Potential role of modifier genes influencing transforming growth factor-beta1 levels in the development of vascular defects in endoglin heterozygous mice with hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder because of mutations in the genes coding for endoglin (HHT1) or ALK-1 (HHT2). The disease is associated with haploinsufficiency and a murine model was obtained by engineering mice that express a single Endoglin allele. Of a total of 171 mice that were observed for 1 year, 50 developed clinical signs of HHT. Disease prevalence was high in 129/Ola strain (72%), intermediate in the intercrosses (36%), and low in C57BL/6 backcrosses (7%). Most mice first presented with an ear telangiectasia and/or recurrent external hemorrhage. One-third of mice with HHT showed severe vascular abnormalities such as dilated vessels, hemorrhages, liver and lung congestion, and/or brain and heart ischemia. Disease sequelae included stroke, hydrocephalus, fatal hemorrhage, and congestive heart failure. Thus the murine model reproduces the multiorgan manifestations of the human disease. Levels of circulating latent transforming growth factor (TGF)-beta1 were significantly lower in the 129/Ola than in the C57BL/6 strain. Intercrosses and 129/Ola mice expressing reduced endoglin also showed lower plasma TGF-beta1 levels than control. These data suggest that modifier genes involved in the regulation of TGF-beta1 expression act in combination with a single functional copy of endoglin in the development of HHT.

Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis.

CONTEXT: Cirrhosis is widely regarded as being irreversible. Recent studies have demonstrated that fibrosis may decrease with time in humans and experimental animals if the disease activity becomes quiescent. The histologic appearance of regressing cirrhosis in the human has not been described in detail. OBJECTIVES: To define histologic parameters that indicate regression of cirrhosis and to provide an interpretation of how regression occurs from a histologic point of view. DESIGN: A patient who underwent a series of biopsies that showed apparent regression of hepatitis B cirrhosis is presented. In addition, 52 livers removed at transplantation having cirrhosis or incomplete septal cirrhosis were graded for histologic parameters that suggest progression or regression of fibrosis. Progression parameters were steatohepatitis, inflammation, bridging necrosis, and piecemeal necrosis. The regression parameters (collectively called the hepatic repair complex) were delicate perforated septa, isolated thick collagen fibers, delicate periportal fibrous spikes, portal tract remnants, hepatic vein remnants with prolapsed hepatocytes, hepatocytes within portal tracts or splitting septa, minute regenerative nodules, and aberrant parenchymal veins. RESULTS AND CONCLUSIONS: Regression parameters were found in all livers and were prominent in the majority. Livers with micronodular cirrhosis, macronodular cirrhosis, and incomplete septal cirrhosis demonstrate a histologic continuum. A continuum of regressive changes was also seen within individual livers. These appearances allow one to understand visually how fibrous regions of hepatic parenchyma can be returned toward a normal appearance. Many examples of incomplete septal cirrhosis could be the product of regressed cirrhosis.

Hepatitis C-related cirrhosis: a predictor of diabetes after liver transplantation.

Hepatitis C virus (HCV) infection has recently been suggested to be a risk factor for the development of diabetes mellitus. The aim of our study was to investigate whether the prevalence of diabetes is increased among liver transplant recipients infected with HCV. We compared the prevalence of diabetes among 278 liver transplant recipients whose original cause of liver failure was HCV infection (110 patients), hepatitis B virus infection (HBV; 53 patients), and cholestatic liver disease (CLD; 115 patients). The pretransplantation prevalence of diabetes was higher in the HCV group (29%) compared with the HBV (6%) and CLD (4%) groups (P <.001). The prevalence of diabetes remained higher in the HCV group 1 year after transplantation: 37%, 10%, and 5% in the HCV, HBV, and CLD groups, respectively (P <.001). The cumulative steroid dose during the first year of transplantation was significantly lower in the HCV group compared with the CLD group. Multivariate analysis revealed that HCV-related liver failure (P =.002), pretransplantation diabetes (P <.0001), and male sex (P =.019) were independent predictors of the presence of diabetes 1 year after transplantation. The high prevalence of diabetes persisted in the HCV group, with 41% diabetic at 5 years. The majority of patients with diabetes mellitus (89%) required insulin therapy after transplantation. Patient and graft survival rates were similar among patients with and without diabetes. In conclusion, our study shows that there is a high prevalence of diabetes among liver transplant recipients infected with HCV both before and after transplantation.

Outcome of long-term ribavirin therapy for recurrent hepatitis C after liver transplantation.

Ribavirin therapy was initiated at a median of 181 days after liver transplantation in 18 patients with persistent elevation of alanine aminotransferase values and biopsy-proven hepatitis, and continued for 23 months (12-44 months). All patients had a prompt biochemical response, with alanine aminotransferase decreasing by 69%; complete normalization occurred in 5 (28%). Serum hepatitis C virus RNA levels did not change during therapy. Liver biopsies obtained after 17 months (9-38 months) of therapy showed no improvement in necroinflammation. However, worsening of fibrosis occurred in 12 patients; and cirrhosis developed in 5 patients (28%), with 3 patients progressing to graft failure. Biopsies from 27 untreated patients who did not fulfill treatment criteria (median follow-up, 38 months) and 4 patients who received 3 months of ribavirin (44 months) showed cirrhosis in 11 and 75%, respectively. Patient and graft survival rates for treated and untreated patients were similar. Although ribavirin improves alanine aminotransferase, it does not prevent the development or progression of fibrosis in patients with recurrent hepatitis C virus.

Asymptomatic primary biliary cirrhosis: a study of its natural history and prognosis.

OBJECTIVE: To document the natural history of asymptomatic primary biliary cirrhosis and identify prognostic features that would predict the development of symptomatic disease. METHODS: A retrospective chart review of all patients with abnormal liver biochemical tests and antimitochondrial antibody-positive, liver biopsy-compatible primary biliary cirrhosis who were seen in a single tertiary care center between 1983 and 1994 was performed. Statistical analysis using Cox regression was employed to compare survival of the study population with an age- and gender-matched control population and to identify potential prognostic variables. RESULTS: Ninety-one patients were included. Median age at presentation was 53.2 yr. Ninety percent were female. Median follow up was 61.2 months (range 7-206 months). Thirty-six percent (33 patients) became symptomatic with 11% (10 patients) progressing to death or liver transplant. Median predicted length of survival from onset of disease for the entire cohort was 14 yr. Patient survival was less than that predicted for an age- and gender-matched control population (p < 0.05). Univariate and multivariate analysis on a broad spectrum of clinical, biochemical, and histological features at the time of initial presentation failed to reveal any prognostic variables that would distinguish those who would become symptomatic from those who would remain symptom-free. Specifically, three primary variables of interest (associated autoimmune disorders, hepatomegaly, and histological stage) were not found to predict prognosis. CONCLUSION: Patients who present with asymptomatic primary biliary cirrhosis have a shorter life span than the general population. Presently, there are no prognostic features that identify the patients who will develop progressive disease from those who will remain symptom-free. Therefore, treatment should be offered to all patients.

Pathology of the liver in Budd-Chiari syndrome: portal vein thrombosis and the histogenesis of veno-centric cirrhosis, veno-portal cirrhosis, and large regenerative nodules.

Hepatic vein (HV) thrombosis causes ascites, hepatomegaly, and severe congestion of the liver (Budd-Chiari syndrome [BCS]). Severe hepatic fibrosis develops in this syndrome with a variety of histological patterns. Some livers have a pattern of cirrhosis in which there is fibrous bridging between HVs and portal tracts (veno-portal cirrhosis). Other livers have a pattern of "reversed-lobulation cirrhosis" (veno-centric cirrhosis), in which fibrous bridging between HVs and portal tracts is minimal. The prevalence and pathogenesis of these forms of cirrhosis and the effect of portal vein (PV) thrombosis in this disease have not been studied. We examined 15 resected livers from patients with BCS to determine the distribution of vascular obstruction and the character of the parenchymal response. Six livers had veno-portal cirrhosis, and all of these had severe PV obliteration caused by thrombosis. Three livers had veno-centric cirrhosis and had normal medium and large PVs. The remaining six livers had mixed veno-centric/veno-portal cirrhosis and had moderate PV obliteration. The nodules in veno-centric cirrhosis had evidence of an unusual circulation with small arteries supplying a midzonal venous plexus that appeared to drain retrogradely into patent small PVs. Nine livers had large regenerative nodules histologically similar to focal nodular hyperplasia. PV thrombosis is a frequent occurrence in BCS. The correlation between PV thrombosis and the pattern of cirrhosis suggests a role for PV obliteration in the genesis of veno-portal bridging fibrosis in this disease and possibly in other diseases leading to cirrhosis.

The role of granulomatous phlebitis and thrombosis in the pathogenesis of cirrhosis and portal hypertension in sarcoidosis.

Sarcoidosis often involves the liver with mild elevation of serum enzymes and granulomas histologically. Rarely, chronic cholestasis, portal hypertension, cirrhosis, or nodular hyperplasia may be found. The pathogenesis of the portal hypertension and of the cirrhosis are not understood, in part because large samples of tissue have seldom been described. We describe the clinical and anatomic findings of four patients with sarcoid liver disease in whom the whole livers were available for examination. One patient had cirrhosis, one had diffuse nodular hyperplasia, and two had small regions of parenchymal fibrosis. The first two of these had a history of variceal bleeding and healed portal vein thrombosis. One had chronic cholestasis without cirrhosis. We suggest that the cirrhosis and focal fibrosis were caused by ischemia secondary to primary granulomatous phlebitis of portal and hepatic veins. The portal hypertension in two patients was likely secondary to portal vein thrombosis, because cirrhosis was absent at the onset of variceal bleeding.

Role of ischemia in causing apoptosis, atrophy, and nodular hyperplasia in human liver.

Ischemia is known to be a cause of hepatocellular apoptosis and atrophy in experimental animals, but the effect of vascular obstruction on such lesions in the normal or cirrhotic human liver has not been studied. The purpose of this study was to investigate the role of ischemia in the development of apoptosis, atrophy, and nodular hyperplasia in cirrhotic and noncirrhotic human livers. Apoptosis, focal atrophy, and nodular hyperplasia were semiquantitated in 203 liver specimens obtained at transplantation, segmental resection, or autopsy. These parameters were correlated with etiology, stage, activity, and acute and healed portal vein thrombosis (PVT). Large numbers of apoptotic cells were found in livers with acute PVT (17.2/medium-power field [MPF]) and in infarcts of Zahn caused by obstruction of portal veins (PVs) by tumor (16.4/MPF). Smaller numbers of apoptotic cells were found in cirrhosis of various etiologies (3.8-10.0/MPF) and rarely in normal livers (0.16/MPF). Evidence of healed PVT was found in 47% of cirrhotic livers and was associated with nodular hyperplasia (58% vs. 32%, P < .01) and focal atrophy (79% vs. 49%, P < .002). Apoptotic cells were found equally in those with and without healed PVT (40% vs. 38%, not significant). These observations suggest that apoptosis is a transient response to acute ischemia and that atrophy and nodular hyperplasia are chronic responses to ischemia. Vascular obstruction may be an important cause of the apoptosis and atrophy, which are found in nodular regenerative hyperplasia (NRH), infarct of Zahn, chronic hepatitis, and cirrhosis.

Hepatic sinusoidal fibrosis induced by cholesterol and stilbestrol in the rabbit: 1. Morphology and inhibition of fibrogenesis by dipyridamole.

This study documents the hepatic morphology and the ultrastructure of a model of hepatic fibrosis in rabbits. Rabbits were given a cholesterol-supplemented diet (1%), a stilbestrol diet (10 mg subcutaneously twice a week), or both treatments simultaneously for 7 weeks. Rabbits given the combined treatment developed sinusoidal and portal fibrosis with only a mild disturbance of acinar vascular relationships. Ultrastructurally, there was marked widening of the spaces of Disse by collagen fibers, basement membrane material adjacent to endothelial cells and hepatocytes, blunted hepatocellular microvilli, activated stellate cells, lipid droplets in endothelial cells and hepatocytes, and degranulated platelets in sinusoids. The hepatic hydroxyproline content was markedly increased (12.0 +/- 5.2 vs. 4.8 +/- 1.5 mmol/g of liver dry weight; P < .001). Plasma bile acids were markedly increased (222 +/- 180 vs. 12 +/- 5 in controls; P < .001). Dipyridamole (25 mg every 12 hours) that was given in addition to cholesterol and stilbestrol decreased the hepatic collagen content (-49% and -48%, in two experiments; P < .05 in both) and splenomegaly. This model provides a reliable method for the production of extensive sinusoidal fibrosis with capillarization of sinusoids. Hepatocellular degeneration is only mild to moderate, and fibrosis occurs slowly without the sudden pathological changes that occur with other models of hepatic fibrosis, such as with the administration of CCl4 or galactosamine. The mechanism of injury may involve the accumulation of bile salts or the generation of free radicals from cholesterol oxidation products. The possibility that the sinusoidal release of platelet-derived factors may have a role in the activation of stellate cells (lipocytes) is supported by the suppression of fibrogenesis by dipyridamole.

Hepatic sinusoidal fibrosis induced by cholesterol and stilbestrol in the rabbit: 2. Hemodynamic and drug disposition studies.

We assessed hepatic functions and systemic and splanchnic hemodynamics in a new model of hepatic sinusoidal fibrosis. Fibrosis was induced by the simultaneous administration for 8 weeks of diethyl-stilbestrol (DES) (10 mg twice weekly, subcutaneously) and cholesterol-supplemented diet (1%) in rabbits. A marked and progressive impairment of hepatic function was observed during the 8 weeks of treatment with a significant decrease in indocyanine green (ICG) systemic clearance (-89%; P < .001) and aminopyrine elimination (-69%; P < .001). In fibrotic animals, hyperdynamic circulation was found with an increased cardiac output (+73%, P < 0.01) and a decreased peripheral vascular resistance (-50%; P < .005), as evaluated by the microsphere technique in animals that were awake. The total portal venous inflow was not significantly modified in fibrotic rabbits. However, since there was a marked increase in the liver weight, the portal venous inflow was significantly decreased when expressed per gram of liver weight (-30%; P < .05). In contrast, the hepatic artery blood flow was markedly increased, even when expressed per gram of liver weight (+95%; P < .01). Portal pressure was significantly increased in treated rabbits (from 7.4 +/- .4 to 14.4 +/- .6 mm Hg, P < .01). This new experimental model could prove useful to evaluate the influence of extensive perisinusoidal fibrosis on exchanges between plasma and hepatocytes, particularly of protein-bound substances.

Fistula between duodenum and portal vein caused by peptic ulcer disease and complicated by hemorrhage and portal vein thrombosis.

We document a patient with a penetrating peptic ulcer of the first part of the duodenum, that extended into the main portal vein forming a fistula. This is the first reported case of a duodenoportal fistula secondary to peptic ulcer disease. The fistula was complicated by massive gastrointestinal hemorrhage, extra- and intrahepatic portal vein thrombosis, hepatic parenchymal infarction, and intrahepatic portal vein foreign body granulomas containing vegetable matter.

A pilot study of ribavirin therapy for recurrent hepatitis C virus infection after liver transplantation.

Ribavirin is a guanosine analogue that normalizes serum liver enzymes in most nontransplant patients with chronic hepatitis C virus (HCV) infection. We conducted an uncontrolled pilot study of ribavirin in 9 liver transplantation recipients that had persistently elevated liver enzymes, active hepatitis by liver biopsy, and HCV RNA in serum by polymerase chain reaction. Ribavirin was given orally at dosages of 800-1200 mg per day for 3 mo. All 9 patients promptly responded to ribavirin: mean (+/- SD) ALT decreased from 392 +/- 377 IU/L immediately before treatment to 199 +/- 185 and 68 +/- 37 IU/L after 1 and 12 weeks of treatment, respectively, complete normalization of enzymes occurred in 4 patients. None of the patients cleared the virus from their serum during therapy, and biochemical relapse occurred in all patients 4 +/- 4.2 weeks after cessation of therapy. The hepatitis activity index of liver biopsy specimens obtained before and at the cessation of therapy was similar. Ribavirin treatment was resumed in 4 patients because of increasing fatigue (2 patients), rising bilirubin (3), or increasing necroinflammation on liver biopsy (2); the biochemical response to the second course of therapy was similar to the first course in all 4 patients. Ribavirin caused reversible hemolysis in all patients, including symptomatic anemia in 3 patients that resolved after reduction of drug dosage. These results suggest that ribavirin may be of benefit in the treatment of HCV infection after liver transplantation. Further studies are needed to determine the optimal dosage and duration of therapy.

Lipiodol accumulation in hepatic hemangioma. Detection with osmium postfixation.

Lipiodol has been used to increase the detectability of small primary neoplasms in the liver. We report a patient who was found to have lipiodol deposits in the liver one month after intra-arterial injection. The region was resected, under ultrasound control, because of the impression that the lesion was malignant. The specimen contained two small hemangiomas as well as many small dysplastic nodules (adenomatous hyperplasia) in a noncirrhotic parenchyma. To locate the lipiodol deposit in this case, the tissue was radiographed, postfixed in osmium tetroxide, and embedded in paraffin. Black osmium-stained deposits were found within the cavities of the hemangiomas but not in the dysplastic nodules. Most of the deposits were extracellular multivesiculated bodies with a small focus of lipid droplets engulfed by multinucleated foreign-body type giant cells. This report reinforces that hepatic lipiodol retention is not specific for hepatocellular carcinoma. We present, for the first time, the histologic appearance of lipiodol accumulation in an hemangioma. The value of osmium tetroxide postfixation for the detection of lipiodol is also demonstrated.