Biomedical subjects
Publications and source records attributed to F Schaffner.
Two cases of sarcoidosis with predominantly hepatic involvement are reported, both with the gradual development of progressive jaundice and other clinical features of primary biliary cirrhosis without immunologic or morphologic evidence of that disease. The autopsy findings in one case are described.
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Human leukocyte antigen (HLA) class I molecules are normally detected on most nucleated cells, but not on hepatocytes, while the expression of HLA class II antigens is mainly restricted to certain cell types of the immune system. This normal distribution pattern may be altered in human liver in a variety of disorders, particularly in infectious and immune diseases. In view of multiple infections and severe immune alterations in acquired immunodeficiency syndrome (AIDS), we studied the expression of HLA class I and class II antigens in liver obtained at autopsy from ten patients with AIDS and eight control patients, using a panel of monoclonal antibodies and the indirect immunofluorescence method. In spite of viral bacterial, and fungal infections, HLA class I antigens were detected on hepatocytes in only two patients with AIDS. Human leukocyte antigen class II antigens were found unexpectedly on bile duct epithelium in five of ten patients with AIDS and in one of eight control patients. The aberrant HLA class II antigen expression on bile ducts does not appear to be linked to bile duct damage or infection with cytomegalovirus or other agents, but may be related to immune alterations in patients with AIDS.
The natural history and prognostic factors of primary sclerosing cholangitis (PSC) are poorly defined. We reviewed our experience with PSC to determine its natural history and whether any factors on presentation or during follow-up were indicative of a favorable or unfavorable prognosis. Thirty-eight patients were followed up for 75.1 +/- 58.7 months; 17 (45%) had a poor outcome, defined as the occurrence of death (11 patients [29%]), variceal hemorrhage, hepatic encephalopathy, or hepatic transplantation. We found the following: the rate of progression of PSC is highly variable; an asymptomatic presentation may not indicate a more favorable outcome or prolonged survival; a serum bilirubin value of four times or more the upper limit of normal, particularly if sustained so as to exclude a reversible cause, is indicative of late-stage disease with a likelihood of subsequent poor outcome and death; and variceal hemorrhage may occur before the terminal stage of the disease.
To analyze the tissue distribution of mononuclear cells and HLA antigens in primary biliary cirrhosis, we studied liver biopsies of 12 patients at different stages of the disease, using the avidin-biotin-peroxidase technique and monoclonal antibodies directed against T and B lymphocytes, T-cell subsets, macrophages, NK/K cells, dendritic cells, and HLA class I and II antigens. To evaluate the proportion of activated T cells we used anti-interleukin-2-receptor antibodies and a double-staining technique for T cells and class II HLA antigens. In all biopsies activated T cells predominated in the portal areas and around the damaged bile ducts. T4 cells almost always outnumbered T8 cells. While B cells, NK/K cells, and dendritic cells were always scarce, macrophages constituted about 30% of the cellular infiltrate. Biliary epithelium, which normally expresses HLA class I antigens, displayed mainly HLA class II antigens. The predominance of T4 cells around the bile ducts, which express class II antigens, suggests that class II-restricted T4 lymphocytes may mediate liver damage in primary biliary cirrhosis.
More than 25% of undirected percutaneous liver needle biopsies that are performed in search of metastatic neoplasms yield false negative specimens. Often, however, histologic changes are observed in the liver adjacent to space-occupying lesions due to focal obstruction of bile and blood flow. These alterations were defined by semi-quantitative evaluation of 20 liver biopsy specimens with metastatic neoplasms, and revealed a characteristic histologic triad consisting of proliferated and abnormal bile ductules, polymorphonuclear leukocytes in edematous portal tracts and focal sinusoidal dilatation. When 15 patients with this combination of histologic alterations, but without malignant cells in liver biopsy specimens, were investigated prospectively, 13 patients (87%) were found to have hepatic metastases. Therefore, the observation of the histologic triad described here should lead to a continued search for space-occupying lesions in the liver.
Recent studies have demonstrated aberrant expression and topographical heterogeneity of HLA Class I and Class II antigens in tissues of patients with certain immunologic or neoplastic diseases. Current information about the expression of HLA antigens by normal and diseased hepatocytes is controversial. We analyzed the HLA antigenic profile of 4 normal fetal livers, 5 normal adult livers, 7 cases of chronic hepatitis B virus (HBV) infection, 14 cases of cirrhosis of various etiologies, 11 hepatic neoplasms, and 5 continuous cell lines derived from hepatic tumors. The specimens were tested by the indirect fluorescent antibody method with a panel of monoclonal antibodies to distinct monomorphic determinants of HLA Class I and Class II antigens and to beta 2-microglobulin. HLA Cells I antigens were not detected on normal fetal and adult hepatocytes, but were displayed on the plasma membrane of hepatocytes in the majority of all hepatic diseases tested and of the 5 hepatic tumor cell lines. There was a significant correlation between the expression of HLA Class I antigens on hepatocytes and the intensity of intralobular inflammation. Double immunofluorescent staining of livers infected with hepatitis B virus demonstrated simultaneous expression of HLA Class I antigens and HBsAg or HBcAg only in a small percentage of hepatocytes, suggesting lack of a specific association between HLA Class I and these viral antigens. HLA Class II antigens were not detected on hepatocytes from any of the liver diseases tested but were expressed by one of the 5 liver carcinoma cell lines analyzed. These findings confirm that HLA Class I antigens are not detectable within the limits of several immunohistochemical methods on normal hepatocytes and suggest that injury by a variety of factors directly or indirectly leads to induction of these antigens on the plasma membrane of hepatocytes.
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Primary biliary cirrhosis (PBC) is a chronic nonsuppurative, destructive cholangitis, whose etiology is unknown. Morbidity arises early from pruritus and later from hypercholesterolemia with xanthoma formation. Therapy is supportive and directed at the complications of cholestasis. Plasmapheresis has been reported to benefit patients with hyperlipidemia and PBC; thus a pilot study of plasmapheresis utilizing the Haemonetics Model 30 with replacement by albumin and saline was conducted. Five patients (four female and one male) with a mean age of 43 (range 29-58) and a mean duration of illness of 9.5 years (range 6-21) with marked jaundice, xanthomas, xanthelasma, hepatomegaly, fatigability, anorexia, and pruritus, as well as mild nausea were studied. Peripheral neuropathy was present in two patients. Two patients had splenomegaly. Two patients had an associated Sjogren syndrome. All patients had high serum bilirubin, alkaline phosphatase, and cholesterol levels and mild elevations in aspartate amino transferase and alanine amino transferase activities. Immune complexes measured in four patients were present. Antimitochondrial antibody titers were significant in all patients. Patients underwent a mean of 63 plasmapheresis procedures over a mean of 112 weeks removing a mean of 94.7 liters of plasma. No serious toxicity was seen. All patients showed a reduction in pruritus, xanthomas, xanthelasmas, and serum cholesterol values. The two patients who had evidence of Sjogren syndrome noted subjective improvement. All patients who had fatigue, anorexia and nausea also noted moderate improvement. There was no change in hepatomegaly or splenomegaly in patients demonstrating such organomegaly. Liver function did not change significantly. Overall, four patients had improvement in their condition and one patient achieved stability.(ABSTRACT TRUNCATED AT 250 WORDS)
We reviewed the clinical and histologic features, course and response to therapy of 18 postmenopausal women with autoimmune chronic active hepatitis (CAH). The presentation of these patients was similar to that of younger patients, except for the lower incidence of associated autoimmune disease. Nuclear antibodies (ANA) were associated with complications, while smooth muscle antibodies (SMA) correlated with an uncomplicated course. Steroid therapy appeared to have less benefit and greater risk in our patients than in studies of all ages. The applicability of results of previous trials demonstrating benefit of corticosteroid therapy for CAH to postmenopausal women is questioned.
Although penicillamine is used in the treatment of primary biliary cirrhosis, its mechanism of action in this disease is unknown. As an immunologic action had been attributed to the drug, we investigated whether penicillamine might alter serum immunoglobulin levels or immune complex-reactive material in patients with primary biliary cirrhosis. Immunoglobulin levels and immune complex reactivity were measured and clinical tests were performed in 53 consecutive patients entering a double-blind randomized trial of 750 mg vs. 250 mg of penicillamine. Measurement of immune complex reactivity was determined by laser nephelometry, 125I-C1q binding, and Raji cell assays. Immune complex reactivity was detected by at least one assay in 75% of patients tested before treatment. Sixty-two percent were positive in the C1q assay, 28% in the Raji cell assay, and 39% by nephelometry. After therapy with either dose, we found no change in immune complex-reactive material by any assay. Concentrations of immunoglobulins G and M fell (p less than 0.05) after 12 mo of therapy. Concentrations of immunoglobulin A decreased (p less than 0.05) only in the high-dose group. Correlation was not consistent between results of immune complex assays and clinical liver tests. Although immunoglobulin levels fell during penicillamine therapy, no decrease in immune complex-reactive material was detected. The effect of penicillamine in primary biliary cirrhosis is not mediated through alteration of immune complex-reactive material.
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Five patients with primary biliary cirrhosis and prolonged cholestasis underwent intensive plasmapheresis. The indications for plasmapheresis included intractable pruritus or hypercholesterolemia and xanthomatous neuropathy. Patients noted a rapid improvement of pruritus and fatigue which was sustained as long as plasmapheresis was continued. Cholesterol levels were lowered an average of 10.3 mmol/l and xanthomata were reduced in three of four patients. Two patients with painful neuropathy caused by xanthomata experienced relief of this symptom. The liver and spleen size were not affected by plasmapheresis, and activities of aminotransferases, alkaline phosphatase and titres of mitochondrial antibody remained unchanged. We conclude that plasmapheresis has a role in the therapeutic management of patients with advanced primary biliary cirrhosis who are disabled by the complications of pruritus, xanthomatous neuropathy, or hypercholesterolemia with xanthoma formation.
A subset of workers was followed after exposure to polychlorinated biphenyls (PCBs), dioxins, and furans in an occupational medicine clinic setting. Patterns of PCBs found in adipose tissue resembled the pattern seen when soot from the incident or Aroclor 1254 was examined by GC-MS. Adipose tissue also revealed levels of hepta- and octachlorinated furans and dioxins as high as 8400 ppt in one repeatedly exposed worker. Control fat from patients with no known exposure to furans or dioxins was usually in the several hundred parts per trillion range for these isomers, but slightly over 2000 ppt in one sample. Electron microscopic analysis of liver biopsies from three patients who developed mild elevations of hepatic enzymes in their serum revealed morphologic alterations in some ways similar to those seen in animals after feeding experiments with PCBs, dioxins or the Binghamton State Office Building soot. These include pleomorphic mitochondria, giant mitochondria, prominent dense mitochondrial granules, cristae parallel to the long axis of the mitochondria and crystalline structure within same mitochondria as well as lipid droplets in liver cells and slightly dilated smooth endoplasmic reticulum.
Portal-systemic myelopathy is a rare complication of surgically created or spontaneous portal-systemic shunts in patients with chronic liver disease. We treated two patients with this entity, both of whom had undergone portacaval shunt operations.
Primary biliary cirrhosis is characterized by abnormalities in both cellular and humoral immunity. It is associated with presumably autoimmune diseases such as Sjögren's syndrome, rheumatoid arthritis, and scleroderma. Sjögren's syndrome and scleroderma have been noted to have an increased frequency of malignancy. Of 208 patients with primary biliary cirrhosis, followed for one month to 15.9 years, extrahepatic malignancies developed in 11, six of whom were women with breast cancer, and one with hepatocellular carcinoma. The incidence of breast cancer was 4.4 times (p less than 0.01) the incidence expected from the rate prevailing in the same age range in a comparable normal population. The incidence of cancer in sites other than the breast and of primary hepatocellular tumor was not significantly increased.
Changes in the etiology, clinical features, methods of diagnosis, and treatment of pyogenic liver abscess have occurred slowly but continuously over the past century. The earlier changes are well documented in the literature, and continuing variations in the classic patterns of disease are now evident. These include 1) a recent increase in incidence reflecting more accurate diagnostic techniques; 2) changes in bacteriology with a high incidence of Klebsiella infection; 3) a reduction in mortality, reflecting earlier diagnosis and more refined therapeutic methods; and 4) changes in the population at risk namely a large population of terminal cancer patients. Thirty-eight patients treated at the Mount Sinai Hospital over the past 16 years, 1967-1982, have been divided into two groups, each of 8 years duration, reflecting an earlier era before routine use of scanning procedures, and a later period when technetium, gallium, sonographic, and more recently CT imaging procedures were regularly done. During the latter period there was a significant increase in both the total number of liver abscesses diagnosed and in the number estimated as a proportion of all hospital admissions. Mortality has continued to fall to more acceptable levels with a 25% reduction overall. In the early era, extrahepatic intra-abdominal infection caused all four deaths. In the past 8 years obstructing or metastatic cancer has caused four of the five deaths. Bacteremia occurred in six of the nine deaths, five of these being of biliary origin. The decrease in mortality may reflect earlier diagnosis, an increase in the number of solitary abscesses, and better therapy.