A multicentre, randomized study to evaluate the safety and efficacy of histamine dihydrochloride and interferon-alpha-2b for the treatment of chronic hepatitis C.

Interferon- (IFN-)alpha is currently the standard of care treatment for patients with chronic hepatitis C virus (HCV) infection. A significant part of the benefit of IFN-alpha in chronic hepatitis C is believed to be related to the activation of lymphocytes such as T cells and natural killer (NK) cells, which participate in the elimination of infected cells. Histamine dihydrochloride (HDC) has been shown to potentiate the IFN-alpha-induced activation of T cells and NK cells by a mechanism that involves the protection of these lymphocytes against oxygen radical-induced functional inhibition and apoptosis. This study was designed to examine the efficacy and safety of HDC in combination with IFN-alpha-2b in treatment-naïve patients with chronic HCV infection. All patients received IFN-alpha-2b, 3 MIU, three times weekly via subcutaneous injection, and were randomized to one of four HDC regimens (1 mg of either: once a day, three times a week; once a day, five times a week; twice a day, three times a week or; twice a day, five times a week). The doses of HDC in combination with IFN-alpha-2b resulted in sustained viral response rates ranging from 31% to 38%. Sustained biochemical response rates ranged from 28% to 41% across the four treatment groups. Patients infected with HCV genotype 1, and those with high baseline viral levels, which are characteristics associated with poor prognosis, had sustained virologic response rates ranging from 18% to 42% and 15% to 39%, respectively. Combination treatment was generally well tolerated. We propose that the potential benefit of HDC + IFN therapy for chronic HCV infection should be the focus of further investigation.

Antioxidant properties of colchicine in acute carbon tetrachloride induced rat liver injury and its role in the resolution of established cirrhosis.

Antioxidant and antifibrotic properties of colchicine were investigated in the carbon tetrachloride (CCl(4)) rat model. (1) The protective effect of colchicine pretreatment on CCl(4) induced oxidant stress was examined in rats subsequently receiving a single lethal dose of CCl(4). Urinary 8-isoprostane, kidney and liver malondialdehyde and kidney glutathione levels increased following CCl(4) treatment, but only the rise in kidney malondialdehyde was significantly inhibited by colchicine pretreatment. Serum total antioxidant levels were significantly higher in the colchicine pretreatment group. (2) The long term effects of colchicine treatment on CCl(4) induced liver damage were investigated using liver histology and biochemical markers (hydroxyproline and type III procollagen peptide). Co-administration of colchicine with sub-lethal doses of CCl(4) over 10 weeks did not prevent progression to cirrhosis. However, rats made cirrhotic with repeated CCl(4) challenge and subsequently treated with colchicine for 12 months, all showed histological regression of cirrhosis. (3) The antioxidant effect of colchicine in vitro was evident only at very high concentrations compared to other plasma antioxidants. In summary, colchicine has only weak antioxidant properties, but does afford some protection against oxidative stress; more importantly, long term treatment with this drug may be of value in producing regression of established cirrhosis.

Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy: a double-blind, randomized, dose-finding multi-centre study.

OBJECTIVE: To determine the efficacy, tolerability and safety of oral rifaximin given at three dose levels in patients with cirrhosis and mild to moderate hepatic encephalopathy (HE). DESIGN: Prospective, double-blind, randomized, parallel-group study. SETTING: Multi-centre trial in four university teaching hospitals. PARTICIPANTS: Fifty-four patients with cirrhosis and mild to moderate HE. INTERVENTION: Seven days treatment with rifaximin, 600, 1200 or 2400 mg/day in three divided doses. MAIN OUTCOME MEASURE: Change in the portal-systemic encephalopathy (PSE) index between baseline and day 7, calculated on the basis of mental state, asterixis, number connection test time, EEG mean cycle frequency and blood ammonia concentrations. RESULTS: Treatment with rifaximin was associated with an improvement in the PSE index. There was a trend towards a greater treatment effect of rifaximin with the highest dose of 2400 mg/day. Rifaximin was well tolerated; the few treatment-related adverse events showed no consistent pattern or dose relationship. CONCLUSION: Rifaximin may be useful as alternative or adjuvant therapy for grade I-III hepatic encephalopathy in patients with cirrhosis at a dose of 1200 mg/day.

Hepatic sarcoidosis and renal carcinoma.

Sarcoidosis is a relatively common, chronic, multisystem disease of unknown origin. It most commonly affects young adults and usually manifests with bilateral hilar lymphadenopathy or pulmonary infiltrates. Alternatively, it may present with protean manifestations. It has been documented in all organs of the body, with the exception of the adrenal gland. We describe a male patient who presented with hepatic sarcoidosis, with a sclerosing cholangitis-like picture, but without any pulmonary involvement. He was treated with prednisolone and cyclophosphamide, the latter as a steroid-sparing agent. A few years later, renal adenocarcinoma developed. We postulate that this could be related to cyclophosphamide treatment. We present this case history for two reasons: (1) sarcoidosis, selectively affecting the liver and lymph nodes but not the lung, with its hepatic involvement mimicking sclerosing cholangitis, has not previously been reported: and (2) although long-term cyclophosphamide treatment is known to be associated with malignancy, there is only one previous report of its association with a renal adenocarcinoma.

Localisation and semiquantitative assessment of hepatic procollagen mRNA in primary biliary cirrhosis.

BACKGROUND: Chronic liver disease is characterised by excessive deposition of collagen and other extracellular matrix proteins, produced mainly, but not exclusively, by activated hepatic stellate cells in the perisinusoidal space. In primary biliary cirrhosis (PBC) fibrosis is concentrated mainly around the portal tracts. AIMS: To examine the hypothesis that, in addition to hepatic stellate cells, portal tract fibroblasts might play a significant role in the deposition of collagen in PBC. METHODS: Fifty liver biopsy specimens from patients with PBC were studied. An in situ hybridisation technique was adapted to localise and measure semiquantitatively type I procollagen mRNA in formalin fixed, paraffin wax embedded sections, using an 35S labelled cRNA probe specific for the alpha 1 chain of rat type I procollagen. Hepatic fibrogenic activity was also assessed using serum type III procollagen peptide (PIIINP). RESULTS: In PBC, type I procollagen gene expression was significantly increased. Signal was localised mainly in and around inflamed portal tracts, to cells which had the appearances of portal fibroblasts. Signal activity in these cells correlated with the degree of portal fibrosis and inflammation and also with serum PIIINP concentrations. CONCLUSIONS: Results are consistent with the hypothesis that the excessive extracellular matrix, deposited within the liver in PBC, is synthesised not only by hepatic stellate cells but also by portal tract fibroblasts. The semiquantitative assessment of procollagen mRNA in liver biopsy specimens may provide a useful method of evaluating the rate of synthesis of collagen and therefore disease activity in patients with PBC.

The use of TIPS to control bleeding caput medusae.

Two patients with cirrhosis and portal hypertension had persistent bleeding from caput medusae and ascites. Transjugular intrahepatic portosystemic shunt (TIPS) resulted in regression of the caput medusae and ascites in both cases.

Serum type III procollagen aminopeptide for assessing liver damage in methotrexate-treated psoriatic patients.

This study was designed to establish whether measurement of a serological marker of fibrosis might reduce the need for liver biopsy in psoriatic patients receiving methotrexate (MTX). Levels of type III procollagen aminopeptide (PIIINP-O and PIIINP-B) and laminin P1 (LamP1-B) were measured in 147 serum samples taken at the time of liver biopsy in 87 patients receiving long-term MTX treatment for severe psoriasis. Biopsies were classified as: (1) normal, (2) steatosis, (3) inflammation, (4) fibrosis, or (5) cirrhosis. Groups 3-5 were considered to show clinically relevant abnormality. Compared with controls, PIIINP-O was significantly raised in the group of MTX-treated psoriatics (P < 0.001). Within this group, levels were significantly higher in patients with inflammation, fibrosis or cirrhosis compared with those with normal histology or steatosis alone (P < 0.0001). In contrast, PIIINP-B and LamP1-B did not distinguish between controls and MTX-treated patients or between histological groups. Forty-two patients had two or more biopsies with simultaneous PIIINP-O measurement. PIIINP-O levels at the time of the first biopsy were normal in six of the seven patients whose histology was initially normal and subsequently became abnormal. A single measurement of PIIINP-O thus did not predict which patients might develop abnormal histology following further MTX. In a group of 17 patients, PIIINP-O was measured 3-monthly for up to 6 years during MTX treatment. PIIINP-O was elevated at some time during follow-up in all three patients who developed abnormal histology but was consistently normal in eight of the 11 patients whose histology remained or became normal. Our findings indicate that PIIINP-O is of value in detecting liver damage and, particularly if measured serially, may reduce the need for liver biopsy in MTX-treated patients. Although the test does not detect all patients with fibrosis, it would appear that the risk of missing significant liver damage in patients with persistently normal PIIINP-O is low.

Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene.

Familial adenomatous polyposis (FAP) is associated with a number of extraintestinal manifestations, which include osteomas, epidermoid cysts, and desmoid tumors, often referred to as "Gardner syndrome." Recent studies have suggested that some of the phenotypic features of FAP are dependent on the position of the mutation within the APC gene. In particular, the correlation between congenital hypertrophy of the retinal pigment epithelium (CHRPE) and APC genotype indicates that affected families may be divided into distinct groups. We have investigated the association between the dentoosseous features of GS on dental panoramic radiographs (DPRs) and APC genotype in a regional cohort of FAP families. DPRs were performed on 84 affected individuals from 36 families, and the dento-osseous features of FAP were quantified by a weighted scoring system. Significant DPR abnormalities were present in 69% of affected individuals. The APC gene mutation was identified in 27 of these families, and for statistical analysis these were subdivided into three groups. Group 1 comprised 18 affected individuals from seven families with mutations 5' of exon 9; these families (except one) did not express CHRPE. Groups 2 comprised 38 individuals from 16 families with mutations between exon 9 and codon 1444, all of whom expressed CHRPE. Group 3 comprised 11 individuals from four families with mutations 3' of codon 1444, none of whom expressed CHRPE. Families with mutations 3' of codon 1444 had significantly more lesions on DPRs (P < .001) and appeared to have a higher incidence of desmoid tumors. These results suggest that the severity of some of the features of Gardner syndrome may correlate with genotype in FAP.

Hepatitis C-related chronic liver disease among asymptomatic blood donors in the north west of England.

In the first 19 months of screening, the North Western Regional Transfusion Centre (RTC) tested 224,000 consecutive blood donors for antibody to hepatitis C virus (anti-HCV) by second generation enzyme immunoassay (EIA). Of these, 366 repeatedly reactive samples were referred for confirmatory testing at Manchester Public Health Laboratory (PHL). There, the initial EIA was repeated, together with two further EIAs. All the referred samples were subjected to a confirmatory line immunoblot (RIBA-II). Reverse transcription followed by the polymerase chain reaction (RT-PCR), in order to detect viral RNA, was performed on selected samples. Among the donors, 61 accepted offers for medical review and were assessed for risk factors, clinical findings and results of standard liver function tests. Of these donors, 53 proceeded to liver biopsy. The overall prevalence of confirmed positive donors was 0.04%. Main risk factors identified included intravenous drug abuse in 31 (51%) donors and prior blood transfusion in 12 (20%) but a risk factor was not apparent in 11 (18%). Viraemia, detected by RT-PCR, could be predicted with a high degree of accuracy by means of the readily available and simpler screening and confirmatory tests (EIA and RIBA-II). Established chronic hepatitis was demonstrated in 90% of the liver biopsies. A trend towards worsening histological findings accompanied increasing concentrations of serum transaminase. Even so, many donors with normal transaminase values had abnormal biopsies including those showing chronic active hepatitis (CAH). These findings indicate that a substantial proportion of previously unrecognised asymptomatic persons with established chronic liver disease exists among North Western blood donors.(ABSTRACT TRUNCATED AT 250 WORDS)

The histopathological features of asymptomatic hepatitis C virus-antibody positive blood donors.

Since the introduction of screening for hepatitis C virus (HCV) in donated blood, the risk of contracting posttransfusion hepatitis has been greatly reduced and the test has led to the recognition of asymptomatic blood donors positive for anti-HCV antibodies. Following confirmation of the HCV status with second generation RIBA testing followed by counselling, 55 patients had full investigations, including liver biopsy. These were classified by the traditional chronic hepatitis system and were graded according to the Knodell and Scheuer histological activity indices. Seven of the biopsies were normal (12%), apart from minor degrees of steatosis in two. Eleven cases (20%) were in the chronic lobular hepatitis category without portal inflammation, while 37 cases showed portal inflammation, including 20 (36%) cases where chronic persistent hepatitis was the predominant feature and 17 cases (31%) where there was chronic active hepatitis with piecemeal necrosis. Features which have previously been described in chronic HCV-associated hepatitis were noted: portal lymphoid aggregates (58%), lymphoid follicles with germinal centres (15%), bile duct damage (11%), lobular inflammation (80%), sinusoidal mononuclear cell infiltration (26%), acidophil body formation (11%), and steatosis (47%). Fibrosis was present in 46% of cases but was generally of mild degree; 9% of biopsies demonstrated bridging fibrosis but no cases of cirrhosis were present. Even though serum transaminase levels correlated well with the presence of chronic hepatitis and with the Scheuer and Knodell activity indices, a proportion of patients with significant liver damage had normal transaminase levels, and this study suggests the need for liver biopsy in the evaluation of asymptomatic HCV-positive blood donors.

Hepatitis C virus in autoimmune liver disease in the UK: aetiological agent or artefact?

Hepatitis C virus antibody titres (anti-HCV) were measured in serum from 122 patients with autoimmune liver disease (96 with primary biliary cirrhosis and 26 with autoimmune chronic active hepatitis using three generations of enzyme immunoassay (EIA): first generation--Ortho, EIA1; second generation--Abbott, EIA2; and third generation--Murex, EIA3. Anti-HCV was below the positive cut-off level in all 26 autoimmune chronic active hepatitis patients for all tests, while seropositivity values in primary biliary cirrhosis were 31% (EIA1), 14% (EIA2), and 0% (EIA3). In primary biliary cirrhosis, anti-HCV values as measured by all three tests correlated positively with serum IgG concentrations, serum storage time, and a number of other indices of hepatic dysfunction. Multiple regression analysis showed that anti-HCV values were independently affected by both serum IgG and the length of storage time, although the magnitude of the effects varied between tests. When all three multiple regression models were applied to an extreme clinical example, however, EIA3 was least likely to give a false-positive result. The difference in test performance was emphasised further by examination of anti-HCV values in nine primary biliary cirrhosis patients (confirmed negative by recombinant immunoblot assay 2) in whom serial samples were tested (seven to 14 per patient, stored for one to 138 months). Apparent anti-HCV values (EIA1 and EIA2) increased with increasing serum storage time, but were unchanged when measured by EIA3. A similar pattern was evident in a limited study of five autoimmune chronic active hepatitis patients. As the second generation EIA is in widespread use and confirmatory testing is not always available, the effect of serum storage in addition to hyperglobulinaemia should be considered in the interpretation of positive results in auto immune and in other types of chronic liver disease.

Raised liver enzymes in asymptomatic patients: investigation and outcome.

Asymptomatic patients with raised liver enzymes are frequently encountered in clinical practice. The commonest lesion in such patients appears to be fatty liver, which may be found in those only modestly overweight. Proven treatments other than abstention from alcohol and weight loss are available for approximately 20% of asymptomatic people with abnormal liver enzymes. However, if experimental therapies are taken into account this would rise to over 50%, making an early accurate diagnosis important. Most conditions can be diagnosed non-invasively, especially in those people with markedly abnormal transaminases. The recent introduction of new non-invasive tests decreases the need for liver biopsy for diagnostic purposes, however liver biopsy retains an important role in establishing patient prognosis and response to treatment.

Androgen associated hepatocellular carcinoma with an aggressive course.

The hepatocellular carcinomas that develop in patients treated with androgens have previously been associated with a benign clinical outcome. We describe a man who developed a hepatocellular carcinoma after 24 years of androgen treatment, whose tumour initially showed partial regression after withdrawal of androgens but subsequently pursued an aggressive and fatal course.

Colchicine in primary biliary cirrhosis.

Colchicine, which has been used for hundreds of years in the treatment of gout, has found a new use in the treatment of cirrhosis. In the experimental animal, and in vitro, colchicine decreases inflammation, inhibits collagen synthesis and also increases collagen degradation by activating collagenase. Many of the putative beneficial actions of the drug in cirrhosis, as well as its toxic side effects, are due to the fact that it binds to tubulin and thereby disrupts microtubules; however, it is unclear which of these actions, mostly demonstrated in the experimental animal, are present in the doses currently used in man. There have been 4 controlled trials of colchicine in various forms of cirrhosis, three of which have concerned primary biliary cirrhosis. Data are currently available on 146 colchicine-treated patients, of which 92 had primary biliary cirrhosis. Colchicine improves the conventional liver function tests in primary biliary cirrhosis and also reverses the basic defect in hepatic excretory capacity characteristic of this disease. The drug appears to have no significant effect on symptoms, clinical features or liver histology, but in 2 of the 3 primary biliary cirrhosis trials, as in the Mexican study of alcoholic and post-hepatitic cirrhosis, colchicine treatment was associated with improved survival.

Chylous reflux into abdominal skin simulating lymphangioma circumscriptum in a patient with primary intestinal lymphangiectasia.

A 47-year-old man with primary intestinal lymphangiectasia developed chylous reflux into the skin of the right flank. The clinical appearance resembled lymphangioma circumscriptum with multiple dome-shaped vesicles filled with milky-white fluid which discharged on to surrounding skin. Backflow of chyle into the skin of the lower limb, perineum or external genitalia has been described as a rare finding in patients with primary lymphoedema but we believe this to be the first case involving the abdomen and the first case describing chylous reflux into the skin in a patient with intestinal lymphangiectasia.

IgA nephropathy in non-cirrhotic portal hypertension.

Renal glomerular changes are a well recognised complication of cirrhosis and are frequently characterised by mesangial IgA deposition. We report a patient with non-cirrhotic portal hypertension who developed IgA nephropathy and a nephrotic syndrome with renal histological changes classically associated with cirrhosis. Splenectomy with resection of a splenic artery aneurysm resulted in remission of the nephrotic syndrome. This case illustrates the factors which contribute to the pathogenesis of IgA nephropathy in liver disease.

Endothelial cell transformation in primary biliary cirrhosis: a morphological and biochemical study.

There is increasing interest in the changes of the endothelial lining of the hepatic sinusoids during the development of chronic liver disease. In this study we looked for evidence of hepatic sinusoidal endothelial cell transformation and basement membrane production in patients with primary biliary cirrhosis. Morphological transformation to vascular-type endothelial cells, as evidenced by the development VIII-related antigen, was seen at the interface between portal tracts or fibrous septae and hepatic parenchyma; the most marked changes were observed in patients with established cirrhosis. Increased immunohistochemical staining for the basement membrane components type IV collagen and laminin was also found in a similar distribution. Raised serum levels of hyaluronic acid, a glycosaminoglycan metabolized by normal hepatic endothelial cells, were found in most patients and correlated strongly with advancing histological stage. Furthermore, significant positive correlations were found between serum hyaluronic acid and serum levels of laminin and type IV collagen. The unique structure of the normal endothelial lining of the hepatic sinusoids is important in the maintenance of hepatic function. Our data show that significant changes in endothelial cell structure and function occur in primary biliary cirrhosis and appear to be a contributing factor to the progression of the disease. Further studies are needed to determine the extent and importance of these changes in other forms of chronic liver disease.

Serum type III procollagen peptide, dynamic liver function tests and hepatic fibrosis in psoriatic patients receiving methotrexate.

The serum level of the aminoterminal peptide of type III procollagen (P3NP) was measured in 51 psoriatic patients on long-term, once weekly, low-dose methotrexate and in a control group of patients with extensive psoriasis who had never had systemic treatment. Serum P3NP levels were normal in all control patients, but were elevated in the majority of methotrexate-treated patients, even those with normal or non-specific liver histology. Although the highest P3NP values were found in the groups of patients with fibrosis and cirrhosis, isolated P3NP measurements did not discriminate between individuals with and without significant liver pathology. Neither standard nor dynamic liver function tests were able to identify patients with significant liver damage and in most cases results were in the normal range.