Nodular regenerative hyperplasia of the liver in hematologic disorders: a possible response to obliterative portal venopathy. A morphometric study of nine cases with an hypothesis on the pathogenesis.

Nodular regenerative hyperplasia was found in nine patients who had hematological disease including polycythemia vera, agnogenic myeloid metaplasia, primary thrombocythemia, rheumatoid arthritis with thrombocytosis, multiple myeloma, and erythrocytosis associated with polycystic renal disease. Portal hypertension was suspected in three and features of hypersplenism were present in four. 2. Nodular regenerative hyperplasia occurred in livers which had widespread obliteration of portal vein radicals (obliterative portal venopathy). Morphometric analysis indicated that the portal vein lesions were predominately located in veins up to 0.2 mm in diameter and were significantly more frequent than similar lesions occurring in elderly persons. 3. The following pathogenesis of nodular regenerative hyperplasia is proposed: Thrombi, perhaps largely composed of platelet aggregates formed in the portal venous circulation or spleen, embolize to the liver and results in obliterative vascular lesions. Atrophy and regenerative nodule formation occur in response to the interruption of the portal blood supply.

Liver disease in Felty's syndrome.

Eighteen patients with Felty's syndrome were examined prospectively for the presence of hepatic abnormalities. Twelve patients had abnormal liver histologic features: five with nodular regenerative hyperplasia and seven with portal fibrosis or abnormal lobular architecture. Only seven of the 12 had abnormal liver chemistry results. Four of the 12 had portal hypertension, and three bled from esophageal varices compared with one of six with normal histologic features. When patients with normal and abnormal liver histologic findings were compared, there was no difference in clinical, serologic, or extra-articular manifestations between the two groups, although there was a tendency for the patients with abnormal findings to have a higher incidence of vasculopathy. All patients with Felty's syndrome should be screened for hepatic abnormalities and portal hypertension as they have an increased likelihood of bleeding from esophageal varices.

Nodular regenerative hyperplasia of the liver associated with macroglobulinemia. A clue to the pathogenesis.

Nodular regenerative hyperplasia of the liver is an infrequent condition characterized by transformation of the hepatic parenchyma into nodules with only mild fibrosis. Little is known about the etiology except that there is usually an underlying chronic disease, such as Felty's syndrome, which antedates the development of clinical liver disease. It is poorly understood how the associated diseases contribute to the pathogenesis of nodular regenerative hyperplasia. Presented are four cases of nodular regenerative hyperplasia in which macroglobulinemia was also present. This new association suggests to us a hypothesis for the pathogenesis of nodular regenerative hyperplasia. Histologic examination of the livers in these and other cases of nodular regenerative hyperplasia reveals widespread obliteration of the small portal veins. Postmortem angiography of one liver in the present series demonstrated that the nodules were well perfused and that the atrophic areas were poorly perfused with portal blood. This supports the view that atrophy of lobules results from a lack of portal blood supply and that nodules develop from lobules well supplied with portal blood. In each of the clinical conditions associated with nodular regenerative hyperplasia, including macroglobulinemia, inflammatory or thrombotic vascular lesions are found in many organs. Therefore, nodular regenerative hyperplasia may be the hepatic expression of a more widespread vascular disease.

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.

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.

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.

The effect of dietary cholesterol on platelet survival in the rabbit--a study using 14C-serotonin and 51chromium double-labelled platelets.

Hypercholesterolemic men and monkeys have shortened platelet survival but attempts to demonstrate this in rabbits have been unsuccessful. The present study examines platelet survival in cholesterol-fed rabbits. Platelets were double-labelled in vitro with 51Cr and 14C-serotonin or in vivo by intravenous injection of 14C-serotonin. In the double-label experiments 51Cr survival was always shorter than 14C survival but changes in survival of one label were accompanied by similar changes in the other label. Survival was shortened after 4 and 7 weeks of cholesterol feeding. This was demonstrated when the donor platelets were from normal rabbits for both cholesterol and control recipients but no shortening was demonstrated when cholesterol-rich platelets were injected into cholesterol-fed recipients and normal platelets were injected into the control rabbits. When 14C-serotonin was injected intravenously 14C survival was the same as when platelets were labelled ex vivo prior to injection and 14C survival was shortened in rabbits fed cholesterol for 1, 2, and 6 weeks. These results indicate that cholesterol-feeding shortens platelet survival. This effect may be masked if the test platelets are not identical in both test and control groups.

The vascular pathology of human hepatic allografts.

Studies of hepatic transplant vasculopathy (TV) have described arterial lesions in selected cases but have not sought to establish the relative prevalence of various arterial and venous lesions. We examined 20 unselected liver allografts and 12 controls to establish the spectrum and distribution of transplant-related arterial and venous lesions. Sections of 1,175 arteries and 936 portal and hepatic veins were reviewed and several histologic parameters were tabulated. Fibrotic (18 cases: 184 arteries and 17 veins) and cellular (10 cases: 353 arteries and 33 veins) lesions were seen. Three allografts had evidence of severe TV with abundant foam cell, myointimal, and mixed fibrocellular lesions in the intima of arteries. These three grafts also had foam cells in portal veins. Allografts with TV had more stenotic arteries (P < .05) and more intimal cellular proliferation (P < .05) compared with non-TV allografts and with controls. Foam cells often demonstrated immunoperoxidase staining for actin, lysozyme, or UCHL-1. Two of the TV cases had marked paucity of bile ducts and required retransplantation.

Occurrence of alpha-1-antitrypsin deficiency in 155 patients with alcoholic liver disease.

Liver biopsies from 155 patients with alcoholic liver disease were examined for periodic-acid-Schiff-positive, diastase-resistant (PAS-DR) intracytoplasmic globules in hepatocytes. Seven patients had these PAS-DR globules: each was a heterozygote for a deficiency allele of alpha-1-antitrypsin (AAT), or alpha-1-protease inhibitor, with the PAS-DR globules distributed in a pattern characteristic of this deficiency. One further patient with normal AAT had a few intracytoplasmic PAS-DR globules in occasional hepatocytes. The prevalence of AAT heterozygotes in this series did not differ from that in the reference population. The seven heterozygotes included five of PI (protease inhibitor) type MZ, one of PI type SZ, and one heterozygous for a rare deficiency allele, PI type MMmalton. The M and Mmalton alleles may be difficult to distinguish because they have similar mobilities with isoelectric focusing technics. Therefore, if PAS-DR inclusions are found in the liver of a patient with an apparently normal phenotype, the presence of a defective M variant allele, such as Mmalton, should be considered.

"Mesothelioma of the atrioventricular node" with long-standing complete heart block. Report of a case.

A case of mesothelioma of the atrioventricular node is presented. The patient had complete heart block for many years before death. The origin of the tissue in this apparently congenital tumor is discussed with reference to the literature.

Surgical management of hepatocellular carcinoma: resection or transplantation?

Liver resection or transplantation offers the best opportunity for cure of hepatocellular carcinoma (HCC). To determine the relative roles for resection and transplantation and to evaluate the patient and tumor characteristics that might predict survival, the records of 125 patients treated for nonfibrolamellar HCC at The Toronto Hospital between 1981 and 1996 were reviewed. No adjuvant chemotherapy or antiviral protocols were used. Resection was the first operation in 67 patients; one underwent re-resection. Sixty patients underwent transplantation including two who had previously had a resection; 40 had known or suspected HCC and 20 had incidental tumors identified in the explanted liver. The incidence of cirrhosis was 49% for resection and 88% for transplantation. The incidence of hepatitis B virus (HBV) was 58% and 33%, respectively. The operative mortality rate for resection was 4.4% (9.4% in cirrhotic and 0 in noncirrhotic patients) and 13.3% for transplantation. The 5-year cumulative recurrence rate was 55% following resection and 20% following transplantation (P <0.001). The 5-year Kaplan-Meier survival rates were 38% for resection and 45% for transplantation-60% for transplanted HBV-negative and 17% for HBV-positive patients (P <0.001). After resection, recurrent HCC accounted for 86% of deaths, whereas recurrent HBV was responsible for 42% of deaths after transplantation. By univariate analysis, following resection, vascular invasion, advanced stage, multiple tumors, and lack of a capsule were predictive of survival; cirrhosis, HBV, age, tumor size, number, and grade were not. By multivariate analysis, only vascular invasion was predictive for resection and HBV for transplantation. Resection and transplantation are complementary methods of treating HCC. With the current organ shortage, resection should be considered first-line treatment. HBV-positive patients with HCC should only undergo transplantation in combination with effective antiviral therapy.

Voluntary alcohol intake in the hypertension prone Dahl rat.

Previous work in our laboratory has shown that alterations in the sodium content of the diet which alter salt appetite, can modify ethanol self-selection and intoxication. The present experiment investigates the relationship between the intakes of sodium and ethanol on the one hand and the development of hypertension, by measuring voluntary ethanol consumption and blood pressure in two rat lines, the salt sensitive (SS) and salt resistant (SR) Dahl rats, specially bred to show differential sensitivity to dietary sodium supplements. All rats were given 24 hr access to 6% (v/v) ethanol and water and first offered a control diet (0.5% Na) followed by a 4% and then an 8% sodium supplemented diet. While on the control diet there were significant between strain differences in ethanol consumption, suggesting that the SS animals came genetically prepared to consume more ethanol. Blood pressure measured at regular intervals indicated significant changes only in the SS rats even though both lines as well as a group of Wistar rats, added for purposes of comparison, all increased their ethanol intake to the salt supplemented diets. A second experiment suggested that the initial difference in consumption between the SS and SR lines may be related to central nervous system sensitivity since differences were found in salt appetite but not in taste sensitivity or in the absorption, distribution or metabolism of the drug. These findings demonstrate that the Dahl SS rat is predisposed to consume more ethanol than the SR rat even before exposure to the hypertension-inducing diet, and that this predisposition is probably central in origin.(ABSTRACT TRUNCATED AT 250 WORDS)

Fibrous thickening of the splenic capsule. A response to chronic splenic congestion.

Fibrous thickening of the splenic capsule is often seen in patients with hepatic cirrhosis or portal hypertension from other causes. However, most cases of capsular thickening have been considered idiopathic, with no obvious abnormality of the portal circulation. The possibility that these "idiopathic" cases also have evidence of portal hypertension was examined in a retrospective study. The splenic capsule thickness was measured in 434 consecutive autopsy specimens. Various clinical and autopsy parameters relevant to vascular disease were recorded and correlated with splenic capsular thickness. Thickened capsules were significantly more frequent in patients with advanced age, clinical history of severe congestive heart failure, cirrhosis, and hepatic portal sclerosis. It is suggested that most cases of splenic capsular thickening are caused by splenic congestion with organization of capsular and subcapsular hemorrhages.

Mineral oil lipogranulomata in liver and spleen. A study of 465 autopsies.

Lipogranulomata (LG) are commonly seen in human tissues but the location and significance of these lesions are incompletely documented. In a study of 465 autopsies LG were found in 48% of livers and 46% of spleens. Hepatic LG were more common in portal tracts than adjacent to the terminal hepatic venules. There was a close correlation between hepatic LG in liver and in spleen. The incidence and severity of hepatic LG were higher in older adults, especially men. There was no evidence that LG caused hepatic dysfunction or portal hypertension. The absence of correlation with hepatic steatosis supports the suggestion that LG are secondary to mineral oil deposition rather than to steatosis.

Nodular transformation of the liver in hereditary hemorrhagic telangiectasia.

A case of hereditary hemorrhagic telangiectasia with prominent nodular transformation of the liver is described. The presence of enlarged arteries was documented morphometrically. Artery-to-portal vein shunts were also found. The association of abnormal vessels with hepatic nodules supports the hypothesis that abnormalities of blood flow cause nodular transformation. Nodular transformation may be the lesion that has heretofore been termed cirrhosis hepatis telangiectasia or atypical cirrhosis.

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.

Partial nodular transformation of liver in an adult with persistent ductus venosus. Review with hypothesis on pathogenesis.

Partial nodular transformation of the liver (PNT) is a rare condition of unknown pathogenesis in which nodules composed of hepatocytes replace portions of the parenchyma. There is usually evidence of portal hypertension and portal vein thrombosis. We present a case of PNT in a man with persistent ductus venosus and hypoplasia of the major intrahepatic portal veins but without evidence of portal hypertension or portal vein thrombosis. Portal venules were largely absent between nodules, as documented by morphometry. We suggest the pathogenesis of PNT is similar to that previously proposed for nodular regenerative hyperplasia, that is, atrophy occurs in parenchyma with insufficient blood supply and nodules arise by hyperplasia in areas with adequate supply. Partial nodular transformation and nodular regenerative hyperplasia differ mainly in the cause and distribution of the portal vein obliteration.