Shigeo Sugano

Retinal complications and plasma C5a levels during interferon alpha therapy for chronic hepatitis C

Objective:The pathogenesis of retinal complications, such as retinal hemorrhage and cotton-wool spots formation, during interferon (IFN) therapy is unclear. We studied the relationship between the presence of retinal complications and levels of plasma-activated complement 5 (C5a), a known potent intravascular aggregator of granulocytes, during IFN-α therapy.Methods:Forty-five patients with chronic hepatitis C but without diabetes mellitus and hypertension were studied. IFN-α was used 10 MU per day for 2 wk and 3 times weekly for an additional 22 wk. In 25 patients with IFN therapy, the optic fundi were examined before therapy began, every 4 wk thereafter, and whenever patients complained of visual symptoms. C5a levels were measured before, and during the 4th, 8th, 12th, and 24th wk, and at any time that a retinal complication was discovered. Twenty patients served as IFN-untreated controls. They had six optic fundi examinations, each 4 wk apart. C5a levels were measured three times, 4 wk apart, in 10 controls.Results:No retinal hemorrhage or cotton-wool spots were detected before IFN-α therapy or in any of the controls. However, retinal hemorrhage occurred in six patients (24%) during IFN-α therapy. Five of six episodes occurred within the first 8 wk. Only three patients with retinal hemorrhage had visual symptoms. Cotton-wool spots developed in four patients with retinal hemorrhage. Retinal hemorrhage and cotton-wool spots resolved gradually despite continuous administration of IFN-α. Before IFN therapy and in controls, all C5a levels were <7 ng/ml. When retinal hemorrhage occurred, C5a was significantly increased (27.3 ± 15.6 ng/ml, p < 0.01) relative to levels from the same patients before and after the hemorrhage (5.7 ± 1.1 ng/ml), and also relative to levels in IFN-α–treated patients without retinal hemorrhage (5.7 ± 1.1 ng/ml) and compared with levels in IFN-untreated controls (5.4 ± 0.7 ng/ml).Conclusion:Retinal hemorrhage or cotton-wool spots often occur during IFN-α therapy for chronic hepatitis C. This study suggests that a high C5a level may be an important step in the pathogenesis of retinal capillary infarction, hemorrhage, and cotton-wool spots formation.

HEPATIC ACTINOMYCOSIS : CASE REPORT AND REVIEW OF THE LITERATURE IN JAPAN

Hepatic actinomycosis is rare. We report an 86-year-old Japanese man with a 3-day history of high fever and anorexia who had an actinomycotic liver abscess complicated by disseminated intravascular coagulation (DIC). A definitive diagnosis was made when anActinomyces species was cultured from aspirated pus. The clinical course was satisfactory. Treatment included prompt percutaneous drainage coupled with long-term intravenous administration of high-dose minocycline and piperacillin, combined with therapy for DIC. We reviewed 11 cases in Japan ofActinomyces involving the liver, including the case reported here. In most patients, there were no predisposing factors. Common symptoms and laboratory findings included fever, abdominal pain, leukocytosis, and elevated C-reactive protein. In 6 of the 11 patients a partial hepatectomy was performed because hepatic tumor was suspected. Five patients presented with a liver abscess. Hepatic actinomycosis should be considered in the differential diagnoses of pyogenic liver abscess and space-occupying lesions of the liver.

Incidence of ultrasound-detected intrahepatic hematomas due to Tru-cut needle liver biopsy.

This is a prospective study in which 120 patients with diffuse liver disease undergoing liver biopsy were followed by serial ultrasounds to determine the incidence of postbiopsy intrahepatic hematoma formation. Forty-five of the patients had a blind biopsy, while the remaining 75 patients had a biopsy performed during laparoscopy. In both groups a 2.0-mm Tru-cut needle was employed. The overall incidence of postbiopsy hematoma formation was 18.3%, with approximately the same results occurring in blind biopsy patients (20%) and laparoscopy-guided biopsy patients (17%). Only two patients had significant pain associated with the hematoma formation (one from each group), one of whom had evidence of intraperitoneal bleed and rebleed. Our results suggest that postbiopsy asymptomatic hematomas occur more frequently than had been generally thought and that laparoscopy-guided biopsy is not safer than blind biopsy.

Azygos venous blood flow while fasting, postprandially, and after endoscopic variceal ligation, measured by magnetic resonance imaging.

Abstract: Using cine phase-contrast magnetic resonance (MR) imaging, we measured fasting and postprandial azygos blood flow in 15 cirrhotic patients with portal hypertension and 11 healthy controls. In 10 of the cirrhotics, measurements were made before and after prophylactic endoscopic variceal ligation therapy (EVL). Flow volume was measured in the azygos vein at the level of the midthoracic vertebra. Azygos blood flow was measured under basal fasting conditions and 30–40 min after ingestion of a 500 Kcal meal. Fasting azygos blood flow was 139 ± 43 ml/min in controls vs 519 ± 249 ml/min in cirrhotics (P < 0.01). Eating significantly increased azygos blood flow, by 38% in controls (P < 0.02) and by 27% in cirrhotics (P < 0.02), compared with fasting conditions. EVL markedly decreased azygos blood flow, by 25% compared with pre-EVL (P < 0.03). The cine phase-contrast MR velocity mapping method measured flow volume in the azygos veins. Azygos blood flow was markedly greater in the cirrhotics than in the controls. In the cirrhotics and controls, blood flow volume increased after eating. Azygos blood flow was significantly reduced by successful EVL.

PORTAL VENOUS BLOOD FLOW WHILE BREATH-HOLDING AFTER INSPIRATION OR EXPIRATION AND DURING NORMAL RESPIRATION IN CONTROLS AND CIRRHOTICS

Abstract: In this study, we used magnetic resonance (MR) imaging to measure portal blood flow in 12 healthy controls and 17 cirrhotics while they were breath-holding after inspiration and after expiration. We then compared the results with measurements made during normal respiration in the healthy controls and cirrhotics. Blood flow in the main portal vein under basal fasting conditions was quantitated using the cine phase-contrast MR velocity mapping method. Three measurements were made on one occasion, as follows: (1) throughout the cardiac cycle during normal respiration, (2) with the subject breath-holding after maximal inspiration, and (3) with the subject breath-holding after maximal expiration. During normal respiration, portal blood flow was 1.3 ± 0.2 l/min in controls vs 1.0 ± 0.1 l/min in cirrhotics (P < 0.0001); while subjects were breath-holding after inspiration, portal blood flow was 1.0 ± 0.2 l/min in controls vs 0.9 ± 0.1 l/min in cirrhotics; and while subjects were breath-holding after expiration, portal blood flow was 1.5 ± 0.2 l/min in controls vs 1.1 ± 0.2 l/min in cirrhotics (P < 0.0001). The differences were primarily due to changes in flow velocity. When the magnitude of these hemodynamic changes in the three respiratory conditions was compared in controls and cirrhotics, analysis of variance (ANOVA) showed a significant difference (P < 0.0001). In controls, portal blood flow decreased during maximal inspiration relative to flow during normal respiration (−24.6 ± 8.3%). Changes in portal blood flow in controls were greater than in cirrhotics (−13.5 ± 4.5%) (P < 0.0001); however, the difference in blood flow increase associated with maximal expiration between the two groups (+11.8 ± 9.4% vs +5.9 ± 11.5%) was not significant. We found that the respiration-induced hemodynamic variation in portal blood flow was less in cirrhotics than in the healthy controls. Portal blood flow measurements made during normal respiration using MR imaging closely reflect nearly physiologic conditions.

Chronic Splanchnic Hemodynamic Effects of Spironolactone with Unrestricted Sodium Diet in Patients with Compensated Cirrhosis

The purpose of this study is to determine thehemodynamic effects of spironolactone administrationassociated with an unrestricted sodium diet (salt 10 g)in patients with compensated cirrhosis and portal hypertension. We studied the hemodynamicchanges following eight weeks of administration ofeither placebo (N = 6) or spironolactone (100 mg/day) (N= 6 Pugh-Childs A and 6 B). No significant changes were observed after the administration of theplacebo. Spironolactone induced a significant reductionin the hepatic venous pressure gradient (HVPG)(–10.1 ± 13.3%, P < 0.05), which wasassociated with a significant reduction of cardiac output(–11.5 ± 9.3%, P < 0.01), plasma volume(–8.1 ± 4.7%, P< 0.01), and wedgedhepatic venous pressure (–10.5 ± 11.6%, P< 0.05). There was no significant change in hepatic blood flow and there was nosignificant correlation between the change in the HVPGand the change in circulating plasma volume. A decreasein the HVPG greater than 10% was observed in eight of 12 patients (67%), defined asresponders, at eight weeks. Six of six (100%) grade Apatients and two of six (33%) grade B patientsresponded. This study demonstrated that spironolactonewith an unrestricted sodium diet decreased the HVPG ingrade A patients but did not significantly decrease theHVPG in grade B patients.

Relationship of Portal Pressure and Colorectal Vasculopathy in Patients with Cirrhosis

We studied the relationship between portalpressure and colorectal mucosal vascular lesions incirrhotics and the effectiveness of drug therapy intreating these lesions. Colonoscopy and hepatic venous pressure gradient (HVPG) studies were performedin 21 cirrhotics. Oral spironolactone plus transdermalnitroglycerin were given to patients who had diffusemucosal cherry-red spots and/or rectal varices. The colonoscopy and HVPG determinations wererepeated after four weeks. Colonoscopic findingsincluded vascular ectasias in 13 patients (62%), diffusecherry-red spots in the rectum in five patients (24%), and rectal varices in eight patients (38%).Overall, colorectal mucosal vascular lesions were foundin 16 cirrhotics (76%). These findings were not found in21 age- and sex-matched noncirrhotic controls. Vascular ectasias appeared without relationshipto the HVPG. Patients with diffuse cherryred spots (N =5, 22.4 ± 3.4 mm Hg) had a significantly higherHVPG than those without (N = 16, 16.6 ± 3.3 mm Hg, P < 0.01). However, no significantdifference was found in HVPG between patients withrectal varices (N = 8, 19.4 ± 4.6 mm Hg) andpatients without rectal varices (N = 13, 17.2 ±3.8 mm Hg). After four weeks of drug therapy, diffusecherry-red spots became less obvious when the HVPGdecreased more than 20% . Rectal varices did not changetheir appearance with HVPG reduction. We found thatcolorectal vascular lesions are common in cirrhotics.Diffuse cherry-red spots are probably dependent onelevated portal pressure, but vascular ectasias andrectal varices are not related to the degree of portalpressure. Chronic drug therapy with reduction of portalpressure improves colonoscopic findings such as diffusecherry-red spots.

Daily variation of azygos and portal blood flow and the effect of propranolol administration once an evening in cirrhotics

BACKGROUND/AIMS Esophageal variceal bleeding occur more often at night, however, the mechanism for this remains unclear. This study investigated the daily variation of azygos blood flow (AzBF) and portal blood flow (PBF) and the effects of propranolol administration given once in evening in cirrhotics. METHODS Blood flow were measured using magnetic resonance imaging. Hemodynamic parameters were determined at 08:00, 16:00 24:00 and again 08:00 h, and were measured at baseline and after 14 days oral administration of propranolol (30 mg, n = 7) or placebo (n = 7) at 19:00 h in 14 patients. RESULTS A daily fluctuation of AzBF and PBF was observed, peaking at 24:00 h in nine patients. In three other patients, peak AzBF and PBF were observed both at 16:00 and 24:00 h. Two patients were constant throughout the day. When the daily variation was compared, ANOVA showed a significant difference (P < 0.001). Propranolol administration at 19:00 h reduced AzBF (-40.7 +/- 17.9% vs. baseline, P < 0.001) and PBF (-26.5 +/- 10.7% vs. baseline, P < 0.01) at 24:00 h. CONCLUSIONS We found that in most cirrhotics, AzBF and PBF peaks at midnight. Dosing of propranolol in the evening may be important for its role in preventing variceal bleeding.

Chronic Splanchnic Hemodynamic Effects of Low-Dose Transdermal Nitroglycerin versus Low-Dose Transdermal Nitroglycerin Plus Spironolactone in Patients with Cirrhosis

We studied the hemodynamic changes following afour-week administration of either low-dose transdermalnitroglycerin (a constant release of 5 mg ofnitroglycerin/day) (N = 10) or low-dose transdermalnitroglycerin plus spironolactone (100 mg/day) (N = 9) inpatients with cirrhosis and portal hypertension. Twopatients in the latter group did not undergo repeatmeasurements after dropping out because of severeheadaches or developing ascites during the study.Transdermal nitroglycerin induced a significantreduction in the hepatic venous pressure gradient (HVPG)(–11.7 ± 14.9%, P < 0.05), which wasassociated with a significant reduction of cardiac output (–10.5± 7.3%). Nitroglycerin plus spironolactoneinduced a significant reduction in the HVPG (–18.3± 16.0%, P < 0.05) associated with asignificant reduction of cardiac output (–13.8± 5.6%), right atrial pressure (–35.0± 30.0%), mean arterial pressure (–7.5± 6.8%), and plasma volume (–10.2 ±7.0%). The difference of the mean HVPG reduction betweenthe groups was insignificant. A decrease in the HVPG greater than 10% was observed insix of 10 patients (60%) and in five of seven patients(71.4%), defined as “responders,” at fourweeks. The difference in percentage of respondersbetween the groups was insignificant. We found that insome cirrhotic patients, low-dose transdermalnitroglycerin is potentially useful in the treatment ofportal hypertension. Spironolactone as an adjunct to low dose transdermal nitroglycerin did notdemonstrate therapeutic advantages in the treatment ofportal hypertension in cirrhotics. That there werenonresponders indicates that there are variableresponses in splanchnic hemodynamics to thesedrugs.

Postprandial middle cerebral arterial vasoconstriction in cirrhotic patients. A placebo, controlled evaluation

BACKGROUND/AIMS The objective of this study was to determine whether cerebral arterial vasoconstriction occurs in relation to postprandial splanchnic blood pooling in cirrhotic patients. METHODS The pulsatility and the resistive indexes and blood flow in the middle cerebral artery were measured by magnetic resonance imaging in 21 cirrhotics and 14 controls. These measurements were repeated 30 min after ingestion of a 400 kcal liquid meal or placebo. Seven controls and 14 patients received the meal, and seven controls and seven patients received placebo. RESULTS In the fasting conditions, cirrhotics had a greater pulsatility index (0.81 +/- 0.10 vs. 0.67 +/- 0.05, P < 0.001) and a greater resistive index (0.61 +/- 0.04 vs. 0.53 +/- 0.04, P < 0.001) and a lower blood flow (127 +/- 42 ml/min vs. 167 +/- 37 ml/min, P < 0.03) in the middle cerebral artery compared with controls. Meal ingestion significantly increased the pulsatility index (P < 0.03) and the resistive index (P < 0.01) and decreased blood flow (P < 0.03) in the middle cerebral artery in cirrhotics but not in controls. In contrast, placebo ingestion had no effect on the hemodynamic parameters in the middle cerebral artery in the two groups. CONCLUSIONS Results support the hypothesis that middle cerebral arterial vasoconstriction seen in cirrhotic patients is one of the cerebral arterys homeostatic responses to underfilling of the splanchnic arterial circulation.