Support of sinusoidal endothelial cell glutathione prevents hepatic veno-occlusive disease in the rat.

Depletion of sinusoidal endothelial cell glutathione (GSH) has been proposed as a common mechanism leading to hepatic veno-occlusive disease (HVOD). This study examines whether intraportal infusion of GSH can prevent HVOD in the monocrotaline rat model. HVOD was induced in rats with monocrotaline 160 mg/kg i.g. on day 0. GSH was infused intraportally by mini-osmotic pump. Monocrotaline decreased GSH in sinusoidal endothelial cells, but not in liver homogenate. Infusion of GSH, 2 micromol/hr starting day - 1, prevented the decrease in sinusoidal endothelial cell GSH and protected against histological and clinical evidence of HVOD. Protection by GSH was dose-dependent (0.5-2 micromol/hr). In rats receiving continuous GSH infusion, treatment with buthionine sulfoximine starting day - 2 decreased sinusoidal endothelial cell GSH and attenuated the protective effect of GSH against monocrotaline. GSH infusion starting 24 hours after monocrotaline ("glutathione rescue") offered substantial protection to most rats. N-acetyl-L-cysteine conferred protection, but N-acetyl-D-cysteine (an antioxidant that is not a precursor for GSH) had little or no protective effect, and 4-hydroxy TEMPO, a free radical scavenger, was not protective. Discontinuation of the GSH infusion 5 days after monocrotaline administration led to severe hepatic veno-occlusive disease on day 6. In conclusion, monocrotaline selectively depletes sinusoidal endothelial cell GSH. Intraportal infusion of GSH protects against monocrotaline toxicity, at least partially by maintaining sinusoidal endothelial cell GSH levels. Glutathione infusion started after monocrotaline is partially protective. Monocrotaline induces prolonged changes in the liver that remain suppressed as long as GSH is infused.

Characterization of a reproducible rat model of hepatic veno-occlusive disease.

Lack of a reproducible animal model has hampered progress in understanding hepatic veno-occlusive disease (HVOD). This article characterizes a reproducible model of HVOD. Rats gavaged with monocrotaline, 160 mg/kg, were killed between days 1 and 10. Sections were evaluated by light microscopy with a standardized scoring system, by immunoperoxidase staining with ED-1 (monocytes, macrophages) and ED-2 (Kupffer cells) antibodies, and by transmission (TEM) and scanning electron microscopy (SEM). On days 1 and 2, the earliest manifestations were progressive injury to the sinusoidal wall with loss of sinusoidal lining cells, sinusoidal hemorrhage, and mild damage to central vein (CV) endothelium. On days 3 through 5 ("early HVOD"), there was centrilobular coagulative necrosis, severe injury to sinusoids, severe sinusoidal hemorrhage, and severe CV endothelial damage; inflammation with ED-1-positive cells was most marked on these days. Days 6 and 7 ("late HVOD") were characterized by subendothelial and advential fibrosis of CVs, damage of the CV endothelium with subendothelial hemorrhage, and some restoration of the sinusoidal wall. Between days 8 and 10, sections showed interindividual variation ranging from mild, residual fibrosis to severe, late HVOD. From days 1 through 10, ED-2-positive cells were decreased in number, and the number of ED-1-positive cells was increased. Sinusoidal damage is the earliest change in HVOD. Coagulative necrosis follows sinusoidal injury and resolves with improvement in sinusoidal endothelial cell (SEC) morphology. Moderate-to-severe CV fibrosis occurs after reappearance of sinusoidal lining cells and resolution of hepatocyte necrosis. The inflammatory response within the lobule and CVs is a result of recruitment of monocytes, whereas Kupffer cells are decreased in number.

Diagnostic features of tuberculous peritonitis in the absence and presence of chronic liver disease: a case control study.

PURPOSE: To determine diagnostic features of tuberculous peritonitis (TBP) in the absence and presence of chronic liver disease. PATIENTS AND METHODS: Thirty-four patients with TBP (13 without [Group I] and 21 with chronic liver disease [Group II] and 26 controls with cirrhosis and uninfected ascites (Group III) were studied. RESULTS: The clinical features in Groups I and II were similar and all patients had elevated ascitic fluid total mononuclear cell count. In Groups I, II, and III, respectively, ascitic fluid protein was > 25 g/L in 100% (13/13), 70% (14/20), and 0% (0/26); serum-ascites albumin gradient (SAAG) was > 11 g/L in 0% (0/13), 52% (11/21), and 96% (25/26), (0% [0/13], 71% [15/21], and 96% [25/26] after correction for serum globulin); and ascitic fluid lactate dehydrogenase (LDH) level was > 90 U/L in 100% (12/12), 84% (16/19), and 0% (0/20), respectively. In Groups I and II combined, ascitic fluid acid-fast stain was negative in all but Mycobacterium tuberculosis culture was positive in 45% (10/22); peritoneal nodules occurred in 94% (31/33), granulomas in 93% (28/30), and positive peritoneal M tuberculosis culture in 63% (10/16). CONCLUSIONS: In patients with suspected TBP, ascitic fluid protein of > 25 g/L, SAAG of < 11 g/L and LDH of > 90 U/L have high sensitivity for the disease. With coexistent chronic liver disease, a lower protein level and higher SAAG are usually not helpful but LDH > 90 U/L is a useful parameter for screening. Diagnosis is best confirmed by laparoscopy with peritoneal biopsy and M tuberculosis culture.

Fatal intrathoracic hemorrhage in a patient with von Recklinghausen's disease.

Neurofibromatosis can involve the mediastinum. A 44-year-old woman with a dumbbell-shaped mediastinal mass developed a large pleural effusion, respiratory failure and fatal hemoptysis. Autopsy revealed systemic neurofibromatosis involving the mediastinum and pleura. Mediastinal and pleural hemorrhage probably occurred as a result of an eroded thoracic artery. Massive hemorrhage in mediastinal neurofibromatosis occurs uncommonly but with potentially fatal results.

Clinical significance of concomitant hepatitis C infection in patients with alcoholic liver disease.

The significance of antibodies to hepatitis C virus in patients with chronic alcoholic liver disease is unclear. Prior studies have utilized the first-generation enzyme-linked immunosorbent assay, which is limited by problems with sensitivity and specificity. Hepatitis C virus infection in 137 patients with biopsy-proven alcoholic liver disease was assessed with second-generation hepatitis C virus antibody assays and reverse transcription-polymerase chain reaction for detection of hepatitis C virus RNA in the serum. The patients were categorized into three groups according to results of serological testing. Discriminant-function analysis was used to determine which factors (risk, biochemical and histological) could best differentiate the three groups. Thirty-three patients were reactive on second-generation enzyme-linked immunosorbent assay/second-generation recombinant immunoblot assay and RNA positive (group 1). Twelve were reactive on second-generation enzyme-linked immunosorbent assay/second-generation recombinant immunoblot assay but RNA negative (group 2). Eighty-six were nonreactive on second-generation enzyme-linked immunosorbent assay, and six were reactive on second-generation enzyme-linked immunosorbent assay but negative on second-generation recombinant immunoblot assay and negative for hepatitis C virus RNA (group 3). Seventy-six percent of patients in group 1 and 58% in group 2 had parenteral risk factors, compared with only 1% in group 3 (p < 0.00001). The mean ALT level was higher in group 1 patients (p < 0.05). The mean histologic activity index was significantly higher in group 1 (p = 0.0007).(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatic lesions resembling alcoholic liver disease.

Patients who do not consume alcohol may have hepatic lesions that are characteristic of those of alcoholic liver disease: portal fibrosis, sinusoidal collagen deposition, fatty change, parenchymal neutrophilic exudate, and Mallory body deposition. Here, the author discusses entities that mimic alcoholic liver disease on biopsy and disorders that have morphologic features also seen in alcoholic liver disease.

Ultrasonographic diagnosis of acute alcoholic hepatitis 'pseudoparallel channel sign' of intrahepatic artery dilatation.

BACKGROUND: In an ultrasound pilot study of acute alcoholic hepatitis (AAH), parallel tubular structures within the liver subsegments were observed. Pulse-Doppler flowmetry revealed that these structures were formed by a dilated hepatic arterial branch and an adjacent portal venous branch. This finding was termed the "pseudoparallel channel sign" (PPCS). The aims of this study were to assess the significance of this sign and show the characteristic ultrasound findings of AAH. METHODS: PPCS was specifically searched for on ultrasonography by two physician operators in consecutive patients (77 AAH, 119 other alcoholic liver disease, 49 nonalcoholic liver disease, and 15 healthy patients). RESULTS: PPCS was observed in 90% of patients with AAH and in 23% of patients with other alcoholic liver disease. This sign was not detected in nonalcoholic liver disease or healthy patients. Biopsy specimens were available in 100 patients, 51 of whom were patients with alcoholism. In those 51 patients, PPCS gave a sensitivity of 82%, a specificity of 87%, and an accuracy of 84% in diagnosing AAH. Patients with criteria of AAH had more segments involved with PPCS than patients without. CONCLUSIONS: PPCS may be an important diagnostic finding in AAH.

Control of ventilation, respiratory muscle strength, and granulomatous involvement of skeletal muscle in patients with sarcoidosis.

Granulomatous involvement of skeletal muscle occurs in 50 to 80 percent of patients with sarcoidosis. How this may affect respiratory muscle function in sarcoidosis is not known. To attempt to answer this question, we compared respiratory function and muscle force generation, and control of ventilation in 12 untreated patients with 12 healthy, nonsmoking subjects. While seated, room air breathing, measurements included expiratory reserve volume (ERV), components of breathing pattern, and occlusion pressure at 1 s (P0.1). Three of nine patients who consented to muscle biopsy demonstrated granulomatous involvement on histologic examination, and Pmax values less than the group mean; however, some patients without muscle granulomas also demonstrated low Pmax values. Breathing pattern in the sarcoid patients was rapid and shallow, but not related to the degree of radiographic infiltration or respiratory elastance. Mean inspiratory flow (VT/TI), minute ventilation, and P0.1 were, in general, greater than in the control subjects, indicating an increase in central drive. There was a significant inverse correlation between FVC and P0.1, and a weak inverse relationship between ERV and P0.1. With no significant difference between group "effective impedances" (P0.1/(VT/TI)), findings indicate that in the sarcoidosis group, decreased muscle force generation was compensated for by an increase in central drive. Granulomatous infiltration may be one of many factors contributing to respiratory muscle weakness in sarcoidosis.

Portal vein thrombosis complicating endoscopic variceal sclerotherapy. Convincing further evidence.

Portal vein thrombosis occurred in a patient who bled from gastric varices that developed after obliteration of esophageal varices by endoscopic sclerotherapy. This complication was recognized only at surgery when thrombectomy and endovenectomy preceded the successful placement of an end-to-side portocaval shunt. At histopathology, the presence of an amorphous, eosinophilic material staining negatively for fibrin and similar to sclerosant injected at sclerotherapy was observed within the clot. This latter finding, previously unreported, provides convincing evidence for the causal relationship of portal vein thrombosis to endoscopic sclerotherapy.

Cocaine-induced liver cell injury: comparison of morphological features in man and in experimental models.

Although investigative research of animal models in cocaine metabolism and associated liver cell injury has been fairly extensive during the past 10 yr, little evidence of hepatotoxicity has been documented in man. We report a case of fulminant hepatic failure and acute rhabdomyolysis resulting from cocaine use. Coagulative-type perivenular and midzonal necrosis and periportal microvesicular fatty change were the predominant morphological features throughout all lobules of the liver, in contrast to periportal necrosis described in the only previous case report with biopsy. Differences in zonal necrosis caused by the same drug are not typically seen in man experiencing direct or indirect intrinsic hepatotoxicity. However, experimental models have shown cocaine to have this ability, dependent on enzyme induction or inhibition, sex and dose. Therapeutic approaches for prevention of possible liver cell injury by cocaine toxicity are discussed.

Twenty isoniazid-associated deaths in one state.

Twenty deaths from isoniazid-associated hepatitis are known to have occurred in California over a 14-yr period in persons ranging in age from 5 to 73 yr. Because no comprehensive survey was carried out, more such deaths probably occurred. With one exception, the patients were not seen or contacted monthly throughout the course of treatment. However, in 16 patients where the information was known, eight were seen by a member of the group giving the isoniazid (INH) within 30 days prior to the patients presenting with hepatitis. In 12 of 17 cases, symptoms were present for 7 days or more before the patient presented for medical care. In at least 35% of cases where the information was known, a management error occurred, usually failing to immediately stop INH when the patient presented with symptoms. The duration of treatment before hepatitis developed varied from 9 to 53 wk. Four of the 20 patients had cholelithiasis or a history of cholelithiasis. With one possible exception, no excessive alcohol use was noted. Concomitant acetaminophen, barbiturate, and tetracycline use occurred in several cases. There were no deaths in Orientals. Sixteen of the 20 deaths occurred in women who had started to receive INH between the ages of 15 and 55. Four of these women began receiving INH during pregnancy and continued it postpartum. Eight deaths occurred in persons starting INH before 35 yr of age. The continued occurrence of INH-associated deaths suggests that indications and precautions for INH preventive treatment be carefully reconsidered.

Risk lesions in cirrhosis and development of hepatocellular carcinoma: an autopsy study.

Non-neoplastic morphologic changes in various types of cirrhosis were evaluated in relationship to the presence or absence of hepatocellular carcinoma (HCC), using autopsy livers from Hokuriku (Japan) and Los Angeles (USA). Macronodular cirrhosis was closely related to HCC in B-viral cirrhosis, alcoholic cirrhosis and cirrhosis of uncertain type. Liver cell dysplasia was most frequently seen in cases with and without HCC in B-viral cirrhosis but was significantly more frequent with HCC in cases of alcoholic cirrhosis and cirrhosis of uncertain type. Nodular bulging activity within regenerative nodules was closely related to HCC in alcoholic cirrhosis. A positive relationship between HCC and Mallory bodies was found in non-alcoholic cirrhosis. These data suggest that patients with macronodular cirrhosis, liver cell dysplasia, nodular bulging activity and Mallory bodies may have an increased risk of developing, or having HCC dependent on the etiology of cirrhosis. The geography and race differences had some relationship to the incidence of HCC.

Noninvasive evaluation of hepatic fibrosis using frequency demodulation of ultrasound signals.

A new ultrasound image can be produced by frequency demodulation (FM) of the conventional ultrasound signal. This new FM image appeared to produce a more accurate representation of the fine structure of the liver. The individual features of the FM image were correlated with hepatic portal fibrosis and cirrhosis on liver biopsy in 34 patients with minimal hepatic fat and sinusoidal collagen. An overall ultrasound score correlated with portal fibrosis (r = 0.788; P less than 0.001). We conclude that the FM image may be helpful in measuring and following the progression of hepatic fibrosis in patients with chronic liver disease.

Osteomyelitis associated with pressure ulcers.

Bone biopsies were performed in spinal cord injured patients with pressure ulcers in whom osteomyelitis was suspected. Roentogenograms and bone and gallium scans were also evaluated to determine their usefulness in diagnosing osteomyelitis. Infected bone underlying pressure ulcers revealed only mild focal inflammatory changes which did not correlate well with x-ray and nuclear scan abnormalities. Negative scans, however, essentially ruled out osteomyelitis. There was no clear association of delayed healing or recurrence of pressure sore with osteomyelitis. Antibiotic therapy of greater than three weeks' duration did not significantly affect the outcome of the disease.

Hepatorenal syndrome without avid sodium retention.

A urinary sodium concentration [U(Na)] of less than 10 mmoles per liter is considered important in differentiating hepatorenal syndrome from other causes of progressive renal impairment in patients with liver disease. However, occasionally, patients with hepatorenal syndrome have been recognized in whom the U(Na) is consistently greater than 10 mmoles per liter. Eight such patients, in all of whom there was no clinical or laboratory evidence to implicate other causes of progressive renal impairment, were identified. The clinical features, hepatic and renal status and hospital course were compared with eight other patients who had hepatorenal syndrome and a U(Na) consistently less than 10 mmoles per liter. The mean U(Na) was 24 +/- 4 mmoles per liter in the high U(Na) group and 3.7 +/- 1.8 mmoles per liter in the low U(Na) group. All patients in both groups had acutely decompensated alcoholic hepatitis of similar severity and activity. The high U(Na) group had significantly less clinical ascites and peripheral edema and higher serum levels of sodium and chloride both at the onset of the hepatorenal syndrome and throughout the clinical course. Significant differences in the serum potassium and blood urea nitrogen levels became apparent between the two groups of patients as renal failure progressed, and the mean average blood urea nitrogen to serum creatinine ratio was significantly higher (p less than 0.025) in the low U(Na) group (13.8 +/- 0.9 vs. 10.1 +/- 1.1). Mean urinary potassium concentration was significantly higher in the high U(Na) patients but urinary creatinine concentrations, specific gravity and sediment were similar in both groups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Delta agent superinfection. Rapidly progressive liver disease in a hepatitis B virus carrier.

We report a case of rapidly progressive chronic active hepatitis (CAH) following acute delta infection in a previously asymptomatic hepatitis B virus carrier. Serologic evidence of delta superinfection coincided with an acute icteric hepatitis, and was followed by the development of clinically evident chronic liver disease. The liver biopsy specimens documented the acute hepatitis and subsequent progression of severe CAH. This case illustrates the clinical and pathologic changes that may follow acute delta infection in chronic hepatitis B carriers.

Tubular dysfunction in the deeply jaundiced patient with hepatorenal syndrome.

We examined beta 2-microglobulin (B2MG) excretion, an index of tubular function, in patients with hepatorenal syndrome, in whom tubular function is generally regarded as normal. Urine B2MG was significantly higher in these patients than in control patients with normal serum creatinine concentration. Patients with high urine B2MG concentration had markedly higher serum bilirubin than did patients with normal values (31 +/- 3 vs. 10 +/- 8 mg%, p less than 0.001), whereas prothrombin activity, serum albumin and serum B2MG concentration were similar. A "threshold" serum bilirubin concentration of about 23 mg% differentiated patients with normal and high urine B2MG values. Renal morphology at autopsy was unremarkable in both groups. Tubular dysfunction, manifested by increased urinary excretion of B2MG, occurs in patients with hepatorenal syndrome and deep jaundice. This measurement cannot, therefore, be used to make a diagnosis of acute tubular injury, as due to aminoglycosides, in such patients.