki E, et al. Intrahepatic bile duct injury and nodular regenerative hyperplasia of the liver in a patient with polyarteritis nodosa. J Hepatol 1997;26:727-730.
20. Henrion J, Schapira M, Heller FR. Ischemic hepatitis: the need for precise criteria. J Clin Gastroenterol 1996;23:305.
21. Hoffman HD, Stockland B, von der Heyden U. Membranous obstruction of the inferior vena cava with Budd-Chiari syndrome in children: a report of nine cases. J Pediatr Gastroenterol Nutr 1987;6:878-881.
22. Horrocks P, Tapp E. Zahn's “infarcts” of the liver. J Clin Pathol 1966;19:475-478.
23. Jacobs MB. Hepatic infarction related to oral contraceptive use. Arch Intern Med 1984; 144:642-643.
24. Kage M, Arakawa M, Kojiro M, et al. Histopathology of membranous obstruction of the inferior vena cava in the Budd-Chiari syndrome. Gastroenterology 1992;102:2081-2090.
25. Kameda H, Yamazaki K, Imai F, et al. Obliterative portal venopathy: a comparative study of 184 cases of extrahepatic portal obstruction and 469 cases of idiopathic portal venous obstruction. J Gastroenterol Hepatol 1986;1:139-149.
26. Khuroo MS, Datta DV. Budd-Chiari syndrome following pregnancy. Report of 16 cases, with roentgenologic, hemodynamic and histologic studies of the hepatic outflow tract. Am J Med 1980;68:113-121.
27. Knochaert DC, Robaeys GK, Cox EJ, et al. Suppurative pylethrombosis: a changing clinical picture. Gastroenterology 1989;97:1028-1030.
28. Labadie H, Stoessel P, Callard P, et al. Hepatic venoocclusive disease and perisinusoidal fibrosis secondary to arsenic poisoning. Gastroenterology 1990;99:1140-1143.
29. Larrie D, Fréneaux E, Berson A, et al. Peliosis hepatis induced by 6-thioguanine administration. Gut 1988;29:1265-1269.
30. Lefkowitch JH, Mendez L. Morphologic features of hepatic injury in cardiac disease and shock. J Hepatol 1986;2:313-327.
31. Lewis JH, Tice HL, Zimmerman HJ. Budd-Chiari syndrome associated with oral contraceptive steroids. Review of treatment of 47 cases. Dig Dis Sci 1983;28:673-683.
32. Maddrey WC. Hepatic vein thrombosis (Budd-Chiari syndrome). Hepatology 1984;4: 44S-46S.
33. Maksoud JG, Mies S, da Costa Gayotto LC. Hepatoportal sclerosis in childhood. Am J Surg 1986;151:484-488.
34. Martini GA. The liver in hereditary haemorrhagic telangiectasia: an inborn error of vascular structure with multiple manifestations. A reappraisal. Gut 1978;19:531-537.
35. McDermott WV, Stone MD, Bothe A Jr, et al. Budd-Chiari syndrome. Historical and clinical review with an analysis of surgical corrective procedures. Am J Surg 1984;147:463-466.
36. McDonald GB, Hinds MS, Fisher LD, et al. Venoocclusive disease of the liver and multi-organ failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med 1993;118:255-267.
37. Mikkelson WP, Edmondson HA, Peters RL, et al. Extra- and intrahepatic portal hypertension without cirrhosis (hepatoportal sclerosis). Ann Surg 1965;162:602-618.
38. Mills LR, Mwakyusa D, Milner PF. Histopathologic features of liver biopsy specimens in sickle cell disease. Arch Pathol Lab Med 1988;112:290-294.
39. Nadell J, Kosek J. Peliosis hepatis. Twelve cases associated with oral androgen therapy. Arch Pathol Lab Med 1977;101:405-410.
40. Nakano M, Worner TM, Lieber CS. Perivenular fibrosis in alcoholic liver injury: ultrastructure and histologic progression. Gastroenterology 1982;83:777-785.
41. Nakanuma Y, Ohta G, Kobayashi K, et al. Histological and histometric examination of the intrahepatic portal vein branches in primary biliary cirrhosis without regenerative nodules. Am J Gastroenterol 1982;77:405-413.
42. Nasrallah SM, Nassar VH, Galambos JT. Importance of terminal hepatic venule thickening. Arch Pathol Lab Med 1980;104:84-86.
43. Okuda K, Nakashima T, Okudaira M, et al. Liver pathology of idiopathic portal hypertension. Liver 1982;2:176-192.
44. Omata M, Johnson CS, Tong M, et al. Pathologic spectrum of liver diseases in sickle cell disease. Dig Dis Sci 1986;31:247-256.
45. Pati HP, Dayal S. Budd-Chiari syndrome: aetiology and geography. Q J Med 1996;89: 719-721.
46. Powell-Jackson PR, Melia W, Canalese J, et al. Budd-Chiari syndrome presenting as fulminant hepatic failure. Gut 1986;27:1101-1105.
47. Rolfes DB, Ishak KG. Liver disease in pregnancy. Histopathology 1986;10:555-570.
48. Rolfes DB. Ishak KG. Liver disease in toxemia of pregnancy. Am J Gastroenterol 1986;81: 1138-1144.
49. Rollins BJ. Hepatic veno-occlusive disease. Am J Med 1986;81:297-306.
50. Roughton BJ. Hepatic and portal vein thrombosis. Closely associated with chronic myeloproliferative disorders. Br Med J 1991;302:192-193.
51. Rowland R, Pieterse AS, Kimber RJ, et al. Radiation veno-occlusive liver disease. Aust N Z J Med 1981;11:534-538.
52. Seely TT, Blumenfeld CM, Ikeda R, et al. Hepatic infarction. Hum Pathol 1972;3:265-276.
53. Sekiya M, Sekigawa I, Hishikawa T, et al. Nodular regenerative hyperplasia of the liver in systemic lupus erythematosus. The relationship with anticardiolipin antibody and lupus anticoagulant. Scand J Rheumatol 1997;26:215-217.
54. Shimamatsu K, Wanless IR. Role of ischemia in causing apoptosis, atrophy, and nodular hyperplasia in human liver. Hepatology 1997;26:343-350.
55. Shimamura K, Oka K, Nakazawa M, et al. Distribution patterns of microthrombi in disseminated intravascular coagulation. Arch Pathol Lab Med 1983;107:543-547.
56. Shulman HM, Gown AM, Nujent DJ. Hepatic venoocclusive disease after bone marrow transplantation. Immunohistochemical identification of the material within occluded central venules. Am J Pathol 1987;127:549-558.
57. Shulman HM, Fisher LB, Schoch HG, et al. Venooclusive disease of the liver after marrow transplantation: histologic correlates of clinical signs and symptoms. Hepatology 1994;19:1171-1180.
58. Slater LN, Welch DF, Min K-W. Rochalimaea henselae causes bacillary angiomatosis and peliosis hepatis. Arch Intern Med 1992;152:602-606.
59. Tanaka M, Wanless IR. Pathology of the liver in Budd-Chiari syndrome: portal vein thrombosis and the histogenesis of veno-centric cirrhosis, veno-portal cirrhosis, and large regenerative nodules. Hepatology 1998;27:488-496.
60. Walter E, Möckel J. Images in medicine: peliosis hepatis. N Engl J Med 1997;337:1603.
61. Wanless IR. Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules. Hepatology 1990;11:787-797.
62. Wanless IR, Peterson P, Das A, et al. Hepatic vascular disease and portal hypertension in polycythemia vera and agnogenic myeloid metaplasis: a clinicopathologic study of 145 patients examined at autopsy. Hepatology 1990;12:1166-1174.
63. Watanabe K, Iwaki H, Satoh M, et al. Veno-occlusive disease of the liver following bone marrow transplantation: a clinical-pathological study of autopsy cases. Art Organs 1996; 20:1145-1150.
64. Wold LE, Ludwig J. Peliosis hepatis: two morphologic variants? Hum Pathol 1981;12: 388-389.
65. Zafrani ES, Pinaudeau Y, Dhumeaux D. Drug-induced vascular lesions of the liver. Arch Intern Med 1981;143:495-502.
66. Zafrani ES, Bernuau D, Feldmann G. Peliosis-like ultrastructural changes of the hepatic sinusoids in human chronic hypervitaminosis A. Hum Pathol 1984;15:1166-1170.
