Vasopressin and nitroglycerin decrease portal and hepatic venous pressure and hepato-splanchnic blood flow.

BACKGROUND: Various methods are used to reduce venous blood pressure in the hepato-splanchnic circulation, and hence minimise blood loss during liver surgery. Previous studies show that combination of vasopressin and nitroglycerin reduces portal pressure and flow in patients with portal hypertension, and in this study we investigated this combination in patients with normal portal pressure. METHOD: In all, 13 patients were studied. Measurements were made twice to confirm baseline (C1 and BL), during vasopressin infusion 4.8 U/h (V), and during vasopressin infusion combined with nitroglycerin infusion (V + N). Portal venous pressure (PVP), hepatic venous pressure (HVP), central haemodynamics and arterial and venous blood gases were obtained at each measuring point, and portal (splanchnic) and hepato-splanchnic blood flow changes were calculated. RESULTS: Vasopressin alone did not affect PVP, whereas HVP increased slightly. In combination with nitroglycerin, PVP decreased from 10.1 ± 1.6 to 8.9 ± 1.3 mmHg (P < 0.0001), and HVP decreased from 7.9 ± 1.9 to 6.2 ± 1.3 mmHg (P = 0.001). Vasopressin reduced portal blood flow by 47 ± 19% and hepatic venous flow by 11 ± 18%, respectively. Addition of nitroglycerin further reduced portal- and hepatic flow by 55 ± 13% and 30 ± 13%, respectively. Vasopressin alone had minor effects on central haemodynamics, whereas addition of nitroglycerin reduced cardiac index (3.2 ± 0.7 to 2.7 ± 0.5; P < 0.0001). The arterial-portal vein lactate gradient was unaffected. CONCLUSION: The combination of vasopressin and nitroglycerin decreases portal pressure and hepato-splanchnic blood flow, and could be a potential treatment to reduce bleeding in liver resection surgery.

Plumbagin Alleviates Capillarization of Hepatic Sinusoids In Vitro by Downregulating ET-1, VEGF, LN, and Type IV Collagen.

Critical roles for liver sinusoidal endothelial cells (LSECs) in liver fibrosis have been demonstrated, while little is known regarding the underlying molecular mechanisms of drugs delivered to the LSECs. Our previous study revealed that plumbagin plays an antifibrotic role in liver fibrosis. In this study, we investigated whether plumbagin alleviates capillarization of hepatic sinusoids by downregulating endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), laminin (LN), and type IV collagen on leptin-stimulated LSECs. We found that normal LSECs had mostly open fenestrae and no organized basement membrane. Leptin-stimulated LSECs showed the formation of a continuous basement membrane with few open fenestrae, which were the features of capillarization. Expression of ET-1, VEGF, LN, and type IV collagen was enhanced in leptin-stimulated LSECs. Plumbagin was used to treat leptin-stimulated LSECs. The sizes and numbers of open fenestrae were markedly decreased, and no basement membrane production was found after plumbagin administration. Plumbagin decreased the levels of ET-1, VEGF, LN, and type IV collagen in leptin-stimulated LSECs. Plumbagin promoted downregulation of ET-1, VEGF, LN, and type IV collagen mRNA. Altogether, our data reveal that plumbagin reverses capillarization of hepatic sinusoids by downregulation of ET-1, VEGF, LN, and type IV collagen.

Magnetic Resonance Elastography Shear Wave Velocity Correlates with Liver Fibrosis and Hepatic Venous Pressure Gradient in Adults with Advanced Liver Disease.

Background. Portal hypertension, an elevation in the hepatic venous pressure gradient (HVPG), can be used to monitor disease progression and response to therapy in cirrhosis. Since obtaining HVPG measurements is invasive, reliable noninvasive methods of assessing portal hypertension are needed. Methods. Noninvasive markers of fibrosis, including magnetic resonance elastography (MRE) shear wave velocity, were correlated with histologic fibrosis and HVPG measurements in hepatitis C (HCV) and/or HIV-infected patients with advanced liver disease enrolled in a clinical trial of treatment with simtuzumab, an anti-LOXL2 antibody. Results. This exploratory analysis includes 23 subjects: 9 with HCV monoinfection, 9 with HIV and HCV, and 5 with HIV and nonalcoholic steatohepatitis. Median Ishak fibrosis score was 4 (range 1-6); 11 subjects (48%) had cirrhosis. Median HVPG was 6 mmHg (range 3-16). Liver stiffness measured by MRE correlated with HVPG (r = 0.64, p = 0.01), histologic fibrosis score (r = 0.71, p = 0.004), noninvasive fibrosis indices, including APRI (r = 0.81, p < 0.001), and soluble LOXL2 (r = 0.82, p = 0.001). On stepwise multivariate regression analysis, MRE was the only variable independently associated with HVPG (R2 = 0.377, p = 0.02). Conclusions. MRE of the liver correlated independently with HVPG. MRE is a valid noninvasive measure of liver disease severity and may prove to be a useful tool for noninvasive portal hypertension assessment. Trial Registration Number. This trial is registered with NCT01707472.

Feeding soy protein isolate and n-3 PUFA affects polycystic liver disease progression in a PCK rat model of autosomal polycystic kidney disease.

OBJECTIVE: In polycystic liver disease (PCLD), multiple cysts cause liver enlargement, structural damage, and loss of function. Soy protein and dietary ω-3 polyunsaturated fatty acids (n-3 PUFAs) have been found to decrease cyst proliferation and inflammation in polycystic kidney disease. Therefore, the aim of the study was to investigate whether soy protein and n-3 PUFA supplementation attenuates PCLD. METHODS: Young (age 28 days) female PCK rats were fed (n = 12 per group) either casein + corn oil (casein + CO), casein + soybean oil (casein + SO), soy protein isolate + soybean oil (SPI + SO), or SPI + 1:1 soybean/salmon oil blend (SPI + SB) diet for 12 weeks. Liver histology, gene expression by real-time quantitative polymerase chain reaction, and serum markers of liver injury were determined. RESULTS: Diet had no effect on PCLD progression as indicated by no significant differences in liver weight and hepatic proliferation gene expression between diet groups. PCK rats fed SPI + SB diet, however, had the greatest (P < 0.05) histological evidence of hepatic cyst obstruction, portal inflammation, steatosis, and upregulation (P = 0.03) of fibrosis-related genes. Rats fed SPI + SB diet also had the lowest (P < 0.001) serum cholesterol and higher (P < 0.05) serum alkaline phosphatase and bilirubin concentrations. CONCLUSIONS: Feeding young female PCK rats SPI and n-3 PUFA failed to attenuate PCLD progression. Furthermore, feeding SPI + SB diet resulted in complications of hepatic steatosis attributable to cysts obstruction of bile duct and hepatic vein. Based on the results, it was concluded that diet intervention alone was not effective at attenuating PCLD associated with autosomal recessive polycystic kidney disease.

Acute intraoperative effect of intravenous amiodarone on right ventricular function in patients undergoing valvular surgery.

BACKGROUND: Amiodarone is commonly used in the acute care setting. However the acute hemodynamic and echocardiographic effect of intravenous amiodarone administered intraoperatively on right ventricular (RV) systolic and diastolic function using transesophageal echocardiography (TEE) has not been described. METHODS: The study design was a randomized controlled trial in elective cardiac surgical patients undergoing valvular surgery. Patients received an intravenous loading dose of 300 mg of either amiodarone or placebo in the operating room, followed by an infusion of 15 mg/kg for two days. Hemodynamic profiles, echocardiographic measurement of RV and left ventricular (LV) dimensions, Doppler interrogation of tricuspid and mitral valve, hepatic and pulmonary venous flow combined with tissue Doppler imaging of the tricuspid and mitral valve annulus were obtained before and after bolus. RESULTS: Although more patients in the placebo group had chronic obstructive lung disease (14 vs 6, p=0.05) and diabetes (14 vs 5; p=0.0244), there was no difference in terms of baseline hemodynamic, 2D and Doppler variables. After bolus, a significant increase in pulmonary artery pressure, central venous pressure and pulmonary vascular resistance index (p<0.05) was observed in the amiodarone group with reduction in systolic to diastolic (S/D) ratio of the hepatic (p=0.0247) and pulmonary venous (p=0.0052) velocity. CONCLUSION: Acute administration of amiodarone is associated with alteration in RV diastolic properties and has minimal negative inotropic effect on RV systolic function in cardiac surgical patients with valvular disease.

Reversal of attachment to or invasion of major intrahepatic vessels by colorectal liver metastases according to prehepatectomy chemotherapy regimen.

BACKGROUND: Tumor reduction by present-day prehepatectomy chemotherapy can render initially unresectable disease resectable. However, little is known about whether effects on liver metastases with radiologically defined "attachment to or invasion of" major intrahepatic vessels differ between chemotherapy regimens with or without monoclonal antibodies. We compared histologically the relationships between liver tumors and major intrahepatic vessels after chemotherapy according to regimens used to treat colorectal liver metastasis. METHODS: In 38 patients who underwent chemotherapy and hepatectomy with pretreatment images showing metastases attached to or invading major intrahepatic vessels, 62 metastases showed attachment to or invasion of 88 vessels. After resection, attachment, invasion, and separation were determined histopathologically in resected specimens. RESULTS: Thirteen patients received cytotoxic drug combinations alone, whereas 25 were treated with regimens including a monoclonal antibody (bevacizumab in 15 and cetuximab in 10). By imaging, 16% (5/32) of vessels in patients receiving cytotoxic drugs alone, 23% (8/35) of vessels in those also receiving bevacizumab, and 48% (10/21) of vessels in those also receiving cetuximab showed detachment after chemotherapy (P = .015 for cetuximab versus cytotoxic and P = .039 for cetuximab versus bevacizumab). Excluding 8 vessels not evaluated histologically, 23 of 31 vessels in the cytotoxic group remained attached or invaded, as did 16 of 29 in the bevacizumab group and 8 of 20 vessels in the cetuximab group (P = .05 versus cytotoxic). CONCLUSION: Prehepatectomy chemotherapy regimens including monoclonal antibodies, particularly anti-epidermal growth factor receptor antibodies, eradicated attachment or invasion between vessels and metastases more frequently. Individualized strategies for prehepatectomy chemotherapy based on intrahepatic location of metastases may offer advantages according to proximity of the metastases to the major intrahepatic vessels.

Review article: the therapeutic and prognostic benefit of portal pressure reduction in cirrhosis.

BACKGROUND: Hepatic venous pressure gradient (HVPG) measurement is not a routinely used technique, despite its therapeutic and prognostic value. AIM: To review the role of HVPG from published literature. METHODS: Systematic literature review. RESULTS: In acute variceal bleeding, HVPG is prognostic identifying 'difficult to treat' group, which now has defined clinical correlations. In secondary prevention of portal hypertensive bleeding, a reduction to < or = 12 mmHg confers near complete protection against rebleeding. The target of > or = 20% HVPG reduction from baseline needs prospective assessment to test a change of therapy, if no reduction occurs. The acute HVPG response to beta-blockade needs further assessment. In primary prevention, the cost-effectiveness of HVPG measurement is not favourable given the efficacy of medical therapy. In chronic liver disease, wedge hepatic venous pressure (WHVP) is prognostic for survival. Pharmacological reduction in portal pressure decreases complications and improves survival, possibly independent of a concomitant improvement in liver function. This latter requires urgent confirmation as it is clinically very relevant. HVPG monitoring can be used to assess anti-viral therapy particularly in cirrhosis, ergonomically combined with transjugular biopsy. CONCLUSIONS: The prognostic and therapeutic value of HVPG is established beyond portal hypertensive bleeding for which there are some clinical surrogates. HVPG measurement should now be part of everyday clinical practice.

improved patency of transjugular intrahepatic portosystemic shunt: the efficacy of cilostazol for the prevention of pseudointimal hyperplasia in swine TIPS models.

PURPOSE: To investigate the efficacy of oral administration of cilostazol to inhibit pseudointimal/intimal hyperplasia in swine TIPS models. METHODS: Successful TIPS creation was carried out in 11 of 12 healthy young pigs (20-25 kg). In the treatment group (n = 6), both cilostazol and aspirin were administered daily, from the first day of TIPS creation. The control group (n = 5) was administered only aspirin. The animals were followed-up for 2 weeks and then killed. The specimen (including portal vein, hepatic parenchymal tract, hepatic vein, and inferior vena cava) and stents were carefully bisected in a longitudinal fashion. The control group was compared with the treatment group by means of a gross and histologic evaluation of the degree of pseudointimal/intimal hyperplasia in the shunt. RESULTS: At the gross evaluation, the control group showed considerably more pseudointimal/intimal hyperplasia than the treatment group. Using microscopic evaluation, there was a statistically significant difference (p < 0.05) in the mean maximum pseudointimal/intimal hyperplasia thickness between the control group (2.97 +/- 0.33 mm) and treatment group (0.73 +/- 0.27 mm). CONCLUSION: Oral administration of cilostazol may have been effective in reducing pseudointimal/intimal hyperplasia in swine TIPS models.

Rapid alterations of serum oxidant and antioxidant status with the intravenous administration of n-6 polyunsaturated fatty acids.

In an attempt to achieve the safe intravenous administration of two n-6 polyunsaturated fatty acids (PUFAs), gamma-linolenic acid (GLA) and arachidonic acid (AA), and to study the subsequent changes on the total oxidant and antioxidant status, various steadily increasing doses of each acid were injected intravenously at different infusion times in 28 male rabbits. Blood samples were collected at 15-min time intervals by the hepatic veins and from the carotid artery; oxidant status was determined by the thiobarbiturate assay and total antioxidant status (TAS) was assessed by a colorimetric assay. Both n-6 PUFAs were administered with safety at a dose of 25 mg/kg within 10 min accompanied by an increase of malonodialdehyde concentrations in the hepatic veins and in the carotid artery 30-45 min, respectively, after the end of the infusion of GLA and/or AA. Similar changes did not occur in red cell membranes after the infusion of AA. TAS presented reciprocal changes to malonodialdehyde production; the main consumption of TAS was observed in all samples 30-60 min after the end of the infusion of n-6 PUFAs. The above-mentioned rapid alterations occurring in both serum oxidant and antioxidant status after GLA might have a future clinical therapeutic significance in conditions like cancer and disseminated infectious diseases.

The effects of vasoactive drugs on hepatic blood flow changes induced by CO2 laparoscopy: an animal study.

UNLABELLED: Laparoscopic surgery is associated with systemic and splanchnic hemodynamic alterations. Recent data suggest that small-dose dobutamine may attenuate the reduction in splanchnic blood flow associated with increments in intraabdominal pressure. We conducted this study to analyze the effects of dopamine and dobutamine on the hepatic circulation in this setting. Twenty-one pigs were anesthetized and mechanically ventilated. A flow-directed pulmonary artery and carotid artery catheters were inserted. Perivascular flow probes were placed around the main hepatic artery and the portal vein. CO2 was insufflated into the peritoneal cavity to reach an intraabdominal pressure of 15 mm Hg. After 60 min, animals received dopamine (5 microg x kg(-1) x min(-1); n = 8), dobutamine (5 microg x kg(-1) x min(-1); n = 8), or saline (n = 5) for 30 min. Pneumoperitoneum induced significant increases in heart rate, mean arterial pressure, and systemic vascular resistance, with decreases in cardiac output and hepatic artery and portal vein blood flows. Dobutamine infusion, in contrast to dopamine, corrected, at least in part, cardiac output, systemic vascular resistance, and hepatic artery blood flow alterations, but neither drug restored total hepatic blood flow. IMPLICATIONS: Hepatic blood flow decreases during laparoscopic surgery. A small-dose infusion of neither dobutamine nor dopamine corrects the total hepatic blood flow impairment, but the former is able to restore the hepatic arterial blood supply in an animal model mimicking this condition.

Experimental model of hepatic venoocclusive disease (VOD) caused by dactinomycin--preliminary report about hepatoprotective effect of amifostine.

UNLABELLED: The purpose of the study was elaboration of the experimental model of hepatic venoocclusive disease (VOD) induced by dactinomycin and investigation of possible hepatoprotective effects of amifostine and heparin individually or in combination with dexamethasone. 198 Wistar strain male rats were used in the trial in two series of experiments. In the first series the experimental model of VOD induced by dactinomycin was elaborated on the group of 18 animals (divided into 3 groups receiving intraperitoneally isotonic salt solution, dactinomycin or nitrosamine). Nitrosamine--a well-known agent causing VOD--was used as positive control. Open biopsies of the liver and blood collections were repeated in order to determine liver enzymes' concentrations. Histopathological examinations demonstrated that dactinomycin caused liver lesion corresponding with VOD picture. Second series of animals was divided into 6 groups receiving the following drugs: I--0.9% NaCl solution, II--dactinomycin (ACT), III--ACT + fraxiparine s.c., IV--ACT + fraxiparine + dexamethasone, V--ACT + amifostine. Five animals from each group were sacrificed on the 3rd and 7th day after each cycle of drug administration. Blood was drawn in order to determine the following: AspAT, AlAT, Falk, GGTP and LDH. Intravital wedge biopsies under anesthesia with the use of inactin were also performed. Liver samples were stained with the use of H&E, p. a. S and Gomory's techniques. We did not find significant differences in liver enzymes' levels between the groups. Pathological changes corresponding with VOD picture of different intensification were found in liver samples from all the rats receiving ACT. Changes became more and more intensive after consecutive cycles. Lesion of central veins' and liver sinusoids' endothelium dominated. Fraxiparine administered individually or in combination with dexamethasone did not prevent the lesion. Administration of amifostine before ACT decreased pathomorphological changes in liver. Dactinomycin caused homogenous subclinical liver lesion corresponding with VOD. It may also occur in children receiving ACT in the course of nephroblastoma's treatment. But probably the changes are too subtle to manifest themselves clinically with exception of patients particularly sensitive (for example after previous radiotherapy). Lack of differences observed in liver enzymes' levels between the groups supports the explanation. Markers of lesion of liver vessels' endothelium should be looked for to make more specific diagnostics of VOD possible. Hepatoprotective properties of amifostine need further studies. CONCLUSIONS: 1. It is possible to create the experimental model of VOD induced by dactinomycin administration. 2. Amifostine seems to act hepatoprotectively to liver lesions caused by dactinomycin.

Pharmacokinetics of octreotide in patients with cirrhosis and portal hypertension; relationship between the plasma levels of the analogue and the magnitude and duration of the reduction in corrected wedged hepatic venous pressure.

In healthy subjects octreotide is largely metabolised by the liver suggesting that the plasma half-life of the somatostatin analogue may be prolonged in patients with hepatic dysfunction. The aim of this study was therefore (a) to determine the pharmacokinetics of octreotide following its subcutaneous injection in 6 patients with cirrhosis and portal hypertension and (b) compare the magnitude and duration of the effects of intravenous administration of 250 micrograms somatostatin and 50 micrograms octreotide on corrected wedged hepatic venous pressure (WHVP) and to relate the findings to the plasma levels of the analogue 1 h after administration in 13 patients with cirrhosis and portal hypertension. Following subcutaneous administration of 50 micrograms octreotide the circulating half life (range 2.4 to 4.79 h) was prolonged whereas the clearance (range 2.101 to 4.775 L/h) was decreased compared to healthy controls. Intravenous bolus administration of 250 micrograms somatostatin or 50 micrograms octreotide resulted in a reduction in WHVP of approximately the same magnitude and duration despite appreciable quantities of the analogue in the blood 1 h after administration (1944 +/- 226 pg/ml). These results indicate that the circulating half-life of octreotide is prolonged in cirrhotics suggesting that the dosage regimens should be modified in such patients to avoid accumulation of the analogue in the blood which may result in undesirable side-effects or toxicity. Furthermore, since the magnitude and duration of the reduction in WHVP elicited by IV octreotide is similar to that observed with somatostatin, the analogue, like the native hormone, must be administered by continuous IV infusion to produce a sustained response and hence a therapeutic effect in the management of acute variceal bleeding.

Nitroglycerin versus epoprostenol: effects on hemodynamics, oxygen delivery, and hepatic venous oxygenation after liver transplantation.

Our objective was to determine the effects of vasodilatory treatment with epoprostenol (PGI2) and nitroglycerin (NTG) on systemic oxygen delivery index (DO2) and hepatic venous oxygen saturation (SvhO2) after liver transplantation. This prospective study used repeated-measures design. Fifteen adult patients undergoing orthotopic liver transplantation (OLT) were enrolled. Postoperatively, a fiberoptic pulmonary artery catheter was inserted into the right hepatic vein and a timed infusion of PGI2 and NTG was sequentially performed in random order at the following rates: PGI2 at 5 ng/kg/minute and NTG at 0.1 microgram/kg/minute. Each step in each sequence lasted 45 minutes, followed by a control interval of 45 minutes. Measurements were taken at the end of each period when hemodynamic function was stable. Systemic hemodynamics, DO2, oxygen uptake index (VO2), mixed venous oxygen saturation (SvO2), and SvhO2 were assessed. We found that PGI2 induced an increase of cardiac index (+18%, p < .05); DO2 (+16%, p < .05); and SvhO2 (+11%, p < .05). Mean arterial pressure was decreased during PGI2 infusion (-9%, p < .05), as well as during infusion of NTG (-10%, p < .05). NTG significantly decreased DO2 (-6%, p < .05) and SvhO2 (-4%, p < .05). Neither drug affected VO2. We conclude that PGI2 induced vasodilation and increased systemic oxygen delivery in parallel with SvhO2, suggesting a corresponding increase of hepatic oxygen supply. NTG induced systemic vasodilation and significantly impaired hepatic venous oxygen saturation and DO2. Thus, if vasodilatory therapy is indicated in the patient after liver transplantation, PGI2 appears to be better than NTG in improving DO2 without impairing splanchnic oxygenation.

[Computed sonography observation on the effects of cimetidine on the liver blood flow in cirrhotic patients with portal hypertension].

The effects of cimetidine on the hepatic and portal vein blood flow were investigated in 20 cirrhotic patients with portal hypertension by computed sonography. Cimetidine given intravenously at a dose of 0.4g significantly increased the hepatic vein blood flow (60.2% +/- 63.6%, P < 0.01), at the same time its calculated cross section area increased by 40.2% +/- 81.3% (P < 0.01). The portal vein blood flow increased by 53.2% +/- 52.3% (P < 0.01). While its cross section area was 16.8% +/- 17.3% (P < 0.01). These results showed that the histamine H2-receptor antagonist cimetidine may dilate liver vascular bed and reduce portal blood flow resistance in cirrhotic patients with portal hypertension.

Vascular hepatotoxicity related to heroin addiction.

The hepatotoxic effect of heroin has been demonstrated in liver biopsies by morphometric analysis of four groups of patients: twenty-one drug abusers (DA) at the time of the biopsy, eighteen patients who had stopped drug consumption for at least six months (ex-DA), twelve patients with post-transfusional chronic active hepatitis (PTCAH), and eleven controls (CONTROL). Semiquantitative assessment showed the extent of sinusoidal dilatation and the inflammatory and fibrotic reaction in the terminal hepatic vein (THV). Thickening and cellularity of the venular wall and the volume density of sinusoidal lumen (Vsl) in the Zone I and III of the hepatic acinus, were also evaluated. The morphometric analysis used computerized measurements. In DA, the sinusoidal dilatation (100% of cases), the sinusoidal and THV inflammation (81% and 67.7%, respectively), localized mainly in the centrilobular zone, were more pronounced than in ex-DA, in patients with PTCAH and in CONTROL (significantly different P less than 0.0001). Conversely, the fibrotic reaction (perisinusoidal fibrosis--44.4% and perivenular fibrosis--61.1%) was more frequent in ex-DA. The THV inflammation in DA was replaced by a fibrotic matrix deposit in the THV wall (wall surface/internal surface = 2.72 +/- 0.37 in ex-DA; 1.38 +/- 0.32 in DA; 0.87 +/- 0.14 in PTCAH and 0.45 +/- 0.03 in CONTROL--significantly different P less than 0.001), associated with a perisinusoidal fibrosis, after drug withdrawal. Moreover, there was significantly decreased venular wall cellularity in ex-DA (wall surface/mesenchymal cells = 949 +/- 158 in ex-DA; 622 +/- 40 in DA; 619 +/- 61 in PTCAH; 547 +/- 23 in CONTROL--P less than 0.001). Semiquantitative and morphometric data suggest that these vascular lesions and their reversibility may be due to the direct hepatotoxic effects of heroin.

The effect of cimetidine on liver blood flow in anesthetized man.

In eight patients subjected to abdominal surgery, the effect of intravenous cimetidine (Tagamet) on hepatic arterial blood flow and portal blood flow was studied, utilizing electromagnetic blood flowmetry. Following cimetidine an increase in hepatic arterial blood flow concomitant with a decrease in mean arterial pressure were detected. Calculated hepatic artery vascular resistance was therefore significantly decreased by 28% after 2 min and 17% after 10 min. There was no change in portal blood flow. It is suggested that this effect of cimetidine is due to increased plasma histamine levels after acute H2 receptor blockade.

[Liver and the pill]. / Leber und Pille.

PIP: Several liver diseases have been associated with oral contraceptive use. The estrogen component appears to be responsible for the hepatic diseases, as the liver contains estrogen receptors. Some less serious hepatic effects of o.c. use are changes in laboratory values, a jaundice similar to pregnancy jaundice, and gallstone formation, all of which are generally reversible. There are 2 serious hepatic diseases which can be caused by o.c. use. The Budd-Chiari syndrome involves obliteration of the hepatic veins; ca. 30-40% of the cases are fatal during the first months. Benign tumors, e.g. liver adenoma and focal nodular hyperplasia can lead to a dangerous rupture of the liver. Although these diseases were rare, they are becoming more common. The physician must consider such possibilities when prescribing o.c.s, and regular check-ups should be given to assure early diagnosis of such illnesses if they should occur.^ieng

Veno-occlusive disease of the liver after chemotherapy of acute leukemia. Report of two cases.

Two adult male patients with acute leukemia developed a fatal Budd-Chiari-like illness while receiving 6-thioguanine. Both had previously received cytosine arabinoside. Antemortem and postmortem specimens of liver showed changes characteristic of toxic veno-occlusive disease. Similar findings have been described after ingestion of certain plant alkaloids and after treatment with arsphenamine, urethane, and ionizing radiation to the liver. We are unaware of any published reports of veno-occlusive disease of the liver after treatment with either 6-thioguanine or cytosine arabinoside. Although 6-thioguanine was most likely responsible for this syndrome, it is not possible to eliminate cytosine arabinoside as the causative agent. Since both drugs are occasionally used for benign conditions, physicians should be aware of this possible complication.