Emilio Pisi

HCV-associated liver cancer without cirrhosis

Chronic infection with hepatitis C virus (HCV) is regarded as a risk factor for hepatocellular cancer, mostly in patients with liver cirrhosis. We looked for HCV genomes in the livers of patients with hepatocellular cancer who did not have cirrhosis to see whether HCV was directly oncogenic. Cancerous and non-cancerous liver tissue, and serum samples from 19 patients negative for hepatitis B surface antigen were analysed by polymerase chain reaction for the presence of HCV genome, HCV replication, HCV genotyping, and HBV genome. 13 of 19 patients were HCV RNA-positive in cancerous and non-cancerous liver tissue; 8 of 17 tested were anti-HCV positive. Among the 13 HCV RNA-positive patients, 11 had genotype 1b and 2 had genotype 2a. 7 of 13 serum samples were HCV RNA positive. 7 of 19 patients were HBV DNA positive in cancerous and non-cancerous liver tissue, 5 of them anti-HBc positive. 4 patients were both HCV RNA and HBV DNA positive and 3 were both HCV RNA and HBV DNA negative. Our results provide evidence for the association of HCV, mostly genotype 1b, with hepatocellular cancer without the intermediate step of cirrhosis.

Efficacy of a Surveillance Program for Early Detection of Hepatocellular Carcinoma

Contrasting data have so far been reported on the utility and efficacy of screening patients with cirrhosis for early detection of hepatocellular carcinoma (HCC). The goal of this study was to evaluate the efficacy of a regular ultrasonographic and laboratory follow‐up for the early detection of small HCC, and to identify parameters correlated with a higher risk of developing HCC.

Desmin and actin in the identification of Ito cells and in monitoring their evolution to myofibroblasts in experimental liver fibrosis

SummaryIt has been reported that myofibroblasts contain actin and that Ito cells are positive for desmin. The distribution of desmin and actin detected by immunofluorescence, of vitamin A autofluorescence and of Sudan III staining of lipid droplets has been evaluated in sequential stages of experimental liver fibrosis induced in rats by intraperitoneal injections of swine serum. In the normal rat liver Ito cells were positive for desmin and weakly positive for actin. Prior to the development of hepatic fibrosis a clearcut increase in number and desmin staining of lobular Ito cells was observed in treated rats, but the overall actin pattern was unchanged. In the fibrotic rat livers, highly cellular septa contained large numbers of strongly desmin-positive, actin-weakly positive Ito cells and strongly desmin-and actin-positive myofibroblasts. These observations indicate that both Ito cells and myofibroblasts are positive for desmin, but only myofibroblasts contain large amounts of actin. Visualization of actin and desmin using relatively simple techniques, allows the monitoring of Ito cells proliferation, the accumulation of these cells in fibrous septa and their evolution into myofibroblasts as characterized by their increased desmin and actin content; it also allows an indirect evaluation of the process of fibrogenesis.

Vegetable versus animal protein diet in cirrhotic patients with chronic encephalopathy. A randomized cross-over comparison

Abstract. In a randomized cross‐over comparison, the effects of a mainly vegetable protein diet were compared with an animal protein diet in eight patients with cirrhosis and chronic permanent encephalopathy, under optimum lactulose therapy. After a run‐in period, patients were fed two equi‐caloric, equi‐nitrogenous diets for 7 days (71 g total proteins), containing either 50 g protein of animal origin or 50 g vegetable proteins. In the last 3 days of each period, nitrogen balance was significantly better during the vegetable protein diet (+ 0.2 (SD 1.4) g vs. — 1.7 (2.4): P < 0.01), the difference being entirely due to a reduced urinary nitrogen excretion. Average daytime integrated blood glucose was slightly higher during vegetable proteins, whereas insulin, plasma amino acids and ammonia were lower. The clinical grading of encephalopathy improved slightly on vegetable proteins, and psychometric tests improved significantly, but remained grossly abnormal. Compliance to dietary manipulation was good. The data prove that a mainly vegetable protein diet is worthwhile in cirrhotic patients with chronic encephalopathy under optimum lactulose therapy. Improved nitrogen balance may be related to more effective nitrogen use for protein synthesis, probably due to blunted hormonal response, and largely outweighs the effects on encephalopathy.

Prognostic significance of portal hemodynamics in patients with compensated cirrhosis

The prognostic value of portal hemodynamics, measured by pulsed echo-Doppler, was prospectively evaluated, together with clinical, biochemical and endoscopic parameters, in a series of 50 consecutive patients with compensated cirrhosis. After a mean follow-up of 6 years, 25 patients had died, all from complications of liver disease. Among conventional variables, the step-wise Cox model showed that only the Child-Pugh score independently predicted death (chi 2 = 18.66; p < 0.001). When hemodynamic parameters were added to the Child-Pugh score in the same model, portal blood velocity was shown to add prognostic significance (improvement in chi 2 = 14.06; p = 0.0002; Wald test). The present study shows that a portal blood velocity below the lower limit of controls (10 cm/s) characterizes patients with shorter survival, and suggests that this non-invasive parameter should be associated to the Child-Pugh score in the evaluation of patients with cirrhosis.

CAN ANTIGLIADIN ANTIBODY DETECT SYMPTOMLESS COELIAC DISEASE IN CHILDREN WITH SHORT STATURE

Duodenal biopsy and tests for antigliadin antibodies were done in 108 children with short stature unassociated with gastrointestinal symptoms. Other investigations for causes of growth failure were also carried out. In 88 patients, the cause of short stature could not be determined (group I). In 9 patients (8.3%) biopsy showed total villous atrophy, indicating probable coeliac disease (group II), while 7 patients had mild partial villous atrophy (group III). 4 patients (3.7%) had complete growth hormone deficiency. Antigliadin antibodies detected by immunofluorescence (IFL-AGA) were positive in 8 of the 9 group II patients. Symptomless coeliac disease is therefore a commoner cause of short stature than is hypopituitarism; by use of the IFL-AGA test it is possible to select patients for biopsy, thereby identifying most of the coeliac patients. If duodenal biopsies had been limited to IFL-AGA positive patients, 18 biopsies would have been carried out and coeliac disease would have been diagnosed in 8 of the 9 patients.

Functional hepatic flow and Doppler-assessed total hepatic flow in control subjects and in patients with cirrhosis

Functional hepatic flow and total hepatic flow were determined by non-invasive techniques in 32 patients with cirrhosis and in 32 paired control subjects. Functional hepatic flow was measured by the hepatic clearance of D-sorbitol, while total hepatic flow was determined by pulsed echo-Doppler, as the sum of portal and hepatic arterial blood flow. Functional hepatic flow was significantly reduced in patients with cirrhosis (927 +/- 314 vs. 1287 +/- 315; p < 0.0001), while total hepatic flow was slightly increased (1511 +/- 540 vs. 1261 +/- 321 in controls; p = 0.028). In control subjects functional hepatic flow significantly correlated with total hepatic flow (r = 0.823; p < 0.001), while no correlation was observed in cirrhosis. Functional hepatic flow and the difference between total hepatic flow and functional hepatic flow significantly correlated with the Child-Pugh score in patients with cirrhosis. The data obtained in control subjects support the measurement of functional hepatic flow and total hepatic flow by non-invasive techniques. The finding that in cirrhosis functional hepatic flow is significantly decreased, while Doppler-assessed total hepatic flow is preserved or even increased, confirms that a relevant part of blood flowing through the liver is diverted by intrahepatic shunts. The simultaneous assessment of these two parameters by non-invasive techniques may be proposed as a reliable tool for the study of functional shunting of cirrhosis.

Immunomorphological characterisation of antinuclear antibodies in chronic liver disease.

Two immunofluorescence procedures to evaluate antinuclear antibodies were compared in a series of 221 patients with chronic liver disorders of various aetiologies. The use of HEp-2 cells allowed us to discriminate with more confidence between the homogeneous and speckled patterns, to show the presence of associated patterns in the same serum, and, above all, to identify two specificities, unrecognizable on tissue sections. The anticentromere antibody was found in 10% of cases of primary biliary cirrhosis and occasionally in other conditions; the antibody staining multiple nuclear dots was strictly confined to primary biliary cirrhosis (17%). With the exception of autoimmune chronic active hepatitis the prevalence of antinuclear antibodies increased in all groups, particularly in primary biliary cirrhosis. Homogeneous antinuclear antibody was associated by both immunofluorescence procedures with autoimmune chronic active hepatitis. The multiple nuclear dot antinuclear antibody turned out to be an additional marker of primary biliary cirrhosis, helpful for the positive diagnosis of primary biliary cirrhosis in a proportion of cases negative for antimitochondrial antibody. Absorption experiments showed that multiple nuclear dot and antimitochondrial antibody are antigenically distinct. Moreover, multiple nuclear dot antinuclear antibody was associated with the finding of a dry Schirmers test.

Insulin and glucagon levels in liver cirrhosis

Alterations in insulin and glucagon levels migh account for the plasma amino acid imbalance of cirrhotics. In order to verify this hypothesis we evaluated basal insulin, glucagon, branched-chain amino acids, aromatic amino acids, and free tryptophan in 13 controls and 37 cirrhotics divided on the basis of their mental state; in 4 patients the hormonal and amino acid patterns were sequentially studied during various stages of encephalopathy. Glucagon is high in cirrhotics and progressively increases with the worsening of the mental state. Free tryptophan and aromatic amino acids show a similar behavior and significantly correlate with glucagon levels (r=0.67 and r=0.81, respectively). On the other hand insulin levels, which are high in cirrhotics without encephalopathy, fall in the presence of deep coma. Insulin did not correlated with any of the plasma amino acids considered. Our data suggest that the catabolic state associated with increased glucagon levels may account for some of the alterations in the plasma amino acid profiles of cirrhotics. Portal-systemic shunting does not seem to be the common cause of both hyperglucagonemia and hyperaminoacidemia. Decreased branched-chain amino acid levels may be related to factors different from those involved in the alterations of carbohydrate homeostasis.

Prevalence of subclinical hepatic encephalopathy in cirrhotics and relationship to plasma amino acid imbalance

Neuropsychological status, as assessed by trailmaking test; plasma amino acids, and ammonia, were studied in 54 cirrhotics without clinical evidence of encephalopathy to determine the prevalence of subclinical mental dysfunction and its relationship to metabolic abnormalities. Control values for psychometric performance were established in 54 normal subjects matched for age, sex, educational level, and employment status. Of these subjects, 16 were also used as controls for fasting ammonia and plasma amino acids. Eighteen cirrhotics (33%) showed impaired performances of the psychometric test; free tryptophan and the ratio free tryptophan to neutral amino acids were increased in 37% and 62% of cases and correlated with the psychometric scores (r=0.45 andr=0.70, respectively). In eight cirrhotics with mild encephalopathy, psychometric and metabolic evaluations were repeated several times during the infusion of amino acid solutions rich in branched-chain amino acids. Again significant correlations were observed between the psychometric scores and plasma amino acids. We conclude that a considerable proportion of clinically normal cirrhotics have neuropsychological deficits. The severity of impairment may be related to the plasma amino acid imbalance, namely to an increased passage of tryptophan across the blood-brain barrier.