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In primary biliary cirrhosis (PBC) liver copper retention occurs as a complication of cholestasis. By analogy with Wilson's disease, it has been suggested that copper retention is hepatotoxic in PBC, and this has been the rationale for the use of D-penicillamine in this disease. The hypothesis that copper is hepatotoxic in PBC has not been tested and in this study we have evaluated the role of liver copper retention in the pathogenesis of PBC. Sixty-four patients with PBC have been studied. Fifty-four had increased liver copper concentrations. Liver cell synthetic function was well preserved. All the patients had normal prothrombin times, and only two had subnormal serum albumin concentrations. There was no correlation between liver copper concentrations and the degree of liver cell damage assessed biochemically (aspartate transaminase), and histologically. Electron microscopy was performed on liver biopsies from five patients with markedly increased liver copper concentrations. The liver cell ultrastructure was compatible with cholestasis. Liver cells contained electron dense lysosomes, which were shown to contain copper and sulphur by x-ray probe microanalysis. The characteristic organelle changes associated with copper toxicity in Wilson's disease were not observed. The biochemical, histological, and histochemical differences between PBC complicated by liver copper retention, and Wilson's disease, indicates that there are differences in the handling of copper in these disease. In this study we could find no evidence to suggest that copper plays an important role in the pathogenesis of liver dysfunction in PBC.

This memorandum provides guidelines on the definition, nomenclature, and classification of cirrhosis, chronic hepatitis, and hepatic fibrosis. These are considered according to morphological characteristics and aetiology. It is hoped that this system will serve as a standard for diagnostic, research, and epidemiological purposes. The relationship of cirrhosis to liver cell carcinoma is briefly discussed and the possible morphological markers of an increased risk of malignancy are defined.

Liver biopsies were performed on 51 regularly transfused patients with beta thalassaemia, age range 5-36 (mean 18.6) years, who had received regular subcutaneous desferrioxamine (DFX) treatment for periods between one and eight years (40 for eight years). The biopsy specimens were examined by light microscopy and immunofluorescence for hepatitis B virus surface and core antigens (HBsAg and HBcAg), and the iron content was determined chemically. The results were compared with serum ferritin concentration and aspartate transaminase (AST) activity and with hepatitis B virus serology. Biopsy specimens, in which chemical liver iron had been determined in 12, were also available from 17 patients. Mean serum ferritin (+/- SD) had fallen from 5885 (3245) micrograms/l to 1638 (976) micrograms/l in 36 patients after eight years' chelation, while mean (+/- SD) liver iron concentration had fallen from 2945 (900) micrograms/100 mg dry weight to 857 (435) micrograms/100 mg dry weight in 12 of them. All biopsy specimens examined were negative for HBs and HBc antigens. The presence of histological features of hepatitis was associated with increased liver iron content, increased fibrosis, and with progression of fibrosis between the two biopsies. Procollagen III peptide was assayed in 28 patients but did not correlate with the degree of hepatitis, fibrosis, or with chemical liver iron content. We conclude that with regular subcutaneous DFX, mean concentrations of serum ferritin and liver iron are maintained in these patients at about five and 10 times the normal value, respectively, and that progression of liver damage is more likely to be due to viral hepatitis, presumably related to the parenterally transmitted non-A, non-B agents than to iron overload.

Liver copper concentrations in percutaneous biopsy specimens were measured by neutron activation analysis and compared with histological staining for copper by rubeanic acid and rhodanine, and with copper-associated protein stained by orcein. Liver copper concentrations were elevated in 31 of 35 biopsies from patients with primary biliary cirrhosis (PBC), and discrimination between normal and elevated liver copper was correct in 32 of the 35 biopsies by staining with rubeanic acid, and 31 of the 35 by staining with rhodanine. Orcein staining of copper-associated protein was positive in 33 of the 35 biopsies. All 17 biopsy specimens from patients with Wilson's disease had high liver copper concentrations, but only nine had positive staining for copper, and six were orcein positive. Similarly, histological stains gave little indication of the liver copper concentrations in tissue from 16 patients with chronic active hepatitis. Staining of liver sections can be useful in detecting elevation of liver copper in PBC, but not in Wilson's disease, where the absolute concentration must be measured. Excess copper appears to accumulate in the liver in different chemical forms in PBC and Wilson's disease.

Twelve serologically proven cases of non-A, non-B (NANB) hepatitis have been described. The clinical course was mild in 11 patients. One patient, however, presented in portal systemic encephalopathy and required steroid treatment. Nine of the 12 patients continued to exhibit raised transaminase (AST) activities six or more months after the onset of the acute hepatitis. In these immunoglobulin concentrations were normal and autoantibodies were not present in significant titre. Four patients had evidence of previous hepatitis B infection, suggesting that the route of transmission of NANB might be similar to that of hepatitis B virus. A further four patients gave a history which suggests a possible parenteral mode of transmission. Liver biopsies were carried out both in the acute (8 cases) and chronic (6 cases) phases of the disease. Histological findings in liver biopsies covered the whole spectrum of acute and chronic hepatitis and 1 patient had cirrhosis. One notable feature in these biopsies was the presence of fatty changes.

Liver biopsies from 97 hepatitis B antigen (HBsAG)-positive patients were stained by a modified orcein method described by Shikata et al (1974) in order to detect the antigen in liver tissue. The results were consitently negative in acute hepatitis, but positive in nearly two-thirds of biopsies from 53 patients with chronic liver disease. The distribution of positive staining was frequently irregular so that there is a problem of sampling error in needle biopsies. The deposits were seen in the cytoplasm of liver cells and occasionally in Kupffer cells, but never in nuclei. There was an inverse relationship between staining and parenchymal necrosis. Biopsies from asymptomatic HB(s)Ag carriers were often strongly positive, as were "ground-glass" hepatocytes in carriers and patients with chronic liver disease. The mechanism of staining is unclear but may be related to the presence of disulphide bonds in (HBsAG. The technique is simple and of use both in fresh and stored material.

Pre-eclampsia complicated by deep jaundice occurred in a previously healthy primigravida. The main aetiological factor was disseminated intravascular coagulation; this caused both haemolysis and liver cell necrosis. Liver biopsy showed fibrin thrombi in the capillaries with microhaemorrhages and loss of periportal liver cells. The jaundice was attributed to both haemolytic and hepatocellular processes. Organs other than the liver were relatively unaffected.

One hundred and six consecutive chronic hepatitis B virus (HBV) carriers were studied for the prevalence of delta markers in serum and tissue, and the clinical and histological features of those with and without delta infection were compared. Twenty (18.9%) patients were positive for anti-delta in serum or delta antigen in the liver or both. They presented at a younger age (30.3 v 38 years). All of them were symptomatic at the time of biopsy, in contrast to 35% of patients without delta infection who were not symptomatic. Those with delta infection had higher serum transaminase values and showed more severe liver damage on biopsy: chronic active hepatitis in 45% and cirrhosis in 55%. There was more pronounced disease activity both within the parenchyma and in the portal and periportal zones. The histological diagnosis of the 86 patients without delta infection included minimal disease (10%), chronic persistent hepatitis (9%), chronic active hepatitis (62%), and cirrhosis (19%). Delta infection in chronic HBV carriers is associated with a more active and progressive liver disease.

Serum glutamate dehydrogenase (EC 1.4.1.3.) activity was measured in 73 hospital patients who had a history of chronic alcohol abuse and who all had a liver biopsy performed. High levels of serum GDH activity occurred in those patients with recent excess alcohol consumption independently of the underlying liver histology, and did not discriminate between those patients with and those without alcoholic hepatitis.

Thirty-one patients with primary biliary cirrhosis in whom adequate histological liver material was available were studied by immunological and histological methods. There was no statistically significant correlation between individual histological features and the level of serum mitochondrial antibodies. A relationship between the duration of symptoms and histological stage of the disease supports the present concept of its evolution. However, several stages were often identified in the same specimen. Four cases with negative mitochondrial antibodies were similar to the other 27 clinically and histologically.

Wedge biopsies from the inferior border of the normal liver were studied in 72 cases. They were divided into three groups according to the extent and degree of capsular and subcapsular fibrous tissue. The changes were not sufficiently severe or extensive to cause confusion with nodular cirrhosis or to make wedge biopsy unreliable as a diagnostic tool.

The necropsy findings in a 5-year-old girl with congenital hepatic fibrosis are described. She had been followed since the age of 18 months and finally developed hepatocellular failure. Extensive haemorrhagic necrosis was found at necropsy and was probably related to the terminal illness. Other unusual findings were areas of typical post-necrotic cirrhosis and marked centrilobular and diffuse emphysema of the lungs. It is suggested that the latter was also congenital in origin.