Do serum ALAT values reflect the inflammatory activity in the liver of patients with chronic viral hepatitis?

A retrospective study was carried out in 40 patients with chronic viral hepatitis, to assess whether serum alanine aminotransferase reflects the inflammatory process in the liver. Twenty liver biopsy specimens were included for each disease. Five histological aspects were scored: periportal inflammation, lobular inflammation, ballooning, Councilman bodies and lymphocyte follicles. Logarithmic values of alanine aminotransferase were correlated with each aspect using the Spearman correlation coefficient. For the hepatitis B cohort a statistical significant correlation was found between alanine aminotransferase and periportal inflammation (p = 0.0001), lobular inflammation (p = 0.0002) and Councilman bodies/area (p = 0.003). In the hepatitis C study population alanine aminotransferase correlates with both periportal inflammation (p = 0.007) and lymphocyte follicles/Area (p = 0.02). In conclusion, these results suggest that alanine aminotransferase can be used as an indicator of inflammatory activity. A prospective study is needed, to further analyze the use of alanine aminotransferase, as a monitor of disease activity in patients with chronic viral hepatitis.

Flucloxacillin-associated hepatic injury.

Eleven cases of hepatic injury attributed to the intake of flucloxacillin were reported to the Netherlands Center for Monitoring of Adverse Reactions to Drugs between 1982 and 1992. They concerned four men and seven women, with a mean age of 57 years, treated for 2-28 days with an oral dose varying from 1500-4000 mg per day. Symptoms mostly appeared 10 to 30 days after starting treatment with flucloxacillin. Biochemically, the pattern was compatible with cholestatic hepatitis in seven cases, with a mixed cholestatic-hepatocellular type of injury in one case, a hepatocellular pattern in two cases, and mild liver enzyme elevations in one patient. Two patients died, one due to fatal bleeding from the liver after biopsy, and the second patient to a combination of hepatic and cardiac failure. The other patients recovered, on average 72 days after peaking of serum aminotransferase values. Histology in seven cases showed cholestatic hepatitis in five, with cholangitis or cholangiolitis in four of these patients. In the other two patients, there was centrilobular cholestasis with extensive bridging fibrosis and portal-central bridging necrosis, respectively.

Course of hepatitis B and D virus infection in auxiliary liver grafts in hepatitis B-positive patients. A light-microscopic and immunohistochemical study.

Four patients who received an auxiliary partial liver graft for decompensated liver cirrhosis due to hepatitis B (HBV), associated in two cases with hepatitis D virus (HDV) superinfection, were studied. The sequential appearance of hepatitis B and D antigens in the grafts was investigated in serial liver biopsies by immuno-histochemical methods and compared with the viral antigenic profiles of the host livers. The histological changes in the liver grafts were studied in relation to the viral expression patterns. One week after transplantation, expression of HBsAg was already apparent in two grafts. HBcAg was found in the graft of the only patient with HBcAg in the host liver. HDAg was expressed in the grafts of both patients with HDV superinfection; in one of these cases HDAg was present without HBsAg. At 3 months, viral antigen expression was maximal. Expression of HBsAg and HBcAg in the grafts of the two HDV-positive patients was, however, less extensive than in the two HBV-positive patients. All patients developed a mild lobular hepatitis, histologically demonstrated between the 47th and 107th posttransplantation day. In the two HBV-positive, HDV-negative patients, cirrhotic transformation of the graft occurred within 1 year. In the HDV-positive patients only a mild chronic active hepatitis with slight or moderate fibrosis was observed after 1 year. We conclude that recurrence of HBV and HDV infection in auxiliary liver grafts is demonstrable within 1-3 weeks. HBV infection in liver grafts may be a rapidly progressive disease. Coinfection with HDV does not aggravate the acute hepatitis and may even suppress the progression of chronic HBV.

Cholestatic hepatitis due to antibacterial combination of amoxicillin and clavulanic acid (augmentin)

Five case histories are presented of patients developing cholestatic hepatitis associated with the intake of the antibiotic combination agent amoxicillin and clavulanic acid (Augmentin). In two of these cases, signs of hepatic injury recurred after readministration of this combination but not after the intake of amoxicillin alone. In none of the patients was another cause for cholestatic hepatitis found and extrahepatic causes were excluded by ultrasonography, CT scanning, or ERCP. Most viral causes of hepatic injury were excluded in these patients. With the exception of one patient, who developed a transient rash, no immunoallergic signs were present. Biopsy in two patients showed extensive cholestasis without significant necrosis. Clavulanic acid seems to be responsible for this adverse effect.

Fibrin ring granulomas and allopurinol.

To test the hypothesis that allopurinol-associated granulomatous hepatitis may present itself with fibrin-ring granulomas, we requested details of such cases, as reported to the World Health Organization, from 13 national adverse reaction monitoring centers, and as reported in the literature. Details and histology of 6 cases were obtained and reviewed. All consisted of acute hypersensitivity signs with fever, rash, arthralgia, or eosinophilia as hallmarks, starting within 6 wk of commencing treatment with allopurinol. In all cases there were either epithelioid granulomas or granulomalike lesions, but none of these contained fibrin rings. It is concluded that, if fibrin-ring granulomas are a manifestation of allopurinol-induced granulomatous hepatitis, this feature is probably uncommon.

Hepatic injury associated with the use of nitrofurans: a clinicopathological study of 52 reported cases.

Fifty cases of nitrofurantoin-associated hepatic injury and two cases of nifurtoinol (hydroxymethylnitrofurantoin)-associated hepatic injury reported to the Netherlands Centre for Monitoring of Adverse Reactions to Drugs were analyzed in detail. In 38 cases, a causal relationship was considered likely [i.e., "highly probable" (n = 4), "probable" (n = 23) or "possible" (n = 11)]. In 25 cases, hepatic injury was of the acute type whereas 13 cases presented a chronic type of reaction. Both types were more common in the elderly. Eighty per cent of the acute reactions appeared within the first 6 weeks of treatment and were sometimes accompanied by fever (28%), rash (12%) and eosinophilia (16%). Biochemically, the pattern was mainly hepatocellular (32%), whereas mixed cholestatic-hepatocellular (4%) and cholestatic (4%) patterns were uncommon. Although mild to moderate liver enzyme elevations (60%) were common, these were primarily symptomatic. The reaction was fatal in one "acute" and one "chronic" case. In the chronic cases, nuclear (82%) and smooth muscle (73%) antibodies and LE cells (50%) were frequently present. HLA typing showed no increase of the HLA B8 or HLA DRw3 haplotype. HLA DR2 (56%) and HLA DRw6 (56%) were more frequent than in controls (both 29%), but this was not statistically significant. Histology showed mainly necrosis, varying from spotty to massive, in the acute cases and a pattern consistent with chronic active hepatitis in the chronic cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of cytomorphometry and cytology in the diagnosis of transitional-cell carcinoma of the upper urinary tract.

Because of the rise in incidence of upper urinary tract tumors, there is a need for a simple and reliable method for diagnosing these tumors, especially in people in a "high-risk" group. This retrospective study showed the usefulness of cytology and cytomorphometry in making the diagnosis of transitional-cell carcinoma of the upper urinary tract. The study also emphasized that the methods of collection and processing are of the utmost importance: the cytologic evaluation of ureteral catheterized urine specimens gave 100% accuracy as compared with a 40% false-negative rate in the cytologic diagnosis of voided urine specimens. A higher accuracy of urinary cytology for the diagnosis of upper urinary tract lesions clearly requires selective catheterization of the ureter. Objective cytomorphologic grading of the urinary cytology specimens was shown to compare favorably with histologic grading. Cytomorphologic grading not only can offer important information in determining the prognosis and in planning treatment but can also assist in quality control of other diagnostic methods and can help to resolve apparent diagnostic discrepancies.

Characteristics of IgA deposits in liver and skin of patients with liver disease.

The presence of IgA deposits in a continuous pattern along hepatic sinusoids is a specific entity for alcoholic liver disease. In superficial skin blood vessels of patients with liver disease, IgA deposits can occur. The authors characterized the deposits for IgA-subclass epitope expression and for macromolecular configuration (assessment of [hidden] J-chain determinants and of secretory component-binding capacity). A variety of monoclonal anti-IgA-subclass reagents were applied, which proved to be specific in control experiments on blastoid cells generated by pokeweed mitogen stimulation of blood mononuclear cells and frozen tissue sections of normal jejunum. IgA1 is the major component in IgA deposits in liver (n = 83) and skin (n = 31) of patients with liver disease. Macromolecular IgA is detectable in only one-fifth of the cases. The authors' data do not indicate that hepatic IgA deposits in liver disease are of gastrointestinal origin. Out of the circulating IgA pool, IgA1 appears to be most capable of being deposited in tissue.

Connective tissue stroma in bladder papillary transitional cell carcinoma, carcinoma in situ and benign cystitis.

The stromal characteristics in papillary and non-papillary tumours of the urinary bladder were investigated in an attempt to improve the accuracy of histopathological diagnosis. It appeared to be possible to differentiate true papillary tumours from pseudopapillary structures lined by carcinoma in situ. Stromal differences were not found in cases of carcinoma in situ accompanied by denuding cystitis and cystitis due to other aetiological factors. It is concluded that histopathological examination of the stroma of bladder tumours improves diagnostic accuracy.

Glafenine-associated hepatic injury. Analysis of 38 cases and review of the literature.

Glafenine was associated with hepatic injury in 38 cases. The causal relationship was assessed on the basis of the temporal relationship with drug use, course and exclusion of other causes. In 27 cases a causal relationship was considered likely, i.e. 'probable' (12 cases) or 'possible' (15 cases), whereas in 11 cases it was either unlikely or unclassifiable. In both the 'probable' and 'possible' groups 60-70% of individuals were women. Jaundice was present in three-quarters of cases in both groups. Eosinophilia was more frequent in the group of 'probable' cases, and this group had the highest case-fatality rate (42%). Onset varied from 2 days (after a rechallenge) to 8 months, but most cases appeared between 2 weeks and 4 months after starting therapy. Histology in 22 cases showed a predominantly hepatocellular pattern, varying from spotty panlobular necrosis, centrilobular and (sub)massive necrosis (acute pattern) to fibrosis and cirrhosis (chronic pattern). The chemical structure of glafenine and the clinicopathological pattern it induces resemble that of cinchophen. The incidence is unknown. Either metabolic idiosyncrasy or an immunoallergic mechanism seems to be responsible.

Ketoconazole-associated hepatic injury. A clinicopathological study of 55 cases.

Fifty-five cases of ketoconazole-associated hepatic injury, reported to the Netherlands Centre for Monitoring of Adverse Reactions to Drugs, were analysed in detail. In 50 cases a causal relationship was considered likely, i.e. 'probable' (27 cases) or 'possible' (23 cases). Eighty-four % of individuals were women. Forty-six % of patients were over 50 years of age which suggests that, considering the lower prescription rate in this age group, the elderly are more vulnerable to ketoconazole. In 60% of all cases hepatic injury appeared within the first 6 weeks of therapy but in the group of 'probable'-cases the onset was mostly later. Jaundice was present in 44% of all cases but in 63% of the group of 'probable'-cases. Eosinophilia (10%), fever (6%) and rash (2%) were uncommon. Biochemically the pattern was hepatocellular in 54%, cholestatic in 16% and mixed cholestatic-hepatocellular in 30%. Histology (14 cases) showed a predominantly hepatocellular pattern in 57% with extensive centrilobular necrosis and mild to moderate bridging. In 43% cholestasis predominated. None of the cases had a fatal course. The incidence of symptomatic hepatic injury may be estimated at approximately 1:2000 but is probably higher. The mechanism of ketoconazole-induced hepatic injury seems to be based on metabolic idiosyncrasy although it is not excluded that in some patients an immunoallergic mechanism is causative.

The reproducibility of a quantitative grading system of bladder tumours.

In order to test the reproducibility of a histomorphometrical grading system of bladder tumours, 15 tumours were twice measured independently by three pathologists. The data obtained were then analysed and compared with that of histological grading only. The way in which these morphometrical results are presented to the clinician in a computerized report is described. The need for a satisfactory reliable reproducibility test of every histomorphometrical grading system before introduction in diagnostic pathology is discussed.

Synthesis and degradation of glomerular basement membrane in rats with nephrotoxic nephritis.

Degradation and synthesis of the collagen portion (CLP) of the glomerular basement membrane (GBM) in glomeruli of rats with nephrotoxic nephritis (NTN) were determined in vivo and in vitro. Degradation of CLP in rats with NTN was only increased during the first 24 h after induction of NTN. After 24 h, the half-life of CLP in NTN rats (16.9 days) was not significantly different from that in the controls 15.6 days). The loss of CLP during the first 24 h is accompanied by an increased synthesis, measured in vivo and in vitro. The increased synthesis, however, does not seem to be sufficiently high to result in accumulation of CLP-like material in NTN. Since degradation and synthesis of CLP was not altered during the later phase of NTN, it is unlikely that chronic proteinuria is the result of an ongoing abnormal turnover of CLP.

Chronic nephritis induced by antibodies reacting with glomerular-bound immune complexes.

The pathogenesis of chronic membranous glomerulonephritis induced in rats by passive immunization with heterologous antibodies to rat renal tubular epithelial (RTE) antigens was investigated. This model is designated as "passive Heymann nephritis" (PHN) in order to contrast it with classical Heymann nephritis induced by active immunization with homologous RTE in adjuvant. A single i.v. injection of heterologous (rabbit) antibody to RTE evoked chronic proteinuria after a latent period of one to three days. The onset of proteinuria was accompanied by the granular deposition of rabbit IgG and rat beta1C globulin along the glomerular capillary wall. Renal isografts developed PHN only when transplanted within the first three days following injection of the heterologous anti-RTE antibodies. The data suggest that the heterologous antibodies form immune complexes with RTE antigens preexisting in the circulation, and these complexes subsequently deposit in the glomerular capillary walls. Chronic proteinuria is then perpetuated by a host reaction to the foreign protein in the deposits (i.e., rabbit IgG), in a fashion analogous to that seen in the autologus phase of nephrotoxic serum nephritis. These studies indicate that continued glomerular deposition of preformed circulating immune complexes may not always be a requisite for the perpetuation of glomerular injury in immune complex disease.

Effect of indomethacin on the synthesis of glomerular basement membrane and on proteinuria in rats with nephrotoxic nephritis.

The effect of indomethacin on protein excretion and on the synthesis of glomerular basement membrane (GBM) was studied during various stages of nephrotoxic nephritis (NTN) in the rat. Daily administration of indomethacin (4 mg/kg) was instituted 1, 6, or 21 days after the induction of NTN with 210, 240, or 268 microgram kidney-fixing antibodies (KFAb). Proteinuria in rats with nephritis induced by 210 microgram KFAb decreased under treatment with indomethacin regardless of the day on which treatment was started but was not affected by indomethacin in rats with clinically more severe nephritis induced with higher doses of KFAb. GBM synthesis was measured in vivo and in vitro by determination of the incorporation of 3H-proline into the GBM. NTN rats treated with indomethacin showed increased GBM synthesis early in the course of NTN, over and above an already increased synthesis. In the later phase of NTN indomethacin treatment did not affect GBM synthesis. The absence of a relationship between the effect of indomethacin on proteinuria and its effect on GBM synthesis clearly shows that the reduction of protein excretion occurring under indomethacin treatment is not mediated by alterations in the rate of GBM synthesis.