Hepatitis C and kidney disease.

Hepatitis C virus (HCV) infection is often associated with kidney diseases such as membranoproliferative glomerulonephritis (MPGN), with and without cryoglobulinemia, membranous glomerulonephritis (MGN) or glomerulosclerosis (FSGN). The aim of our study was to determine the frequency of HCV with or without hypertransaminasemia in patients with chronic nephropathy in the predialytic phase. We tested 340 subjects with chronic renal insufficiency (CRI) from our hospital's nephrology outpatient clinic for anti-HCV antibodies. In positive subjects we tested for HCV RNA by PCR method, monitoring, for at least 4 months, common biohumoral parameters including transaminases (AST, ALT). Of the 340 subjects, 46 (13.5%) were positive for HCV RNA, and 8 of these (17%) showed constant alteration of transaminases. HBsAg was found in 8 of the total study population (2.3%), and none of these showed altered transaminases. Type II diabetes mellitus was found in 26% (12/46) of the HCV-RNA positive patients, and in only 12.5% (37/294) of the negative ones. The kidney diseases we found in the 46 HCV-RNA positive patients were: diabetic nephropathy in 11 (23.9%), MPGN in 7 (15.2%), MPGN + cryoglobulinemia in 2 (4.3%), interstitial nephropathy in 4 (8.7%), IgA mesangial GN in 3 (6.5%), hypertensive nephropathy in 2 (4.3%), focal and segmental GN in 1 (2.2%), urologic disease in 4 (8.7%), other (hematological, genetic, iatrogenic) in 3 (6.6%), unknown in 9 (19.6%). Our data show that the most frequent kidney diseases associated with HCV infection were diabetic related nephropathy and MPGN with and without cryoglobulinemia. HCV infection had a positive association with diabetes. It is interesting to note that in this study population the hepatitis C concomitant to kidney disease was unusually mild: only 4 of the 46 subjects (9%) showed clinical, biohumoral and ultrasound evidence of cirrhosis.

Essential hypertension and chronic viral hepatitis.

OBJECTIVE: Both arterial hypertension and chronic hepatitis are common disorders. The relationship between arterial pressure and liver cirrhosis has been extensively studied, but no studies are available in chronic hepatitis (CH). Recently, a few studies have reported that treatment with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs), commonly used in arterial hypertension, reduce hepatic fibrosis in patients with viral CH and in nonalcoholic steatohepatitis. This study was aimed at comparing the evolution of post-viral CH in patients with/without concomitant essential hypertension. METHODS: Two sets of observations were carried out: (a) a cross-sectional cohort study of 95 patients with viral CH, to compare the severity of histological and biochemical data at diagnosis, in relation to pharmacologically treated essential hypertension, and (b) a retrospective study with the observation of 254 patients with CH of viral etiology, followed up from 2 to 20 years, to establish the natural history of viral CH in relation to treated essential hypertension. RESULTS: In the cross-sectional analysis, patients with treated hypertension had a significantly older age at diagnosis of CH (51.4 +/- 8.4 years vs. 46.2 +/- 12.2 in normotensive; P < 0.001) and histological evidence of less severe necro-inflammatory liver damage. ALT levels were also lower (109.8 +/- 62.5 U/L vs. 166.0+/-169.5 in normotensive; P < 0.001) as were endothelin-1 levels (0.74 +/- 0.97 vs. 1.77 +/- 1.51 fmol/mL; P < 0.001). The retrospective study confirmed an older age at diagnosis in patients with treated hypertension (48.7 +/- 9.8 vs. 41.9 +/- 11.8 years; P < 0.001) and lower death rates (2.2% vs. 11%; P < 0.05). CONCLUSIONS: The evolution of post-viral CH seems to be less severe in subjects with essential hypertension, possibly in relation to treatment with antihypertensive drugs.

Relapse response to interferon and ribavirin in liver transplant recipient with hepatitis C recurrence.

After a liver transplantation, hepatitis C virus (HCV) recurs in 90% of cases. The evolution varies according to a number of factors inherent in the host or the graft. The only therapy currently able to modify its evolution is combined interferon/ribavirin, but 22% of cases show a nonsustained response and a mere 8% achieve a sustained response. We report the case of a patient who at age 38 years underwent orthotopic liver transplantation (OLT) for HCV-related cirrhosis that developed over 7 years following blood transfusion. Following HCV recurrence at 5 years, the patient underwent 4 cycles of antiviral therapy over a 4-year period, using various protocols. First, Ribavirin alone evoked no response and the other 3 a nonsustained response. Liver biopsy after the 4th cycle showed no change in inflammation or fibrosis with respect to the biopsy performed before the first cycle. Today, at 14 years after OLT, there is still no evidence of development of cirrhosis despite immunosuppressive therapy. We suggest a benefit of repeating cycles of antiviral therapy in patients who have undergone OLT with HCV reinfection, even if they continue to show a nonsustained response but are able to tolerate the therapy.

Natural history of chronic viral hepatitis in southern Italy: epidemiological changes since the introduction of the anti-HCV test.

We investigated whether there are differences between the natural history of B and C chronic hepatitis in a southern Italian population, and whether the chronic viral hepatitis population was modified by the introduction of the anti-HCV test in 1989. We examined clinical charts of 1120 patients consecutively admitted to our division from January 1979 to December 1998 with the histological diagnosis of chronic viral hepatitis (304 from 1979 to 1988; 816 from 1989 to 1998). We found significant differences only in age at diagnosis (higher in the second decade, P = 0.001), and in aetiology (HBV decreased in the second decade, P < 0.0001). We were able to follow up 449 patients for 2-20 years (311 with HCV and 138 with HBV infection), and found that chronic HCV evolved to cirrhosis more frequently than did chronic HBV; but in both types time to development of cirrhosis and the incidence of death were similar. Our data confirm that a higher onset age of HBV and of HCV is frequently observed in those subjects who have a faster disease progression.

Intestinal permeability after single dose gluten challenge in coeliac disease.

The changes of intestinal permeability before and after a gluten load were studied. The study group comprised 27 patients with coeliac disease (mean age 12.3 years) and 19 healthy controls matched by sex and age. Intestinal permeability was studied by measuring the urinary excretion of two sugars, lactulose and L-rhamnose, before and six hours after the ingestion of five palatable biscuits made with 50 g of gluten powder. The patients with coeliac disease had been on a gluten free diet during the previous two years. After the gluten load lactulose and L-rhamnose urinary excretion changed significantly in patients, and a significant increase in the lactulose: L-rhamnose ratio was also observed. No significant changes were observed in the controls. In view of the modification of the three biopsies diagnostic protocol made by the European Society for Paediatric Gastroenterology and Nutrition, permeability tests associated with single gluten challenges may be an added contribution to the accuracy of the diagnosis in childhood.

Jejunal bacterial overgrowth and intestinal permeability in children with immunodeficiency syndromes.

Seventeen paediatric patients with immunodeficiency syndromes (10 with selective IgA deficiency, four with panhypogammaglobulinaemia, and three with selective T cell deficiency) were investigated for bacterial overgrowth of the small intestine and gut permeability to macromolecules. Five of 12 patients showed viable bacterial counts of more than 2 x 10(5)/ml in jejunal fluid. Bacterial overgrowth was also confirmed indirectly by breath hydrogen determination, which was higher than 10 ppm in four of the five patients with positive jejunal culture. Gut permeability to lactulose and L-rhamnose was abnormal in 16 of the 17 immunodeficient patients, who also had higher mean urinary excretion ratios than control subjects-mean (SD) values were 0.216 (0.160) and 0.029 (0.002), respectively. These studies indicate that bacterial overgrowth of the small intestine is a common feature in immunodeficient patients, regardless of the immunological abnormality. Moreover, these patients have an increased gut permeability to macromolecules.

Bile acids reversible effects on small intestinal permeability. An in vitro study in the rabbit.

To define the action of deconjugated bile acids on the small intestinal permeability in an in vitro system, we investigated the effects of chenodeoxycholic acid and ursodeoxycholic acid on the rate of transmural flux of lactulose in jejunal and ileal mucosa of rabbits, stripped of their muscle layers and mounted in Ussing chambers. In a series of experiments, tissue samples from small intestinal segments either exposed to bile acids or not also were examined by scanning and transmission electron microscopy to study the integrity of the tight junctions. Results show that chenodeoxycholate, starting at the concentration of 0.1 mM, enhanced in a dose-related manner the transepithelial flux of lactulose in the ileum. Both chenodeoxycholate (0.5 mM) and ursodeoxycholate (0.5 mM) significantly increased mucosal permeability to lactulose in jejunum and ileum; the effect of chenodeoxycholate was also shown to be reversible, as it completely disappeared within 40 min after its withdrawal and it did not result in permanent changes of epithelial transport function. Finally, the tight junctions appeared loosened by the addition of 1 mM chenodeoxycholate, suggesting that this is the major site of the transient bile acid increase of small intestinal permeability to compounds such as lactulose, having a molecular radius wider than 0.5 nm.

Malabsorption and nutritional abnormalities in patients with liver cirrhosis.

Cirrhotic patients often present muscle and adipose tissue depletion as well as reduced visceral protein concentration. Impaired absorption of nutrients may contribute to this altered nutritional status. To verify this hypothesis fecal fat excretion, intestinal mucosal function evaluated by means of the combined sugar oral load test, and intestinal clearance of alpha-1-Antirypsin were studied in 25 cirrhotic patients with clinical and biochemical signs of liver insufficiency and with portal hypertension. About 50% of the patients showed clinical evidence of malnutrition. Three of the 12 well-nourished, and 8 of the 13 malnourished patients presented significant steatorrhoea. Cirrhotics showed no impairment in mediated malabsorption and in passive permeability, as plasma D-xylose/3-O-methyl-glucose concentration and urinary lactulose/L-rhamnose excretion ratios were within the normal range. An increased value of alpha-1-Antitrypsin clearance was found only in two patients. These findings indicate that fat malabsorption is frequent in cirrhotic patients, particularly when malnourished, and does not depend on the presence of mucosal intestinal damage.

Effects of anthracycline therapy on intestinal absorption in patients with advanced breast cancer.

Although cytotoxic chemotherapy for human cancer has been reported to induce alterations in intestinal permeability, its effects on the absorptive process are still controversial. We have studied mediated and nonmediated absorption in 10 patients with metastatic breast cancer before and after treatment with Adriamycin by the use of specific test sugars given orally and their subsequent urinary recovery, as measured by chromatography. Mediated absorption was investigated by the use of D-xylose and 3-O-methylglucose, while lactulose and L-rhamnose were used to study nonmediated permeation. Lactulose is considered a marker of unmediated paracellular (tight junction) permeation, while L-rhamnose explores passage across cell membranes. The test was performed on patients before and on the second and the eighth days after Adriamycin administration, and only once in 22 age-matched healthy women. Under basal conditions, as well as 2 and 8 days after chemotherapy, D-xylose and 3-O-methylglucose absorption was 35% lower in patients than in controls (P less than 0.001). Lactulose absorption was significantly higher in patients than in controls under basal conditions (P less than 0.001); it reached levels three times higher the second day after chemotherapy, and returned to basal levels by the eighth day. The data suggest an early reversible effect of Adriamycin on cellular tight junctions with resulting increased permeabilization. This effect seems of a toxic nature rather than due to increased cell loss. It is interesting that both nonmediated absorption and mediated absorption were already altered before chemotherapy in cancer patients, suggesting a preexisting functional damage of the intestine. The significance of this alteration as a potential mechanism of cancer cachexia is discussed.

Investigation of intestine function during acute viral hepatitis using combined sugar oral loads.

One fifth of all cases of A virus hepatitis (AVH) have symptoms of gastroenteritis at the onset. This study investigated the mediated intestinal absorption of D-xylose (D-xyl) and 3-o-methyl-D-glucose (3-omG) and the non-mediated permeation of lactulose (Lacl, mol wt 342) and L-rhamnose (L-rh, mol wt 164) during acute and remission phases of AVH. Ten patients with AVH were given an oral load containing these sugars (5 g D-xyl: 2.5 g 3-omG, 1 g L-rh, 5 g lacl in 250 ml water) once during the acute phase and again during remission. The same load was given once to a group of 22 healthy controls. The mean concentration of D-xyl in urine and the ratio of D-xyl to 3-omG in plasma and urine were normal in both the AVH phases, ruling out intestinal malabsorption even in the acute phase. This study showed a significant increase in non-mediated permeation to Lacl, but not to L-rh, during the acute phase. These data indicate that the barrier function of the intestine is compromised in AVH infection while the absorptive function is not. An abnormally low concentration of D-xyl and 3-omG in plasma at one hour was found in all patients during the acute phase. This finding cannot be explained by alterations in intestinal absorption, but could be accounted for by increased space distribution of the sugars because of increased diffusion into tissue cells and/or expansion of the extracellular space by fluid retention.

Investigation of intestine and liver function in cirrhosis using combined sugar oral loads.

Active and passive intestinal absorption and the efficiency of hepatic galactose clearance were studied in 12 patients with liver cirrhosis and 8 healthy control subjects using differential absorption techniques in which paired sugar markers were ingested simultaneously. Such differential absorption procedures overcome the effects of variation in gastric emptying, intestinal transit, distribution space and renal clearance which could invalidate tests incorporating a single marker only. In the cirrhotic group, active absorption of D-xylose (D-xyl) compared with that of 3-O-methyl-D-glucose (3-OMG), indicated by the ratio of D-xyl/3-OMG concentration in plasma, showed no reduction in respect to the control group. The passive intestinal permeability to lactulose (lac) compared with that of L-rhamnose (rham), indicated by urinary lac/rham excretion ratio, was not raised. These findings indicate no dysfunction of small intestinal mucosa in cirrhotic patients in spite of the clinical evidence of portal hypertension. Urinary galactose (gal) excretion after oral load was 10 times higher in the cirrhotic group (P less than 0.001). The gal/3-OMG excretion ratio correlated well with galactose elimination capacity as assessed by an intravenous method. Estimation of plasma D-xyl/3-OMG concentration and both urinary lac/rham and gal/3-OMG excretion ratios after appropriate oral loads provided a convenient and simultaneous evaluation of intestinal absorption, permeability and hepatic galactose elimination.

[Blood amino acids in chronic HBsAg positive liver disease]. / Gli aminoacidi plasmatici nelle epatopatie croniche HBsAg positive.

Typical changes in blood aminoacid concentrations have been described in patients with severe liver disease. In this study we measured the serum amino acid levels, by Beckman Aminoacid Analyzer, in 11 healthy subjects and 24 HBsAg-positive patients with biopsy-proven liver disease (4 CPH, 10 CAH, 10 cirrhosis). A significant decrease in total aminoacids was observed in CAH and cirrhosis groups (-24% and -22% respectively). The three branched chain aminoacids (BCAA = val + leu + isoleu) were reduced by 24% (P less than 0.002) and 37% (P less than 0.001) in the CAH and cirrhosis groups respectively. Tyrosine was the only of the aromatic aminoacids (AAA) to increase in cirrhotics (+ 34%, P less than 0.02). The molar ratio BCAA/AAA was 3.6 in controls, 3.8 in CPH, 3.1 in CAH (P less than 0.025) and 1.9 in cirrhosis (P less than 0.001). A linear correlation was found between molar ratio BCAA/AAA and serum albumin in all patients (P less than 0.001). These results document the presence of specific quantitative changes in serum aminoacids of HBsAg positive patients, which appear related to severity of liver disease and comparable to the alterations described in non viral chronic liver disease.

Changes in intestinal permeability to lactulose induced by cytotoxic chemotherapy.

Intestinal function during cytotoxic therapy was studied in nine patients with nonintestinal lymphoma. An early, marked, and rapidly reversible increase in passive permeability, as disclosed by the lactulose test, was observed without concomitant changes in active absorption or in intestinal histology. The possibility of a toxic effect by cytotoxic drugs on intestinal intracellular junctions is discussed.

The cholecystokinin effect on human intestinal permeability: influence of chenodeoxycholic and ursodeoxycholic acid administration.

The influence of CDCA and UDCA administration on human intestinal permeability to lactulose, as disclosed by intravenous CCK, has been investigated. For this purpose the fraction of lactulose excreted in the urine during 5 h after an oral load of the disaccharide in hypertonic solution was measured in 12 healthy subjects, with and without intravenous CCK. The lactulose test was performed in each subject before and after a 7-day course of oral CDCA or UDCA (750 mg/day). Under basal conditions CCK induced a 100% increase in lactulose excretion. CDCA treatment further augmented the response to CCK by 33% (p less than 0.001) but UDCA produced no significant change. Finally, the effect of CDCA or UDCA added directly to the lactulose test solution was investigated in 4 subjects following oral and duodenal administration. CDCA only produced an increase in lactulose excretion (more than 100%) when given in hypertonic solution. The possible reasons for these findings are discussed.

Cholecystokinin and human intestinal permeability.

The effect of intravenous cholecystokinin (CCK) on intestinal permeability in normal subjects and patients after cholecystectomy has been studied by measuring the fraction of orally administered lactulose excreted in the urine. CCK induced a marked increase in lactulose excretion in normal subjects when given in a hyperosmolar solution (49.4 mg lactulose during 5 h rising to 114.3 mg with CCK, p less than 0.001). CCK failed to affect lactulose excretion when given to normal subjects in an isosmolar solution, and also when given to post-cholecystectomy patients in either hyper- or isosmolar solutions. The 'CCK effect' is therefore related to gallbladder emptying. It is suggested that conjugated bile acids released following gallbladder contraction can affect intestinal permeability by enhancing the action of hypertonic solutions on the small intestinal mucosa.