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Hepatic dysfunction is common in patients who receive intensive chemotherapy and it is important to determine the etiology in order to institute appropriate therapy. The role of laparoscopic liver biopsy in patients with neutropenia, thrombocytopenia, or both was evaluated as a mean of making treatment decisions and as a determinant of clinical outcome. Laparoscopic liver biopsy was performed in 29 subjects who were receiving intensive cytotoxic therapy with or without bone marrow transplantation. One to three direct-vision laparoscopic liver biopsies were performed in each patient using a Tru-cut needle during general anesthesia. Platelet concentrate transfusions were usually given before, during, and immediately after biopsy. Bleeding was controlled with spatula electrocautery. Thirty-two biopsies were obtained in 29 patients. At the time of liver biopsy, white blood cell and platelet counts ranged from 0 to 14,300/microliters (median: 2500/microliters), and 1000 to 47,000/microliters (median: 20,000/microliters), respectively. Bleeding at the liver biopsy site was readily controlled during the procedure without clinical evidence of significant bleeding; no procedure-related complications were noted and no patients required re-exploration. All biopsies were informative and the lesions observed in 32 biopsies revealed graft-versus-host disease (n = 5), hepatic candidiasis (n =1), hepatic veno-occlusive disease (n = 3), cholestasis (n = 19), hemosiderosis (n = 26), toxic injury (n = 8), hepatic steatosis (n = 4), granuloma (n = 1), viral infection (n =1), and malignancy (n = 1). Laparoscopic liver biopsy has been proven to be an effective means of assessing the cause of liver dysfunction in patients who were thrombocytopenic and immunosuppressed. The diagnosis obtained at laparoscopic liver biopsy altered therapy in nine of 29 (31%) patients.

Adenoviruses may cause severe infections in bone marrow transplant recipients. We report the case of a patient who developed fulminant hepatitis 5 months after bone marrow transplantation. Adenovirus type 2 was cultured from stool and blood samples. The patient died from liver failure. Histologic examination of post-mortem liver samples showed extensive necrosis with nuclear inclusions. Adenovirus was identified in liver cells by electron microscopy and immunohistochemical staining using a monoclonal anti-adenovirus antibody. No other pathogen was identified.

The histological consequences of hepatic venous outflow obstruction were studied in the rat. Circulatory changes as venous congestion and interstitial fluid accumulation are followed by signs of cellular damage progressing till hemorrhagic infiltration and focal necrosis. These are quite completely reversible in a period of 15 days.

Veno-occlusive liver disease (VOLD) is a cause of portal hypertension by non thrombotic obstruction of hepatic venous drainage attributed to multiple etiologies (toxic, irradiation, antineoplastic, conditioning for bone marrow transplantation). One case of VOLD in a senile patient due to continuous two year consumption of Senecio vulgaris tea is reported. This compound, which has a high pyrrolizidine alkaloid content induced a subacute course of portal hypertension and death. The clinicopathologic features of VOLD and the etiopathogenesis in relation to the pyrrolizidine alkaloids present in Senecio vulgaris are discussed. The need for considering the history of medicinal plant ingestion in patients under portal hypertension studies are strongly recommended as is the advice regarding the possible dangers involved in the inappropriate use of remedies provided by herbalists.

Aims: Observation of a patient with the acquired immunodeficiency syndrome and veno-occlusive disease (VOD) at autopsy prompted us to review the liver pathology of autopsied patients with human immunodeficiency virus seropositivity and/or acquired immunodeficiency syndrome (HIV/AIDS) to determine the frequency of occurrence of VOD and the circumstances in which it arose., Methods: the patients studied had been autopsied at The Johns Hopkins Hospital, a referral center, between April 1981 and July 1993. We reviewed 275 adult HIV/AIDS patients autopsied with liver slides available for evaluation. Twenty cases fulfilled the pathologic criteria for VOD, central vein obliteration and sclerosis, sinusoidal congestion and fibrosis, and perivenular hepatocellular degeneration and necrosis. The autopsy cases were compared for age, race, gender, duration of HIV infection, and risk factor for the acquisition of HIV infection. The clinical and pathologic features of the 20 cases with VOD were reviewed., Results: of the 275 HIV/AIDS patients, 20 (7.3%) had VOD. The average age was 41 yr (range 30-58) and most cases were black males (15 black, 5 white, and 18 male). The duration of HIV infection ranged from 6 mo to 8 yr (mean, 19 mo). The risk factor for acquiring HIV infection was primarily intravenous drug abuse (12 of 20, 60%). Six patients had homosexual or bisexual contacts, and two had other or unknown risk factors. In contrast, among the total of 275 HIV/AIDS autopsied patients reviewed, only 72 (26%) reported intravenous drug abuse whereas 157 (57%) individuals listed homosexual or bisexual contacts as a risk for developing HIV infection. Forty-six patients (17%) had other or unknown means of HIV infection. Statistical analysis by risk factor showed that intravenous drug abuse was statistically significant as a predictor for the development of VOD in an HIV/AIDS patient (P < 0.005)., Conclusions: VOD of the liver can be seen in patients with HIV/AIDS and is associated with intravenous drug abuse.

Histopathological findings in the liver in a series of autopsies on 110 patients suffering from leukaemia or lymphoma were reviewed. No treatment had been given to 23 patients, 50 had received chemotherapy alone, 23 chemo- and radiotherapy and 14 underwent bone marrow transplantation. The 23 untreated patients showed neoplastic infiltration in 10 (44%) and fibrosis in 16 cases (70%). The 14 bone marrow recipients showed mainly acute necrosis, zonal in six (43%) and focal in one (7%), and cholestasis in five (36%), together with marked siderosis in 11 (79%). Patients receiving chemotherapy or chemo-/radiotherapy showed similar changes consisting of neoplastic infiltration in 14 (28%) and in five (22%) cases respectively, and fibrosis in 31 (62%) and 17 (74%) cases respectively. Steatosis was seen in 70% of cases in the chemo-/radiotherapy group and in 50% of cases in the other groups. Infections were seen in all groups, particularly in the chemotherapy group (four fungal and two bacterial including one tuberculosis) and in the chemo-/radiotherapy group (one fungal and one bacterial). Cytomegalovirus infection was seen only in the bone marrow transplant group.

Radiation-induced liver disease (RILD), often called radiation hepatitis, is a syndrome characterized by the development of anicteric ascites approximately 2 weeks to 4 months after hepatic irradiation. There has been a renewed interest in hepatic irradiation because of two significant advances in cancer treatment: three dimensional radiation therapy treatment planning and bone marrow transplantation using total body irradiation. RILD resulting from liver radiation can usually be distinguished clinically from that resulting from the preparative regime associated with bone marrow transplantation. However, both syndromes demonstrate the same pathological lesion: veno-occlusive disease. Recent evidence suggests that elevated transforming growth factor beta levels may play a role in the development of veno-occlusive disease. Three dimensional treatment planning offers the potential to determine the radiation dose and volume dependence of RILD, permitting the safe delivery of high doses of radiation to parts of the liver. The chief therapy for RILD is diuretics, although some advocate steroids for severe cases. The characteristics of RILD permit the development of a grading system modeled after the NCI Acute Common Toxicity Criteria, which incorporates standard criteria of hepatic dysfunction.

A 2-yr-old child with idiopathic pulmonary hemosiderosis and autoimmune thrombocytopenia developed hepatic veno-occlusive disease after being treated with long-term, low-dose cyclophosphamide. The authors believe that the injury was induced by cyclophosphamide. Although transplant dosages of cyclophosphamide alone or in conjunction with other drugs have been shown to induce hepatic venocclusive disease, this is the first case of hepatic venocclusive disease associated with nontransplant dosages of cyclophosphamide. Histopathologically, the injury was characterized by occlusive lesions of intrahepatic veins, both the terminal hepatic venules and portal veins branches, together with necrosis (predominately involving Zones 3 and 2) and hemorrhages. An added risk factor could have been release of platelet-derived growth factor that in turn activated and promoted proliferation of fibroblasts and smooth muscle cells in the vessels. Previously reported cases of cyclophosphamide-related injury are reviewed.

99mTc-DTPA-galactosyl human serum albumin (99mTc-GSA) is a new liver imaging agent which binds to heptic binding protein. This study evaluated the sensitivity of 99mTc-GSA kinetics and imaging anatomy to congestive hepatic injury in rats. Regional hepatic congestion was induced by clamping the left hepatic vein for 5, 10, 20, 40, or 90 min. After recanalization, 99mTc-GSA was intravenously administered to rats. A dynamic imaging study was performed, followed by static liver imaging performed for 5 min. A hepatic accumulation index, t90, was obtained on the basis of the dynamic data. A significant difference in t90 was observed between the experimental groups and the controls (p < 0.01). A significant difference in s-GPT also was observed between the experimental groups and the controls (p < 0.01). Excellent correlations were seen between t90 and ligation time (r = 0.967, p < 0.001), and t90 and s-GPT (r = 0.907, p < 0.001). Marked depression in hepatic 99mTc-GSA uptake was observed in rats with 40 or 90 min of hepatic vein occlusion. In conclusion, 99mTc-GSA is useful for evaluating hepatic injury in rats induced by hepatic vein occlusion.

We evaluated the relationship between the signs and symptoms of the clinical syndrome called veno-occlusive disease of the liver after bone marrow transplantation and the histological findings in 76 patients who later came to autopsy. Coded necropsy liver was scored for individual histological features that were correlated with prospectively assessed clinical features that the patients had exhibited during life. Patients were stratified into two groups: those with severe clinical veno-occlusive disease (n = 32) and those without. Clinically severe veno-occlusive disease was statistically correlated with several zone 3 acinar changes: occluded hepatic venules, the frequency of occluded hepatic venules x degree of occlusion, eccentric luminal narrowing/phlebosclerosis, zone 3 sinusoidal fibrosis and zone 3 hepatocyte necrosis (all p < or = 0.03). There was a significant relationship between the number of these histological abnormalities in zone 3 of the liver acinus and a clinical diagnosis of severe veno-occlusive disease (p = 0.003). The presence of ascites was significantly correlated with occluded venules, zone 3 sinusoidal fibrosis and zone 3 hepatocyte necrosis (p = 0.001). Maximum serum bilirubin in the first 20 days after transplant was significantly correlated with sinusoidal fibrosis, hepatocyte necrosis and eccentric luminal sclerosis/phlebosclerosis (p < 0.01) but not with venular occlusion. The clinical syndrome of liver toxicity (commonly called veno-occlusive disease) that results from cytoreductive therapy before bone marrow transplant is strongly correlated with a constellation of histological lesions involving structures in zone 3 of the liver acinus and the hepatic venules into which sinusoidal blood flows. This study suggests that there is no single diagnostic histological feature. The severity of clinical veno-occlusive disease appears to be proportional to the number of such histological changes and is not due solely to occlusion of small hepatic venules.

Three patients with multifocal recurrence of hepatocellular carcinoma following liver transplantation received palliative irradiation. Hyperfractionated irradiation (150 cGy/fraction b.i.d.) was delivered in two cases to the entire liver using parallel opposed oblique portals to a total dose of 30 Gy. Conventional irradiation (180 cGy/fraction) totaling 45 Gy was administered to the liver hilus with concomitant infusional 5-fluorouracil chemotherapy in the third case. Clinicopathologic correlations were performed. At autopsy all patients had massive tumor burden within the liver. Veno-occlusive changes were observed in two patients 1 and 2 months following completion of conventional and hyperfractionated irradiation, respectively. Liver transplantation in these two patients had been performed 18 and 16 months prior to palliative hepatic irradiation. In the third patient, no veno-occlusive changes were pathologically observed at autopsy 1 month after completing hyperfractionated radiation, which was delivered 6 months following liver transplantation. No significant differences in prior immunosuppressive therapy were identified among patients. Veno-occlusive changes are not spared by hyperfractionated radiation. Transplanted livers exhibit responses to radiation similar to those normally observed.

Fibrous stenosis of hepatic venules and other features of venous outflow obstruction, including zone 3 congestion and hemorrhage, are sometimes seen after orthotopic liver transplantation. similar changes associated with endothelial damage have recently been ascribed to azathioprine toxicity and may be forerunners of chronic rejection. Other potential causative agents such as viral hepatitis have yet to be considered. We reviewed 49 liver biopsy specimens from 21 consecutive patients after orthotopic liver transplantation, in whom full data including further follow-up biopsy samples were available. Hepatic venous stenosis was identified in seven patients who had received azathioprine and two additional patients in whom this change could not be ascribed to azathioprine. Stenosis was always associated with zone 3 hemorrhage and congestion and was first noted between 5 and 30 days after transplantation in all but two cases; in these two patients they were first noted after 72 and 133 days. Cellular rejection, including endotheliitis involving terminal hepatic venules, was found in five of the seven patients who had received azathioprine. Chronic (ductopenic) rejection was not seen during a follow-up period of between 97 and 540 days. In three of the nine patients with hepatic venular stenosis, zone 3 changes persisted, and in two of these azathioprine could not be held responsible. Of the 12 patients without hepatic venular stenosis, 10 had received azathioprine. Two of these 12 patients had peliosis-like foci but no other vascular abnormalities. Both also had moderate cellular rejection. Hepatic venular stenosis was found in 43% of patients after liver transplantation; this was usually associated with azathioprine administration and concomitant cellular rejection.(ABSTRACT TRUNCATED AT 250 WORDS)

Purpose: Pigs were used to evaluate temporary segmental hepatic venous occlusion as a means of improving the selective delivery of therapeutic agents within the liver., Materials and Methods: Hepatic angiography and scintigraphy were performed alone and in combination with hepatic venous occlusion., Results: Arteriograms obtained during venous obstruction demonstrated a greater number of peripheral arterial branches in the occluded area compared with the nonoccluded areas. A prolonged hepatogram showing hepatofugal opacification of the portal branches was observed in the occluded area. Microscopically, mild congestion of the sinusoids and central veins was seen immediately after 60-minute occlusion, but these changes were not evident 2 hours after balloon deflation. Severe congestion and focal hemorrhage were found in the occluded segment of the liver 2 hours after 90-minute venous occlusion. When the right or left hepatic vein was occluded during hepatic arterial infusion of technetium-99m macroaggregated albumin, there was a significant (P < or = .05) increase in the amount of radioactivity measured in the obstructed segment and a significant (P < or = .05) decrease in that found in the nonoccluded regions., Conclusion: These results indicate that temporary segmental hepatic vein occlusion is safe for up to 60 minutes and may be clinically applicable as a means of improving the therapeutic index of agents within the liver when they are administered via concomitant hepatic arterial infusion.

Hepatic veno-occlusive disease (VOD) is a non-thrombotic obliteration of the lumina of small intrahepatic veins. VOD has been reported after exposure to a wide variety of pathogens. It has been suggested that the chemoradiotherapy used as the conditioning regimen for bone marrow transplant (BMT) is now the main cause of this disease. However, the pathogenesis of VOD after BMT is probably multifactorial. Endothelial injury of sinusoids and small hepatic veins is considered to be the initial event in genesis of VOD. This injury is followed by deposition of fibrin-related aggregates in the subendothelial zone. These aggregates, and the intramural entrapment of fluid and cellular debris, occlude progressively the hepatic venous outflow and generate a postsinusoidal intrahepatic hypertension. Clinically, VOD is characterized by jaundice, weight gain, ascites, painful hepatomegaly and platelet refractoriness developing early post transplant, although other posttransplant liver disturbances can produce a similar syndrome. VOD diagnosis is usually established by applying the clinical criteria proposed by the Seattle and Baltimore groups. When clinical diagnosis of VOD is uncertain, a transjugular liver study including a transvenous biopsy and measurement of the gradient between wedged and free hepatic venous pressure, is recommended in order to establish an accurate diagnosis. According to the literature data, the incidence of VOD ranges from 0 to 70% and its mortality from 20 to 50%. This very wide range is attributable to the different incidence of risk factors in the different series and to the differences in applying the diagnostic criteria.(ABSTRACT TRUNCATED AT 250 WORDS)

Among 217 patients who received an allogeneic (136 cases) or autologous (81 cases) bone marrow transplant, the diagnosis of hepatic veno-occlusive disease (VOD) was established in 38 according to Seattle clinical criteria. Thirty-two underwent a transjugular liver biopsy and measurement of the hepatic venous pressure gradient (HVPG). The study was completed in 30 patients with no serious complications. Hepatic VOD was histologically confirmed in 18 patients (60%); the remaining 12 were classified as non-VOD. An increased HVPG discriminated well between VOD and non-VOD cases. Thus, hemodynamic data can considerably reinforce the accuracy of histological diagnosis. The predictive value of two vs. three clinical data of the Seattle criteria was analyzed. Among the 19 cases fulfilling two clinical data VOD was confirmed in only eight (42%), whereas VOD was proved in ten of 11 cases (91%) (p = 0.02) suspected on the basis of three clinical data. When reliability of the Baltimore clinical criteria was analyzed, the result was identical to that observed when three Seattle clinical data were present. The specificity of the latter classification was high (92%) while its sensitivity was relatively low (56%). In conclusion, clinical criteria are not reliable for either recognizing or excluding the diagnosis of VOD. Thus, a transjugular liver biopsy, associated with hemodynamic evaluation, is strongly recommended when VOD is clinically suspected.

Azathioprine vascular hepatotoxicity has been described mainly after renal transplantation. We report a new case in a patient who developed veno-occlusive disease of the liver 3 weeks after liver transplantation; regression of lesions were observed after discontinuation of azathioprine therapy. In this case, azathioprine hepatotoxicity may have been enhanced by a previous episode of severe, acute rejection prevailing in the hepatic veins. After liver transplantation, the diagnosis of azathioprine hepatotoxicity is difficult but should be suspected in the presence of non-inflammatory small hepatic veins lesions. Early withdrawal of the drug is mandatory for complete recovery.

Two patients with Stage I papillary serous carcinoma of the endometrium treated with postoperative whole abdominal radiation developed elevated CA-125 levels. In neither patient was evidence of recurrent disease identified. Hepatic veno-occlusive disease, a known complication of whole abdominal radiation and certain chemotherapy regimens, was confirmed by liver biopsy in both cases. CA-125 levels may not be reflective of disease status in this setting.

Hepatic venoocclusive disease is a frequent lethal complication of bone marrow transplantation. It has also been associated with hepatic irradiation and administration of chemotherapeutic agents without BMT. The pathogenesis and therapy of VOD are unclear. The present studies were directed at developing a canine model for VOD. Three groups of dogs were studied. Group one consisted of 8 dogs in which monocrotaline (MC) was administered at 125 mg/kg orally on an intermittent schedule. In 7 of the 8 dogs 6 to 9 doses of drug were administered between 42 and 110 days. Group 2 consisted of 6 dogs receiving busulfan 2 mg/kg/day for 17-25 days, when platelet counts decreased to less than 5 x 10(4)/mm3 or clinical bleeding occurred. Group 3 consisted of 2 dogs receiving 24 Gy and 4 dogs receiving 36 Gy of whole-liver irradiation. Seven of 8 dogs in group 1 developed significant liver function abnormalities and evidence of portal hypertension. Histologic findings of VOD were present at autopsy. Group 2 dogs failed to develop clinical or laboratory liver abnormalities, but 3 of 6 animals had minimal histologic evidence of VOD. Three of 6 dogs in group 3 receiving 36 Gy developed hepatic dysfunction and had findings of fibrosis at autopsy. It was concluded that MC administration produced consistent clinical and histologic features of VOD in dogs. Changes occurring after busulfan or total-liver irradiation administration were less reproducible. Dogs are a suitable large-animal model for studies of VOD.

Veno-occlusive disease (VOD) of the liver is a serious and often lethal sequela to bone marrow transplantation. Although a history of prior hepatitis moderately increases the risk of VOD, reliable screening methods for identifying high risk patients are not available. New approaches to managing patients who develop serious VOD are needed. One approach may be the use of orthotopic liver transplantation in selected patients who are likely to die of the disease. In this report we describe a patient who underwent liver transplantation for life-threatening VOD following allogeneic transplantation for CML. Although this patient died early from interstitial pneumonitis, the orthotopic liver functioned well up to her death. Other reports describing successful liver transplants in patients with advanced VOD or graft-versus-host disease of the liver are discussed and the possible indications for liver transplantation for VOD after marrow transplantation are considered. Taken together, these reports suggest that orthotopic liver transplantation may be a feasible and potentially effective approach to managing select patients with life-threatening liver dysfunction after marrow transplantation.

A 37-year-old man with acute myeloblastic leukemia (FAB M2) in first remission underwent a bone marrow transplant (BMT) following conditioning with high-dose cytarabine and total body irradiation. The donor was an HLA-identical brother. Graft rejection occurred and a second BMT was performed from the same donor following conditioning with cyclophosphamide. Engraftment was achieved, but the patient developed severe jaundice and died of respiratory failure on day +46 after the second BMT. Liver biopsy revealed luminal narrowing of the central veins and a diagnosis of hepatic veno-occlusive disease (VOD) was made. The coagulation studies showed a prolonged kaolin clotting time which was not corrected by 1:1 mixture with normal plasma, and the platelet neutralization test was positive. Dilute tissue thromboplastin time and dilute Russell viper venom time were also prolonged. These results fulfilled the criteria for lupus anticoagulant, which may have contributed to VOD in this patient.

To clarify the relation of pericentral fibrosis to portal hypertension, measurements of portal vascular resistance in vitro and blood pressures of several key points in hepatic vascular pathways in vivo were undertaken in rats given dimethylnitrosamine. Administration of dimethylnitrosamine induced tortuosity and narrowing of the peripheral branches of the hepatic vein due to pericentral fibrosis. No significant change was produced in the sinusoids and the portal vein branches. The portal vascular resistance was increased and the portal vein pressure was elevated markedly. The blood pressure gradient was steep in the intrahepatic vein, but not in the intrahepatic portal vein or the sinusoids, as compared to control. These data suggest that deformation of the peripheral branches of the hepatic vein due to pericentral fibrosis causes a marked increase in vascular resistance in the intrahepatic hepatic vein, i.e. postsinusoidal portal hypertension.

Livers from 54 snow leopards, 4 days to 23 years old, that had died in 23 US zoos, were evaluated histopathologically to determine if the hepatic fibrosis, which has been noted to be prevalent in this species, was due to chronic active hepatitis from hepadnaviral infection, Ito cell proliferation, or hemosiderosis. Forty-two of 54 snow leopards had subintimal vascular fibrosis with partial or total occlusion of central and sublobular veins (veno-occlusive disease) of unknown origin. All 21 leopards older than 5 years were affected. Four leopards had chronic active hepatitis, and 12 leopards had cholangiohepatitis; but these lesions were not connected anatomically to central and sublobular venous fibrosis. Hepatocellular and Kupffer cell siderosis and Ito cell proliferation were prevalent and often coexisted with perisinusoidal, central, and sublobular venous fibrosis; but fibrosis was present in leopards without siderosis or Ito cell proliferation. The pattern and prevalence of veno-occlusive disease in these leopards was similar to that reported in captive cheetah (Acinonyx jubatus), suggesting that a common extrinsic factor may cause the majority of hepatic disease in these large felid animals in captivity.

A rare syndrome of portal hypertension with esophageal varices but without evidence of cirrhosis in the liver biopsy was seen in 3 patients in a series of 1000 renal allotransplant recipients immunosuppressed with azathioprine and prednisone. The liver disease began 3-6 years after transplantation with abnormal liver function tests and esophageal varices with bleeding episodes. One patient had also ascites. Liver biopsy at the beginning of liver disease showed in one patient normal structure which eventually developed to slight diffuse fibrosis and nodular hyperplasia. One patient had diffuse fibrosis, and the third patient had strong sinusoidal engorgement with nodular hyperplasia, later on developing to cirrhosis. One patient is still alive and well, the two others died from liver insufficiency. 39 cases of non-cirrhotic portal hypertension in renal transplant recipients and histologic evidence of peliosis, sinusoidal dilatation, nodular hyperplasia or hepatic veno-occlusive disease have been identified in the literature. The cause of this disease is presumably azathioprine, but its rarity shows that it must depend also on other factors.

Focal veno-occlusive lesions and congestion of the liver are found frequently at autopsy in patients with metastatic carcinoma in the liver. In 6 cases, intimal proliferation of loose connective tissue with dilatation of lymphatic capillaries was seen continuously from the terminal hepatic venule to the hepatic vein, and cancer cells were found only in lymphatic capillaries in the wall of the hepatic vein. In 7 cases, cancer cells infiltrated directly into the adventitia of the sublobular vein and intimal proliferation of loose connective tissue with or without formation of recent thrombi was observed. A main causative factor of hepatic veno-occlusive disease is thought to be leakage of plasma due to endothelial injury to the terminal hepatic venule and sublobular vein. Lymphatic obstruction, in addition to a direct reaction to invasion of cancer cells to the vessel wall, may also cause veno-occlusive lesions due to stasis and leakage of lymph fluid into the intima of the terminal hepatic venule, sublobular vein and hepatic vein.

Hepatic injury secondary to arsenic poisoning has been known long but is poorly documented. A case of a patient with hepatic injury following severe arsenic poisoning is reported. Histological study of the liver demonstrated acute venoocclusive disease and perisinusoidal fibrosis. This case indicates that arsenic poisoning causes veno-occlusive disease in humans. It also suggests that hepatic damage in arsenic poisoning is secondary to vascular endothelial injury and supports the hypothesis that different patterns of hepatic vascular injury might proceed from a common mechanism.

Forty-two cases of hepatic venous outflow obstruction with biopsied and autopsied specimens were studied. The morphological changes in the liver and the value of liver tissue in the diagnosis among the different subgroups of this conditions were evaluated. Seven cases in the group with veno-occlusive disease (VOD) showed prominent changes in the sublobular veins and terminal hepatic venules and were characterized by acute disruption of the vessel walls. Two cases showed thrombosis in which there were history of chemotherapy. In the group with Budd-Chiari's syndrome (BCS), in addition to the involvement of the large veins, thrombosis was observed in the small hepatic vein radicles in five out of six cases with myeloproliferative related disorders. Thrombosis was rarely present in cases associated with idiopathic and web lesions in BCS but frequent large vessel tumor thrombosis was noted in the group with malignant tumors. The hepatic parenchymal changes in the VOD group and the tumor related cases in BCS group were acute perivenular congestion, hemorrhage and coagulative necrosis, whereas the histological changes in other subgroups of BCS were perivenular scarring, dilatation of the sinusoids and rarely, reversed lobulation. Subtle differences were noted in the vascular system and the liver parenchyma between each subgroup. If good clinical information is available, it is possible to differentiate the various etiologies in hepatic venous outflow obstruction in the liver by morphology.

We report two adult patients whose liver biopsy specimens revealed numerous ground-glass hepatocytes due to inclusions resembling Lafora bodies. The inclusions were large, intracytoplasmic, pale, eosinophilic and kidney-shaped and were periodic acid-Schiff positive and HBsAg negative. Immunoperoxidase studies showed that the inclusions were positive for cytokeratins and alpha 1-antitrypsin. In case 1, the inclusions were not membrane-bound and consisted of secondary lysosomes and degenerate organelles including rough and smooth endoplasmic reticulum. In case 2, electronmicroscopy showed the inclusions were not membrane-bound, but consisted of dense granules, fibrils and vacuoles, with appearances very similar to Lafora bodies. Neither patient had myoclonus or epilepsy. Electronmicroscopy is important in differentiating the type of Lafora body like inclusions found in liver biopsies.

In a review of 29 patients who were surgically treated by combined hepatic and portal decompression for intractable ascites, 18 were identified as falling into the category of the Budd-Chiari syndrome, with varying causes. Of this group, 2 patients were distinguished by the classical hepatic venous endophlebitis described by Chiari and later by Bras et al. Recently, this disease entity has been recognized as being due to the toxic effects of pyrrolizidine alkaloids contained in the Senecio and Crotolaria plants. In the first of these two cases the patient had emigrated from Jamaica and was exposed to "bush trees," but no chemical measurements were done. The second patient had consumed a large amount of comfrey teas, which were shown to contain high levels of pyrrolizidine alkaloids. These two cases add further weight to the existing evidence of the toxic effect of these alkaloids, and also demonstrate the effectiveness of hepatic and portal decompression.

A 23 year old man presented with hepatic veno-occlusive disease and severe portal hypertension and subsequently died from liver failure. Light microscopy and hepatic angiography showed occlusion of sublobular veins and small venous radicles of the liver, associated with widespread haemorrhagic necrosis of hepatocytes. The patient had been on a predominantly vegetarian diet and, prior to his illness, took comfrey leaves which are known to contain hepatotoxic pyrrolizidine alkaloids. Comfrey is widely used as a herbal remedy, but so far has only been implicated in two other documented cases of human hepatic veno-occlusive disease. A possible causal association of comfrey and this patient's veno-occlusive disease is suggested by the temporal relationship of the ingestion of comfrey to his presentation, the histological changes in the liver and the exclusion of other known causes of the disease.

The prevalence of Inferior Right Hepatic Veins (IRHVs) in 82 children who had magnetic resonance imaging (MRI) of the abdomen was assessed. IRHVs larger than or equal in size to the Superior Right Hepatic Vein were found in 23% (19/82). In two patients with radiological evidence of Superior Hepatic Venous occlusion and without radiological evidence of portal hypertension, venous drainage was accomplished via large IRHVs. The findings suggest that, in children, IRHVs may act as efficient collaterals and help protect the liver from the consequences of high IVC obstruction.

Severe hepatic venous outflow obstruction and its manifestations often are recorded under the label "Budd-Chiari syndrome." Unfortunately, this label is ambiguous; it does not clearly identify the site of the lesion (hepatic veins versus inferior vena cava), its morphologic features (thrombotic versus nonthrombotic), or its cause. In the literature, implied or expressed definitions vary. Use of a standardized topographic and pathogenetic classification of hepatic venous outflow obstruction would enable investigators to group patients with comparable conditions, as required for therapeutic trials, prognostic evaluations, and studies of pathogenetic pathways. Review of our own cases revealed that hepatic venous outflow obstruction involving large hepatic veins is usually thrombotic and that isolated obstruction of the inferior vena cava or of small hepatic veins is usually nonthrombotic. Application of such a classification seems feasible and may yield useful results.

This paper summarizes the use of morphometry on human autopsy livers to investigate three conditions characterized by the presence of hepatocellular nodules: nodular regenerative hyperplasia (NRH), partial nodular transformation (PNT) and focal nodular hyperplasia (FNH). Vascular abnormalities were seen in all cases. The nodules can be explained in all three conditions as a response to a greater blood supply in the nodules as compared to the surrounding parenchyma. In NRH, there appears to be ischemia caused by arteritis and secondary oblitertion of small portal veins. In PNT, ischemia may be caused by portal vein thrombosis. In FNH, there appears to be hyperemia caused by a spiderlike arterial anomaly.

A 54-year-old woman with metastatic breast cancer developed veno-occlusive disease of the liver following chemotherapy with mitomycin C and doxorubicin. The dose of mitomycin C received by this patient was much lower than that previously described to cause this complication. As both these drugs are used widely physicians should be aware of this complication.

Hepatic venocclusive disease developed in a 14-yr-old white girl after allogenic bone marrow transplantation from an HLA-identical sibling donor. Clinical diagnosis of venocclusive disease was based on the development of ascites, hepatomegaly, and jaundice 3 wk after transplantation. Current treatment of hepatic venocclusive disease is ineffective. The pathophysiology of the hepatic lesion suggests that construction of a side-to-side portacaval shunt should be beneficial in relieving the ascites and preventing further hepatic damage. Because the ascites was refractory to medical therapy and she was clinically deteriorating, a side-to-side portacaval shunt was performed. Histologic examination of a liver biopsy specimen obtained at surgery documented the presence of venocclusive disease. Postoperatively, the patient diuresed and returned to her baseline weight. One year after surgery the patient was doing well, her weight was stable, and she was being maintained on salt restriction alone. While the resolution of ascites and improvement of hepatic function in our patient after side-to-side portacaval shunt does not guarantee that such an approach will be uniformly successful, it should serve to encourage others to consider such therapy for this frequently devastating complication of chemoradiation therapy.

Severe hepatic vascular disease developed in two patients 4 and 8 years after kidney transplantation, while receiving combined immunosuppressive therapy with prednisone and azathioprine. Portal hypertension and marked liver failure were observed in both cases. The diagnosis was established by histological examination of liver biopsies showing typical veno-occlusive disease of the liver associated with peliosis in both cases. Azathioprine was discontinued. Two years later one patient was asymptomatic and liver function tests were normal. The second patient died 3 years later from liver failure. Early recognition of hepatic vascular disease arising in kidney transplant recipients would be of utmost importance, as substitution of another immunosuppressive agent for azathioprine could halt the process leading to portal hypertension.

One hundred and fifty-one consecutive patients underwent allogeneic bone marrow transplantation (B.M.T.) following high-dose chemotherapy and single dose total body irradiation (T.B.I.) for hematologic malignancies between September 1980 and December 1985. All patients included in this study were treated using a 60 Co beam to deliver a prescribed dose of 10 Gy to the mid-plane of the abdomen. Total body irradiation was performed the day before B.M.T. The mean instantaneous dose-rate was 3.5 cGy/min (range: 2.6 to 4.7). The real dose received was measured using thermoluminescent dosimeters (lithium borate). The difference between the doses delivered to the liver and to the mid-plane of the abdomen did not exceed 5%. The mean real dose delivered to the reference point was 10 Gy (range 8.3 to 11.7). Ninety five per cent of the patients received a dose ranging from 9.1 Gy to 10.9 Gy. High-dose cyclophosphamide was given to 126 patients with a "standard-risk" of relapse (60 mg/kg on day 5 and 4 before B.M.T.). Chemotherapy was intensified by the addition of other drugs in 25 patients with "higher-risk" of relapse. We analyzed the effect of the following pretransplant characteristics on the subsequent posttransplant development of V.O.D.: age, sex, ASAT and/or ALAT before conditioning regimen, diagnosis and status of malignant disease, history of liver disease, interval between diagnosis of hematologic malignancy and B.M.T., conditioning regimen (i.e., classical or intensified) and dose delivered to the liver during T.B.I. Seventeen patients were classified as having clinical V.O.D. giving a prevalence of 11.2%. In the first 2 months following B.M.T., death occurred respectively in 9 of 17 (53%) and 23 of 134 (17%) patients with and without clinical V.O.D. Univariate analysis showed that four characteristics were significantly related to an increased prevalence of V.O.D.: sex (11/62 females vs 6/89 males; p less than 0.05); history of liver disease (7/28 vs 10/117 patients without antecedent; p less than 0.01); ASAT and/or ALAT levels greater than 1.5 upper normal limit (11/49 vs 6/102 patients with levels less than 1.5; p less than 0.01) and intensified conditioning regimen (6/25 vs 11/126 patients with classical regimen; p less than 0.05). The conditioning regimen and history of liver disease were highly correlated to transaminases levels. Only two factors, transaminases levels and female sex, remained significantly associated with V.O.D. after multivariate analysis.

The authors attempted to induce hepatic veno-occlusive disease (VOD) in 64 dogs. Preparative treatments included combinations of total-body irradiation (TBI) or localized hepatic irradiation (LI) or both and chemotherapy consisting of dimethylbusulfan (DMB), L-phenylalanine mustard (L-PAM), methotrexate, or monocrotaline. VOD occurred infrequently in those dogs given 9.2 Gy TBI and DMB (1/10), TBI and/or LI (9.2-27 Gy) with L-PAM (2/36) or high dose methotrexate and LI (0/2). Specifically, VOD occurred in the dogs with a shorter interval between TBI and DMB or in the dog that received the glutathione reductase inhibitor, buthionine sulfoximide (BSO) before L-PAM. In contrast, among 17 dogs given monocrotaline, 8 developed VOD, particularly when used with L-PAM +/- irradiation (7/13). The major cause of death, early gastrointestinal toxicity, was further augmented by higher doses of irradiation, by shortening the interval between LI and L-PAM administration to less than 4 weeks, and administering BSO or monocrotaline before L-PAM. Gastrointestinal toxicity was lessened by giving low dose cyclophosphamide given before L-PAM. VOD can be produced in dogs especially with monocrotaline or BSO given before and L-PAM +/- irradiation. However, gastrointestinal toxicity renders the study of VOD beyond the acute phase difficult. Nevertheless, this approach appears useful for the study of VOD in other animals and for developing agents aimed at preventing VOD.

The authors immunostained autopsy liver tissue from 31 marrow transplant recipients, 19 with hepatic veno-occlusive disease (VOD) and 12 without VOD. A panel of monoclonal and polyclonal antibodies was used to characterize the materials within the occluded venous lesions and to define the location and types of injured cells. Most patients with early VOD (survival less than 50 days, n = 11) had dense periadventitial and intramural immunostaining of terminal hepatic and sublobular central venules (CV) with anti-Factor VIII (9/11) and anti-fibrinogen (4/4) but had no immunostaining with antibody to platelet GPIb. Early VOD patients also had marked loss of Zone 3 hepatocyte cytokeratin (8/9) versus late VOD (1/5) or non-VOD (2/7). Patients with late VOD lesions (n = 8, survival greater than 50 days) had increased collagen within occluded VOD lesions. Type III much greater than Type I, and increased sinusoidal collagens Types I, III, and IV. These studies and other data suggest the following events in the genesis of VOD. Initial injury to endothelium of CV and/or sinusoids and possibly also to Zone 3 hepatocytes triggers the coagulation cascade in the periadventitial zone of CV. The late sequela, collagenous CV occlusion, results from activated mural myofibroblasts and/or embolized Ito cells and hepatocytes.

A patient with rheumatoid arthritis developed hepatic veno-occlusive disease following the use of azathioprine. Although azathioprine induced veno-occlusive disease is suspected to occur more frequently in patients with autoimmune dysfunction, it has not previously been reported as a complication of treatment in rheumatoid arthritis. The mechanism responsible for this condition remains unknown.

Review of 235 consecutive patients undergoing bone marrow transplantation was performed in order to define the clinical syndrome of venoocclusive disease of the liver (VOD) in these patients. Analysis of all patients with histologically proven VOD revealed a consistent clinical syndrome of liver dysfunction occurring within the first 3 weeks after marrow infusion. This was characterized by hyperbilirubinemia peaking at greater than or equal to 2 mg/dl with at least 2 of 3 other findings: hepatomegaly, ascites, and 5% or greater weight gain. VOD developed in 22% (52 of 235). A persistently elevated aspartate aminotransferase (SGOT) prior to transplant was associated with an increased risk of developing VOD by multivariate analysis (P = 0.0003), and acute leukemia in first remission was associated with a decreased risk (P = 0.02). Neither the preparative regimen (busulfan and cyclophosphamide versus cyclophosphamide and total body irradiation) nor the type of graft (allogeneic versus autologous) influenced the occurrence. Twenty-four of these 52 patients (47%) died with VOD (10% of the entire group). This makes VOD the third leading cause of death in our allogeneic graft recipients, and the second leading cause in our patients receiving autologous transplants. VOD is a common complication of bone marrow transplantation and has a specific clinical presentation, which usually allows diagnosis without the need of liver biopsy.