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The synopsis presented above attempts to outline what is currently known about the biology of connective tissue as it applied to the liver. Analogies to myelofibrosis should be apparent in almost every paragraph.

Morphological, histochemical, and chemical study of three necropsy specimens of liver in the terminal stage of Indian Childhood Cirrhosis revealed a strikingly high copper content. it is proposed that excess accumulation of copper in the cytoplasm of hepatocytes disturbs the microtubular system, causing hydropic swelling and the formation of Mallory's hyalin. Copper and copper-binding protein showed topographical association with Mallory's hyalin. Diffuse cytoplasmic staining and the lysosomal copper distribution also suggested that copper had a cytotoxic effect. The pattern of copper distribution in Indian Childhood Cirrhosis differs from that in Wilson's disease and in prolonged cholestasis with excessive hepatic copper deposition, indicating a different mechanism of the copper accumulation.

The histogenesis of the various morphologic features in the different types of human viral hepatitis is not established, nor are definite criteria in the histologic distinction agreed upon. Moreover, the mechanism of transition to hepatocellular carcinoma (HCC) is not clarified, including molecular pathobiologic changes. Animal models of viral hepatitis may contribute to the understanding of these problems. The following descriptions are based on histologic material provided by, or studies in cooperation with, H.J. Alter, D.W. Bradley, HP. Dienes, J.L. Dienstag, S.M. Feinstone, M.A. Gerber, J.L. Gerin, S.C. Hadler, P.L. Marion, A. Ponzetto, R.H. Purcell, M. Rizzetto, W.S. Robinson, D.A. Shafritz, B.C. Tennant, and S.N. Thung. Two types of animal model can be distinguished. One results from experimental inoculation of laboratory animals for such purposes as to (a) characterize the viruses and their immunogenic potencies, particularly when virus culture in cells has not succeeded, (b) prove the infectiosity of such material, e.g., to identify hepatitis non-A, non-B (NANB), (c) determine the safety of vaccines, or effects of therapeutic agents, (d) provide material for vaccines, and (e) study the co- or superinfection with two of the viral agents. The other type entails the investigation of spontaneous infections in both domestic and wild animals.

Hepatic fibrosis may result from collapse after hepatocellular necrosis or from new formation of connective tissue. Fibroplasia, particularly within the lobular parenchyma, is a dynamic process. Newer cellular and biochemical investigations clarified its various steps. The process begins with stimulation of cells to connective tissue formation and can be divided into (1) intracellular synthesis, (2) extracellular maturation, and (3) collagen breakdown. The turnover of the connective tissue in the liver is conspicuously increased in chronic hepatitis of any type, as indicated by an elevation of several cellular and metabolic parameters. They are particularly raised in chronic hepatitis and in alcoholic liver injury. Further development of these parameters in the future should facilitate the analysis of the dynamics of fibroplasia. The strongest stimuli for hepatic fibroplasia are hepatocellular necrosis and inflammation, but ethyl alcohol and steatosis are also stimulating, though to a lesser degree. This explains the particular elevation of the fibroplastic parameters in alcoholic hepatitis. It points, however, also to the possibility that cirrhosis might develop without significant hepatocellular necrosis and inflammation. Perihepatocellular, periductular, and septal fibrosis are the functionally most important localizations leading to additional hepatic injury. The initiation of these types of fibrosis by liver injury points to a vicious circle. Specific anti-fibroplastic therapy is still in infancy.

The effect of azathioprine on survival of patients with primary biliary cirrhosis was studied prospectively in a multinational, double-blind, randomized clinical trial including 248 patients of whom 127 received azathioprine and 121 placebo. There were 57 deaths in the azathioprine group and 62 in the placebo group. The actual survival was slightly longer during azathioprine than during placebo treatment. Using Cox multiple regression analysis and adjusting for slight imbalance between the two treatment groups, the therapeutic effect of azathioprine was statistically significant (p = 0.01), with azathioprine reducing the risk of dying to 59% of that observed during placebo treatment (95% confidence interval 40%-90%) or improving survival time by 20 mo in the average patient. Furthermore, azathioprine slowed down progressing incapacitation. Side effects of azathioprine were relatively few. The analysis revealed that the following five variables independently implied poor prognosis: high serum bilirubin, old age, cirrhosis, low serum albumin, and central cholestasis. These factors were combined to a "prognostic index" for prediction of outcome in new patients. The index was validated on independent patient data. On the basis of these results we recommend azathioprine as a routine treatment of primary biliary cirrhosis.

Different types of liposarcomas, and for comparison, lipomas were investigated for their lipid composition. Triglycerides were the main components of lipomas and lipoma-like liposarcomas. Myxoid liposarcomas had a high water content and contained considerable amounts of free cholesterol and phospholipids. One pleomorphic liposarcoma resembled a myxoid liposarcoma in its lipid composition and water content. In 4 liposarcomas of mixed type the lipid composition resembled the main subtype. A glycerol ether-like fraction was found in all lipoma-like (well differentiated) liposarcomas, in one myxoid type but not in the other types.

Although a well-known disease worldwide, cerebral cysticercosis in European countries is a rare event. Due to increased travel to East-Asian and Latin American countries it is possible that the occurrence of brain cysticercosis will become more frequent. These facts should remind us of the possibility of cysticercosis of the nervous system. A case of cerebral and spinal cord cysticercosis is presented, causing symptoms of progressive dementia with ventricular occlusion and hydrocephalus. Differential diagnosis causes a major problem. It is shown that myelography may demonstrate characteristic features of the disease.

The morphology of hepatic lesions in experimental animals and man induced by environmental agents is evaluated as prototype of the tissue changes in other organs. Since more experience exists with effects of drugs than of other environmental agents, these experiences serve as guidelines. Since the liver reacts readily to many incidental extrahepatic alterations, a major difficulty in man, less so in animals is the distinction of these nonspecific injuries from toxicity. This is further complicated in man by the frequent hepatic alterations from clinically not apparent hepatic diseases. The most important alterations are hepatocytic lesions; degenerative changes are separated from anabolic and adaptive responses of which the induction of the microsomal biotransformation system reflected in increased smooth endoplasmic reticulum is most important and raises the question whether this adaptive reaction is an unfavourable phenomenon. The morphologic methods are reviewed. The hepatic reactions are separated into predictable and non predictable, not dose-dependent lesions, the latter usually not reproduced in animals. The manifestations in both are classified. The nodular hepatic lesions in rodents and their predictive value for man are discussed. Similar nodular hepatic lesions were seen in few humans exposed to sex steriods. A characteristic precursor lesion after vinyl chloride exposure (focal hyperplasia of hepatocytes and sinusoidal cells) potentially proceeding to angiosarcoma is presented. Finally, the role of liver biopsy in screening for environmental injury is being evaluated.

Sequential liver specimens of 18 baboons exposed for up to 6 years to alcohol on a nutritionally adequate diet, as well as those of pair-fed controls, were examined by light microscopy. Whereas control animals failed to develop pathologic changes, in all baboons exposed, ethanol produced initial steatosis and subsequently fibrosis. Emphasis was on the pattern of the fiber accumulations as related to lesions of the hepatocytes. Segmented neutrophilic leukocytes were rarely observed, and the picture of frank alcoholic hepatitis was absent, but diffusely increased mononuclear sinusoidal cells and interstitial clusters of such cells with PAS-positive macrophages were abundant. Fibrosis proceeding to septum formation was associated mainly with large-droplet steatosis. Septum formation was initiated by excess layers of reticulin around steatotic hepatocytes or, more frequently, by linking of fiber accumulations around the clusters of mononuclear cells, in both instances with subsequent deposition of collagen fibers. Both processes were prominent in the centrolobular zone, creating a perivenous net-like fibrosis, but septum formation also started within the lobular parenchyma and eventually linked with the barely altered portal tracts. Fifteen alcohol-fed baboons developed septums, with diffuse septal fibrosis in 5; 4 proceeded to septal cirrhosis and 1 each to micronodular and to mixed micromacronodular cirrhosis. Cirrhosis in the baboons thus develops without the conspicuous polymorphonuclear inflammation characteristic of human alcoholic hepatitis. These observations indicate a pathway to cirrhosis over creeping fibrosis that might play a role also in man, instead of (or supplementing) the one proceeding over alcoholic hepatitis.

Epidemiologic studies indicate a close association between hepatocellular carcinoma (HCC) and chronic hepatitis B virus (HBV) infection. HCC, a most frequent malignancy, is far more common in the Far East and Africa than in the West and may be the first to be greatly eliminated because of prevention of HBV infection by vaccination. The conceptual integration of epidemiologic observations, morphologic studies of the human precursor stages and investigations of animal infections by hepadna viruses with biologic and genomic similarity to HBV as well as with clinical and molecular biologic studies contribute to the understanding of the hepatocarcinogensis. In the woodchuck model after laboratory infection, HCC develops regularly without external cocarcinogen in permanent surface antigen carriers. The hypothesis is presented that an episodic necroinflammation in the carrier stage may act as an endogenous cocarcinogen or promoter in that previous integration of hepadna viral DNA in the host chromosone may become disorganized, which induces the clonal development of HCC. This hypothesis may become important in the management of the carrier stage.

Hepatic histologic materials (biopsy or autopsy) and associated clinical data from 155 hemophiliacs were collected by an ad hoc hemophilia study group and analyzed retrospectively in an effort to determine the spectrum of liver disease in this population and to examine the relationship between the severity of liver disease and treatment history. Clinical information on the frequency of complications from 126 biopsies in 115 hemophilic patients provided a unique opportunity to assess the safety of liver biopsy in such patients. The incidence of cirrhosis (15%) and chronic active hepatitis (7%) was lower than previously reported. The frequency of severe liver disease (chronic active hepatitis or cirrhosis) in patients receiving large pooled concentrates was no greater than in patients treated principally with cryoprecipitate or plasma. The risks of liver biopsy in this setting are relatively high: clinically significant hemorrhage followed 12.5% of the procedures.

Hepatocellular carcinoma (HCC) associated with chronic hepatitis B virus (HBV) infection in Yupik Eskimos in southwestern Alaska, detected in early stages as a result of screening, appears to be more frequently associated with variants of chronic portal inflammation in the noninvolved liver than with fully developed cirrhosis, otherwise common in HBV-associated HCC from other geographic areas. Of 38 patients diagnosed with HCC since 1969, adequate tissue was available from both the tumor and nontumorous liver in 17. Of the 17 specimens, 14 had chronic portal inflammation and three had advanced cirrhosis; 12 of the 14 were from hepatitis B surface antigen carriers. These 12 cases were studied in detail to examine the features accompanying the development of HCC unobscured by cirrhotic transformation. In the noninvolved parenchyma they included hepatocytic nodules as apparent precursors to HCC and, as markers of phenotypic alterations, dysplastic hepatocytes and hepatitis B surface antigen-laden ground-glass hepatocytes. The latter were observed in eight instances and often accumulated in nodules. Parenchyma within 1 mm of the HCC exhibited increased confluent hyperplasia and frequently conspicuous necroinflammation associated with pericellular and periductular fibrosis, which contributed, in addition to fibrous connections between displaced and heavily inflamed portal tracts, to the capsule that was forming in all cases to varying degrees in the pericarcinomatous region. The HCC was uniformly trabecular and in a few specimens, a continuous transition from hyperplasia and dysplasia near the periphery of the tumor to increasing anaplasia in the center could be made out in addition to pressure effects of the HCC. The pericarcinomatous changes, including hyperplasia progressing to neoplasia and necroinflammation, are also observed in experimental models, particularly the woodchuck HCC induced by a hepadna virus related to HBV. Coordinated morphologic and molecular biologic studies on such animal models and on human HCC detected by screening, as for instance in Eskimos, neither complicated by cirrhosis, should elucidate the direction of the evolution of the HCC and the postulated promoting role of the inflammation.

Bleomycin (BLM) was given perioperatively and 3 and 6 months postoperatively in a dosage of 150 mg per course (total: 450 mg) to 37 patients with surgically resectable squamous-cell lung cancer. 37 randomized control patients with resectable squamous-cell lung cancer were compared to the chemotherapy-group. 5-year overall survival of the BLM group was 46.3%, that of the controls 40.5% (Mantel-Haenszel test; p greater than 0.05). BLM-treated stage I showed a 5-year survival of 47.9% (controls: 55%), BLM stage II 50% (controls: 33.3%), BLM stage III 40% (controls: 21.4%). The difference is not statistically significant. No severe adverse effects of therapy on either wound healing, or perioperative mortality of lung function were observed.

Twenty patients with chronic type B hepatitis were entered into a randomized, controlled study of adenine arabinoside monophosphate. Before entry, all patients were documented to have stable levels of hepatitis B surface antigen, hepatitis B e antigen, serum hepatitis B virus deoxyribonucleic acid, and deoxyribonucleic acid polymerase activity. Ten patients received adenine arabinoside monophosphate and 10 received no treatment. The two groups were well matched with respect to age, sex, known duration of hepatitis B surface antigen, presence of symptoms, serum aminotransferase levels, and hepatic histopathology. During the 4 wk of therapy, serum levels of hepatitis B virus fell dramatically. However, serum hepatitis B virus-deoxynbonucleic acid or deoxyribonucleic acid polymerase activity, or both, remained detectable, and levels of hepatitis B virus invariably rose once therapy was stopped. From 2 to 9 mo after therapy, 4 of the 10 treated patients became hepatitis B e antigen or hepatitis B virus-deoxyribonucleic acid and deoxyribonucleic acid polymerase negative, or both, and the results of routine serum biochemical tests improved. However, 2 of these 4 patients later relapsed. In the control group, 2 patients became seronegative for hepatitis B virus-deoxyribonucleic acid and deoxyribonucleic acid polymerase and manifested improvement in serum biochemical results by 18-24 mo after randomization. Thus, long-term improvements in clinical and serologic features of disease occurred in 20% of both treated and control patients. Side effects of adenine arabinoside monophosphate therapy were common, and 3 patients developed a severe and prolonged neuropathic pain syndrome. These results suggest that a 4-wk course of adenine arabinoside monophosphate therapy does not induce an increased rate of long-term remissions in chronic type B hepatitis.

An argentaffin carcinoid tumour of the caecum which contained serotonin (167 micrograms/g) and consisted predominantly of EC1-cells, was analysed for the presence of peptides using immunohistochemical, biochemical and pharmacological methods. A very high content of 3.9 micrograms/g of immunoreactive substance P was found. The distribution of cells staining positively for substance P matched that of cells containing serotonin. While some immunoreactive somatostatin (3.2 ng/g) was present in the tumour, neurotensin, glucagon, gastrin, and motilin were not found. Part of the substance P immunoreactivity measured most likely represents authentic substance P: it behaved like substance P in two chromatographic systems and in two bioassays, and its activity on the guinea pig ileum was abolished by specific tachyphylaxis towards substance P.

The authors reviewed the cases of 19 Alaskan Natives (15 men, four women) with primary hepatocellular carcinoma (HCC) diagnosed during 1980-1985. Of these 19 patients, 16 were seropositive for hepatitis B surface antigen (HBsAg). Alpha-fetoprotein (AFP) was elevated in 15 patients (all were HBsAg positive). The patients ranged in age from 8 to 80 years old. Of the 19 patients, 16 were Eskimo, 13 of whom were Yupik. The annual age-adjusted (world standard) incidence of HCC for all Alaskan Natives was 9.3/100,000 for men and 2.2/100,000 for women. The tumor was resected in seven patients; six showed no recurrence of cancer 1 to 4 years after surgery. Histologic evaluation in 18 patients revealed trabecular type of HCC in 15 and acinar HCC in two others. In 16 specimens in which nontumorous liver could be studied, only six had evidence of cirrhosis; ten others showed variants of chronic persistent hepatitis.

In order to see if the term of "plasma cell hepatitis", dating back to the early sixties, is still valid as a morphological diagnosis for autoimmune chronic hepatitis (AICH), and to find out if the existence of several subgroups is reflected by histopathology, we investigated 26 patients with chronic hepatitis, who met the criteria of autoimmune hepatitis based on tests for antinuclear, anti-smooth muscle antibodies (SMA) and on immunoassays for liver-kidney-microsomal (LKM) antigen, liver membrane antigen (LMA), and soluble liver antigen (SLA). In our material autoimmune hepatitis represent the entire spectrum of chronic hepatitis with variable inflammatory activity ranging from chronic persistent hepatitis to severe inflammatory lesions in chronic active hepatitis with transition to cirrhosis. When compared to viral chronic hepatitis A and non-A, non-B, however, characteristic features can be evaluated consisting in broad hypocellular areas of collapse and microacinar transformation of hepatocytes with hydropic swelling being the predominant type of cell lesion. Eosinophilic clumping and acidophilic necrosis were insignificant. Plasma cells were not a constituent feature of AICH. From this histopathologic pattern it may be concluded that the disease seems to run a sluggish course in most patients, however, in few cases a dramatic development may determine the disease with fatal acute episodes which are terminated by death or fade into slow progression. The different subgroups could not be distinguished by histopathology.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatoblastomas are more common in childhood but extremely rare in adults. A further case of hepatoblastoma in an adult is reported: The tumor consisted of two components, epithelial and mesenchymal ones. Both were well-separated from each other and showed different ways of metastasizing in to lymphatic vessels and lymph nodes or in to blood vessels and lung, respectively. It is concluded that hepatoblastomas of mixed type originate from two different cell types: The tubular and, sometimes, acinar malignant cells originate from the epithelium of the foregut and the osteo-osteoid-chondromatous malignant component is derived from mesenchymal cell of the coelomic wall.

Nasal mucosa biopsies were taken from a child with Kartagener's syndrome. The biopsies were prepared for light and electron microscopic examination. Unfixed cryocut sections were stained with the magnesium-activated ATPase reaction. There was a partial loss of the dynein arms within the cilia. Many compound cilia were present and, sometimes, defects of the mitochondria of the lining epithelial cells as well as the glandular cells were observed. Histochemically the ATPase reaction was at first completely negative and sometime later it was greatly reduced within the lining and the glandular epithelial cells, especially in the apical border. Biopsies from children with cystic fibrosis and allergic rhinitis served as controls.

A case of severe therapy-resistant asthma in a young girl with a duration of two years prior to death is reported. At autopsy antibodies of the IgA2-subtype were demonstrated in the lungs on the alveolar basement membranes. We were able to demonstrate intracellular virus-like structures by electron microscopy; this virus infection is taken to be the cause of antibody production. Following antigen-antibody reaction a non-complement-mediated eosinophilic pneumonia with numerous macrophages developed. This inflammatory reaction showed the injurious effect of eosinophilic granulocytes causing fibrinoid necrosis; this is confirmed by the pronounced depletion of the Charcot-Leyden-granules, equivalent to the release of the major basic protein and the Charcot-Leyden crystal protein. Death was caused by IgA2 deposition in the myocardial vessels with consequent eosinophilic myocarditis.

Necrosis of the hepatocytes, as a rule associated with disappearance of cells or their breakdown products, is usually accompanied by an inflammatory reaction composed of macrophages, lymphocytes and occasionally, neutrophilic and eosinophilic granulocytes; particularly with single cell necrosis this is histologically more conspicuous than the loss of the hepatocytes1. In the following discussion the topographic localisation and size of the necrosis is correlated with its functional significance and various aetiologic examples of necrosis are discussed with some emphasis on the features of cholestatic necrosis to provide a basis for the subsequent discussion on the mechanism of necrosis induced by hepatotoxic bile acids by Greim et al. (Chapter 18).

Four cases of childhood hepatic angiosarcoma (HAS), representing the malignant form of infantile hemangioendothelioma, are described. The morphologic appearance of childhood HAS differs from the adult form in the following features: the associated presence of benign infantile hemangioendothelioma; the presence of dysontogenetic features; and an altered appearance of the angiosarcoma itself. It is postulated for these cases that the benign infantile hemangioendothelioma progressed to the malignant angiosarcoma. One of the four cases had exposure to elevated levels of arsenic in the environment that may have contributed to this progression. This latter case adds to published reports associating arsenic exposure with increased risk for hepatic angiosarcoma.