IFNL3/4 genotype is associated with altered immune cell populations in peripheral blood in chronic hepatitis C infection.

Single-nucleotide polymorphisms near the interferon lambda 3 (IFNL3) gene predict outcomes to infection and anti-viral treatment in hepatitis C virus (HCV) infection. To identify IFNL3 genotype effects on peripheral blood, we collected phenotype data on 400 patients with genotype 1 chronic hepatitis C (CHC). The IFNL3 responder genotype predicted significantly lower white blood cells (WBCs), as well as lower absolute numbers of monocytes, neutrophils and lymphocytes for both rs8099917 and rs12979860. We sought to define the WBC subsets driving this association using flow cytometry of 67 untreated CHC individuals. Genotype-associated differences were seen in the ratio of CD4CD45RO+ to CD4CD45RO-; CD8CD45RO+ to CD8CD45RO-, NK CD56 dim to bright and monocyte numbers and percentages. Whole blood expression levels of IFNL3, IFNLR1 (interferon lambda receptor 1), IFNLR1-mem (a membrane-associated receptor), IFNLR1-sol (a truncated soluble receptor), MxA and T- and NK (natural killer) cell transcription factors TBX21, GATA3, RORC, FOXP3 and EOMES in two subjects were also determined. CHC patients demonstrated endogenous IFN activation with higher levels of MxA, IFNLR1, IFNLR1-mem and IFNLR1-sol, and IFNL3 genotype-associated differences in transcription factors. Taken together, these data provide evidence of an IFNL3 genotype association with differences in monocyte, T- and NK cell levels in the peripheral blood of patients with CHC. This could underpin genotype associations with spontaneous and treatment-induced HCV clearance and hepatic necroinflammation.

Oropharyngeal scintigraphy: a reliable technique for the quantitative evaluation of oral-pharyngeal swallowing.

A valid and reliable technique to quantify the efficiency of the oral-pharyngeal phase of swallowing is needed to measure objectively the severity of dysphagia and longitudinal changes in swallowing in response to intervention. The objective of this study was to develop and validate a scintigraphic technique to quantify the efficiency of bolus clearance during the oral-pharyngeal swallow and assess its diagnostic accuracy. To accomplish this, postswallow oral and pharyngeal counts of residual for technetium-labeled 5- and 10-ml water boluses and regional transit times were measured in 3 separate healthy control groups and in a group of patients with proven oral-pharyngeal dysphagia. Repeat measures were obtained in one group of aged (> 55yr) controls to establish test-retest reliability. Scintigraphic transit measures were validated by comparison with radiographic temporal measures. Scintigraphic measures in those with proven dysphagia were compared with radiographic classification of oral vs. pharyngeal dysfunction to establish their diagnostic accuracy. We found that oral ( p = 0.04), but not pharyngeal, isotope clearance is swallowed bolus-dependently. Scintigraphic transit times do not differ from times derived radiographically. All scintigraphic measures have extremely good test-retest reliability. The mean difference between test and retest for oral residual was -1% (95% CI -3%-1%) and for pharyngeal residual it was -2% (95% CI -5%-1%). Scintigraphic transit times have very poor diagnostic accuracy for regional dysfunction. Abnormal oral and pharyngeal residuals have positive predictive values of 100% and 92%, respectively, for regional dysfunction. We conclude that oral-pharyngeal scintigraphic clearance is highly reliable, bolus volume-dependent, and has a high predictive value for regional dysfunction. It may prove useful in assessment of dysphagia severity and longitudinal change.

Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) has multiple etiologic associations, but the pathogenesis is poorly understood. Cytochrome P450 (CYP) 2E1 is induced in the liver of patients who drink alcohol to excess and is important in the pathogenesis of alcoholic liver disease (ALD). We have previously shown that hepatic CYP2E1 is also increased in a rat dietary model of steatohepatitis. The aim of the present study was to test the hypothesis that hepatic CYP2E1 is induced in the liver of patients with NASH, defined on the basis of compatible liver histology and the exclusion of excessive alcohol intake. Sections of paraffin-embedded liver biopsy material from 31 subjects with NASH were evaluated and compared with sections from 10 histologically normal livers and 6 patients with ALD. Hepatic CYP2E1 and CYP3A were detected in liver sections by immunohistochemistry using specific anti-human CYP2E1 and CYP3A antibodies. As expected, normal livers showed CYP2E1 immunostaining confined to a rim, two to three cells thick, around terminal hepatic venule, while livers from alcoholic hepatitis patients showed increased CYP2E1 staining. CYP2E1 immunostaining was also increased in livers from patients with NASH, irrespective of the etiologic association. Further, the pattern of CYP2E1 distribution was similar to ALD, with increased perivenular intensity and more extensive acinar distribution of staining. As in the rat model, the hepatic distribution of CYP2E1 corresponded to that of steatosis. In contrast to CYP2E1, CYP3A immunostaining was decreased in patients with NASH. We conclude that hepatic CYP2E1 is increased in patients with NASH compared with normal livers. Thus, despite many possible etiologic factors for NASH, the pathogenetic mechanisms may be similar and, like alcoholic steatohepatitis, may involve induction of CYP2E1.

Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis is morphologically identical to alcoholic hepatitis and has multiple etiologic associations and an unknown pathogenesis. The present study used a rat nutritional model of hepatic steatosis with inflammation to test the hypothesis that induction of the alcohol-inducible hepatic cytochrome P450 (CYP) 2E1 is associated with production of steatohepatitis. METHODS: Rats received a diet devoid of methionine-choline. CYP2E1 protein was detected in liver sections by immunohistochemistry and in hepatic microsomal fractions by immunoblotting; CYP2E1 activity was detected by N-demethylation of N,N-dimethylnltrosamine (NDMA). CYP2E1 messenger RNA was analyzed by Northern blotting and slot blot hybridization. RESULTS: After 4 weeks of methionine-choline devoid diet, macrovesicular steatosis and an inflammatory infiltrate were prominent in hepatic acinar zone 3. CYP2E1 immunostaining was increased and had a more extensive acinar distribution corresponding to that of the steatosis. Microsomal CYP2E1 protein, NDMA activity, and hepatic CYP2E1 messenger RNA levels were all correspondingly increased. CONCLUSIONS: CYP2E1 is induced, partly at a pretranslational level, in this experimental form of steatohepatitis. The finding of biochemical and histological similarities between this nutritional model of hepatic steatosis with inflammation and alcoholic hepatitis indicates possible clues to common pathogenetic mechanisms. The relevance of this finding to human nonalcoholic steatohepatitis remains uncertain and requires further investigation of human liver specimens.

Coinfection with hepatitis B and C or B, C and delta viruses results in severe chronic liver disease and responds poorly to interferon-alpha treatment.

Chronic coinfection with the hepatitis B (HBV) and hepatitis delta (HDV) viruses is known to cause severe liver disease, but the importance of coinfection with hepatitis C virus (HCV) and HBV has not been well documented. In the present study, the clinical and pathological severity of liver disease among patients with hepatitis resulting from multiple viruses was examined and an open trial of the efficacy of interferon-alpha 2b (IFN-alpha) treatment was conducted. Nineteen patients with chronic HBV and HCV infection and 17 with HBV, HCV and HDV infection were studied; 12 in each group underwent liver biopsy. For each coinfected patient, two patients infected with HCV alone were selected as controls, and these were matched for age and risk factor and were estimated to have been infected for a similar duration. Coinfection with HBV and HCV or HBV, HCV and HDV was associated with more severe liver disease than HCV alone (P < 0.01); total Scheuer score, portal and lobular inflammation and fibrosis were all worse in coinfected subjects. Eight patients with chronic HBV and HCV were treated with recombinant IFN-alpha 2b [3 million units (MU), thrice weekly for 6 months]. Liver function tests normalized in two patients and one lost hepatitis B surface antigen (HBsAg). Seven patients with hepatitis B, C and delta coinfection were treated with the same regimen and only one normalized serum alanine aminotransferase (ALT) during (and after) treatment. It is concluded that coinfection with multiple hepatitis viruses is associated with histologically more severe liver disease than HCV alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatocellular carcinoma in western Sydney. Aetiology, changes in incidence, and opportunities for better outcomes.

OBJECTIVES: To examine the incidence of hepatocellular carcinoma (HCC) in western Sydney over the last 14 years, to assess risk factors for the disease among ethnic groups of Australian residents, and to consider the opportunities for improving its usually poor outcome. DESIGN AND SUBJECTS: Retrospective case-record review of clinical features in all (122) patients discharged from a 900-bed tertiary-referral teaching hospital with a diagnosis of HCC from January 1979 to March 1993. MAIN OUTCOME MEASURES: Annual number of new cases; risk factors according to birthplace; surgical resectability of tumours. RESULTS: New cases admitted each year at least doubled between 1979-1985 and 1986-1992. This apparent increase involved individuals born in Australia (50% of all patients) as well as immigrants. Cirrhosis was found in 93% at liver biopsy or autopsy. Excessive alcohol intake was an associated risk factor for 46% of Australian-born patients and for 13% of those born overseas. Among the latter, HCC was associated with markers of hepatitis B virus infection in 64%. Since hepatitis C virus (HCV) tests became available in 1990, five of nine patients tested were anti-HCV positive. Surveillance screening of patients known to have cirrhosis detected eight cases of early HCC. Seven of these had surgical resection and all are alive. CONCLUSIONS: New diagnoses of HCC have increased recently, irrespective of country of birth. In Australian-born patients alcoholic liver disease remains a major aetiological factor but the role of HCV requires further evaluation. Among immigrants, cirrhosis from chronic viral hepatitis accounts for most cases. We propose that prevention of cirrhosis caused by chronic viral hepatitis should have the greatest long-term impact on prevention of HCC in Australia. The role of surveillance of people with cirrhosis to detect small and potentially resectable tumours should be explored.

Influence of aging on oral-pharyngeal bolus transit and clearance during swallowing: scintigraphic study.

The aim of the study was to determine the influence of normal aging on regional transit and the efficiency of bolus clearance during the oral and pharyngeal phases of swallowing. We compared scintigraphically derived oral-pharyngeal transit times and isotope clearance during swallowing in 21 healthy aged volunteers (mean age 68 +/- 8 yr) and 9 young controls (mean age 28 +/- 7.5 yr). Subjects swallowed 5- and 10-ml water boluses mixed with 30 MBq 99mtechnetium tin colloid. Oral and pharyngeal transit times, pharyngeal clearance time, and postswallow residual counts in each region were derived from time-activity curves. Pharyngeal residual counts were significantly greater in the aged than in controls (P = 0.0008), but age did not influence oral residual. Aging significantly prolonged oral transit time (P = 0.02), pharyngeal transit time (P = 0.0004), and pharyngeal clearance time (P = 0.0001). We conclude that normal impairs the efficiency of pharyngeal clearance during swallowing, prolongs scintigraphic measures of oral-pharyngeal transit, and increases the exposure time of the glottis to the swallowed bolus.

Meningococcaemia complicated by myocarditis. A report of 2 cases.

Two cases of myocarditis complicating meningococcal septicaemia are presented. Neisseria meningitidis infection with bacteraemia is a common entity but the important complication of myocarditis has not often been described. The autopsy findings in 1 of the 2 patients described further illustrates the significance of myocarditis. The pathology, clinical presentation and management of this complication are briefly discussed.

Time-dependent changes in serum gastrin measurements after parathyroidectomy.

A prospective study involving 7 patients with primary hyperparathyroidism and hypergastrinaemia was conducted to assess the time-dependent change in serum gastrin value before and after parathyroidectomy and to determine at which postoperative stage persistent hypergastrinaemia may be indicative of an associated gastrinoma (Zollinger-Ellison syndrome). Five of the 7 patients had hypergastrinaemia in the early postoperative period. One patient had a strikingly high serum gastrin level pre-operatively (1,500 pg/ml). The mean serum gastrin value declined to within the normal range 6 weeks after parathyroidectomy, except in 1 patient who had a gastrinoma. It is concluded that hypergastrinaemia in patients with primary hyperparathyroidism should only be considered significant if pre-operative gastrin levels are strikingly supranormal and/or levels fail to normalise by the 6th postoperative week.