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M M Kaplan

Publications and source records attributed to M M Kaplan.

At least 37 records · Page 2Linked to original sources
PubMed1997

Treatment of chronic hepatitis C with interferon alfa-n3: a multicenter, randomized, open-label trial.

We studied the antiviral effectiveness and safety of interferon alfa-n3, a natural alpha interferon which contains multiple interferon species, in the treatment of previously untreated patients with chronic hepatitis C. Seventy-seven patients were randomized to receive either 1.0, 2.5, 5.0, or 10.0 million units (MU) of interferon alfa-n3 three times a week for 24 weeks and were then followed for an additional 24 weeks. At the end of therapy, 67% of patients in the 10 MU group normalized serum alanine transaminase (ALT) levels and 59% had no hepatitis C virus (HCV) RNA detected by polymerase chain reaction. At the end of the follow-up period, 44% of patients in the 10 MU group maintained normal ALT, and 24% had nondetectable HCV RNA. Lower doses were much less effective. Interferon alfa-n3 was well tolerated and no patient developed neutralizing anti-interferon antibodies during or after the treatment period. Interferon alfa-n3 appears to be effective against hepatitis C virus and deserves further study in larger randomized controlled trials.

Adult↗
PubMed1997

Correlation of biochemical response to interferon alfa with histological improvement in hepatitis C: a meta-analysis of diagnostic test characteristics.

The current goal of interferon treatment for chronic hepatitis C is to normalize alanine aminotransferase (ALT) and to eradicate detectable viral RNA. Many patients do not achieve this objective during treatment, and most do not sustain these outcomes after interferon is discontinued. However, biochemical or virological responses to interferon may not reflect accurately the histological consequences of therapy. The aim of this study was to determine the extent to which the biochemical measures reflect the histological outcomes in the treatment of hepatitis C with interferon alfa using a meta-analysis of diagnostic test characteristics. The data sources were English and non-English language studies retrieved from Medline (from 1966 to December 1995). The study selection included studies in which interferon alfa was used for treatment of chronic hepatitis C with liver biopsies performed before and after therapy. Data on histological and biochemical outcomes were extracted independently by two reviewers. Two separate criteria were used for defining histological response. When strict definitions of histological improvement were considered, histology improved in 28% (95% confidence interval [95% CI], 17%-43%) of patients after interferon treatment. The sensitivity and specificity of the ALT for determining histological change were 70% (95% CI, 56%-81%) and 66% (95% CI, 56%-75%), respectively. As many as 17% (95% CI, 9%-30%) of subjects with an abnormal ALT at the end of therapy may have improved histologically after interferon therapy. When less stringent definitions of histological improvement were considered, 62% (95% CI, 51%-72%) improved after therapy. The sensitivity and specificity of the ALT for determining histological change were 55% (95% CI, 44%-65%) and 75% (95% CI, 67%-81%), respectively. As many as 51% (95% CI, 38%-64%) may have improved, despite failure to normalize ALT. A substantial number of patients may improve histologically after interferon therapy. The significance of histological changes observed after interferon therapy must be weighed against the limitations of liver biopsy and the uncertain natural history of hepatitis C. Nevertheless, the ALT does not always reflect liver histology accurately after interferon alfa treatment and may underestimate histological improvement.

Alanine Transaminase↗
PubMed1997

A novel histological lesion in glucocorticoid-responsive chronic hepatitis.

In patients with chronic hepatitis, the diagnosis of autoimmune hepatitis is made on the basis of increased gamma-globulin levels and the presence of circulating autoantibodies. Because these test results are not abnormal universally in patients with autoimmune hepatitis, liver biopsy remains an important part of the evaluation. The classical histological finding in autoimmune hepatitis is lymphocytic infiltration of the portal triads and periportal zone (zone 1) with periportal hepatocyte necrosis. This case report describes 4 patients with glucocorticoid-responsive hepatitis, presumably autoimmune in nature, who had pericentral necrosis (zone 3) with relative sparing of the portal areas in their liver biopsy specimens, a previously undescribed histological finding in autoimmune hepatitis.

Adult↗
PubMed1997

Utility of hepatic iron index in American patients with hereditary hemochromatosis: a multicenter study.

BACKGROUND & AIMS: A hepatic iron index (hepatic iron concentration divided by age) of more than 1.9 has been proposed as useful to identify patients with homozygous hereditary hemochromatosis (HHC). There are limited data on the diagnostic use of the hepatic iron index in patients with HHC in the United States. This study evaluated the hepatic iron index in the diagnosis of HHC in a multicenter U.S. study. METHODS: Hepatic iron concentration was measured in 509 patients undergoing liver biopsy. The diagnosis of HHC was made using clinical, biochemical, and histopathologic criteria. RESULTS: Fifty-five patients met criteria for HHC; hepatic iron index was > 1.9 in 51 of 55 (93%) patients with HHC but in none of 454 patients with other liver diseases; hepatic iron concentration was > 71 mumol/g dry weight in 54 of 55 patients with HHC but only 1 of the other 454 patients. CONCLUSIONS: A hepatic iron index of > or = 1.9 can identify most U.S. patients with HHC but is < or = 1.9 in 7%. A "threshold" hepatic iron concentration of 71 mumol/g can almost always distinguish patients with HHC from patients with other liver diseases and may be a useful adjunct to the hepatic iron index in the diagnosis of HHC in the diverse U.S. population.

Adult↗
PubMed1997

The use of methotrexate, colchicine, and other immunomodulatory drugs in the treatment of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is an immunologically mediated disease in which activated T lymphocytes attack and destroy epithelial cells in the small intralobular bile ducts of genetically susceptible patients. This article reviews the results of treatment of PBC with immunomodulatory agents. Results with drugs such as glucocorticoids, azathioprine, and chlorambucil have been disappointing because of either limited efficacy (azathioprine), toxicity (chlorambucil), or both (glucocorticoids). Colchicine improved tests of liver function in three prospective studies and was associated with improved survival for up to 4 years. However, survival benefits were lost at 8 years. Colchicine appears to slow the rate of progression of PBC but not to stop it. Preliminary results suggest that colchicine may have synergistic effects if used together with ursodeoxycholic acid, particularly in patients who are only partially responsive to ursodeoxycholic acid. Results with cyclosporine have been disappointing because of limited efficacy and predictable toxicity. The modest improvement in tests of liver function and survival are counterbalanced by the development of hypertension in some and worsening renal function in most. There is little beneficial effect on symptoms or histology. Results with methotrexate are promising. There are improvements in symptoms and tests of liver function that are equal to those seen with ursodeoxycholic acid and significant improvement in liver histology. Some patients, particularly those with striking inflammation and granulomas in portal triads, appear to have achieved sustained remission while on methotrexate. The effects of methotrexate are additive to those of ursodeoxycholic acid in patients whose blood tests have responded only partially to ursodeoxycholic acid. The most effective treatment of PBC will most likely use a combination of drugs such as ursodeoxycholic acid, colchicine, and methotrexate.

Adjuvants, Immunologic↗
PubMed1997

Plasma vitamin K1 level is decreased in primary biliary cirrhosis.

OBJECTIVE: To measure directly plasma vitamin K1 in patients with primary biliary cirrhosis (PBC) and to examine the relationship between vitamin K1 level, prothrombin time, other fat-soluble vitamin levels, and severity of cholestasis. METHODS: We directly measured levels of vitamin K1 (phylloquinone) in the plasma of 77 patients with PBC using reverse-phase high-performance liquid chromatography, along with serum levels of vitamins A, E, and 25-OH vitamin D. RESULTS: Median plasma vitamin K1 level was significantly lower in PBC patients compared with 255 normal subjects (0.65 nmol/L; range, 0.05-4.13, vs 0.95 nmol/L; range, 0.2-4.92; p < 0.0001). Of 77 PBC patients, 18 (23%) patients had levels below the normal range for plasma vitamin K1 (<0.3 nmol/L). Only 1 of the 18 patients with decreased vitamin K1 had a prolonged prothrombin time. There was no correlation between vitamin K1 level and prothrombin time in the PBC patients (p = 0.75); there was also no difference in prothrombin time between PBC patients with low vitamin K1 level and PBC patients with normal vitamin K1 level (10.3 vs 10.0 seconds; p = 0.28). PBC patients with decreased vitamin K1 levels had significantly lower vitamin A and vitamin E levels, and significantly higher serum bilirubin levels than those with normal vitamin K1 levels. CONCLUSION: Decreased plasma vitamin K1 level is common in PBC, and is associated with decreased serum levels of vitamins A and E. However, the majority of PBC patients with decreased plasma vitamin K1 levels have normal prothrombin times. Although the prothrombin time is an insensitive marker of vitamin K1 status in PBC patients, clinically important vitamin K deficiency seems uncommon.

Chi-Square Distribution↗
PubMed1996

Unique autoantibody epitopes in an immunodominant region of thyroid peroxidase.

To define the autoantibody epitopes in amino acids 513-633 of thyroid peroxidase (TPO), a region frequently recognized in thyroiditis, cDNA sequences coding for peptide fragments of this region were amplified and ligated into pMalcRI and pGEX vectors for expression as recombinant fusion proteins. Western blots and enzyme-linked immunosorbent assay were then used to examine the reactivity in sera from 45 Hashimoto's and 47 Graves' disease patients. Two autoantibody epitopes within TPO amino acids 589-633 were identified; 16 of 35 patients reactive to TPO513-633 recognized the epitope of TPO592-613, while 6 patients recognized the epitope of TPO607-633. Eleven other patients with thyroiditis and two with Graves' disease recognized only the whole 589-633 fragment, and this response accounted for the Hashimoto's disease specificity. An amino acid sequence comparison of TPO592-613 with analogous regions of other peroxidase enzymes revealed significant differences in this area, and the substitution of even a single amino acid in one of the epitopes markedly decreased the binding affinity of autoantibodies. Additionally, the exclusive recognition by patients of only one of the epitopes within this region suggests a genetic restriction of the autoantibody response.

Adolescent↗
PubMed1996

Serum hepatitis C RNA titers after liver transplantation are not correlated with immunosuppression or hepatitis.

The degree to which immunosuppression and/or rejection influences recurrent hepatitis C (HCV) after liver transplantation (LT) for end-stage HCV cirrhosis remains poorly defined. We quantified serum HCV-RNA in 84 serum samples from 28 anti-HCV-positive patients taken 223 days prior to and up to 1719 days after liver transplantation to determine if cumulative immunosuppression, rejection, or histologic recurrence correlated with HCV-RNA levels. Histologic, serum chemistry, cumulative steroid, and OKT3 and alpha-interferon (INF) dose data were collected at the time of HCV-RNA sampling. Eighteen of 24 evaluable patients (75%) had HCV-RNA detected in their sera after transplant. Eight patients had 14 rejection episodes, 9 patients received OKT3, and 5 were given INF for histologically moderate hepatitis. Five patients died - two of recurrent hepatitis C - and no retransplants were performed for recurrent hepatitis. Of the 23 survivors, 7 have histologic hepatitis - 2 with persistent ascites, and 2 with mild fibrosis. We could show no correlation between HCV-RNA levels and any of the variables examined although a trend toward increasing HCV-RNA levels with increasing numbers of rejection episodes was observed. In addition, histologic recurrence occurred more frequently for patients treated with OKT3. We conclude that the quantity of circulating viral genome is not influenced by immunosuppressive load and does not correlate with laboratory or histologic signs of recurrence. The roles that rejection, and possibly OKT3, play in the recurrence of HCV after liver transplant need further study.

Female↗
PubMed1996

Use of a designer triple expression hybrid clone for three different lipoyl domain for the detection of antimitochondrial autoantibodies.

The detection of antimitochondrial autoantibodies (AMAs) is critical in the diagnosis of primary biliary cirrhosis (PBC). However, conventional laboratory assays to detect AMA are dependent on the time-consuming method of immunofluorescence microscopy, a method often plagued by problems of nonspecificity. AMAs react against mitochondrial autoantigens including the E2 components of the pyruvate dehydrogenase complex (PDC-E2), the branched-chain 2-oxo-acid dehydrogenase complex (BCOADC-E2), and the 2-oxo-glutarate dehydrogenase complex (OGDC-E2). Interestingly, the immunodominant epitopes of PDC-E2, BCOADC-E2, and OGDC-E2 are all conformational lipoate binding sites, but antibodies against them do not cross-react. Although 80% to 90% of sera from patients with PBC react to PDC-E2, approximately 10% patients with PBC react only to BCOADC-E2 and/or OGDC-E2. We have taken advantage of our epitope-mapping studies of the E2 components of PDC, BCOADC, and OGDC, and constructed a "designer" hybrid clone, designated as pML-MIT3, that coexpresses the immunodominant epitopes within the three distinct lipoyl domains. We examined a total of 321 sera, including 186 sera from patients with PBC, to test the immunoreactivity of pMIT3. Of 186 sera from patients with PBC, 152 sera (81.7%) reacted with recombinant fusion protein of PDC-E2, whereas 171 sera (91.9%) showed positive reactivities when probed by immunoblotting against the recombinant fusion protein expressed from the pML-MIT3 clone. Of 34 PBC sera that did not react with recombinant PDC-E2, 18 sera contained BCOADC-E2-specific AMA and 1 serum possessed only OGDC-E2-specific AMA. We also developed an enzyme-linked immunosorbent assay (ELISA), using affinity-purified recombinant fusion protein of pML-MIT3 clone as the antigen source, to quantify specific AMAs in patients with PBC. None of the 135 control sera from patients with primary sclerosing cholangitis (PSC), chronic autoimmune hepatitis (CAH), systemic lupus erythematosus (SLE), or healthy volunteers showed significant reactivity against pML-MIT3 recombinant fusion protein in the ELISA assay. Our results indicate that an ELISA using recombinant, cloned autoantigen of pML-MIT3 is a powerful and very specific method for the detection of AMA.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1996

Extrahepatic biliary stricture associated with cytomegalovirus in a liver transplant recipient.

We describe a patient who developed a stricture in the distal common bile duct 6 weeks after orthotopic liver transplantation. Histopathologic examination of the bile duct epithelium in the region of the stricture showed characteristic cytomegalovirus (CMV) inclusions. CMV was also identified in pulmonary alveoli and in the duodenum. Although CMV has been demonstrated in the biliary epithelium of AIDS patients with extrahepatic biliary strictures and biliary obstruction, this entity has not, to our knowledge, been described in liver transplant recipients. This report confirms that CMV infection should be included as a probable cause of extrahepatic biliary strictures and bile duct obstruction in liver transplant patients.

Cholestasis, Extrahepatic↗
PubMed1996

The successful treatment of autoimmune hepatitis with 6-mercaptopurine after failure with azathioprine.

Although the treatment of choice for autoimmune hepatitis is glucocorticoids, their side effects make long-term use undesirable. Therefore, other immunosuppressive agents have been used to replace glucocorticoids in the long-term treatment of autoimmune hepatitis, including azathioprine, a purine analogue. It is derived from 6-mercaptopurine, and these two drugs are often used interchangeably. However, these drugs have different toxicity profiles and may have clinically relevant differences in immunosuppressive activity in individual patients. We report 3 patients with autoimmune hepatitis who either could not tolerate or failed to improve on azathioprine but responded well to 6-mercaptopurine.

Adolescent↗
PubMed1995

Methotrexate treatment of idiopathic granulomatous hepatitis.

OBJECTIVE: To test the efficacy and safety of low-dose oral pulse methotrexate therapy in patients with idiopathic granulomatous hepatitis who had complications of, did not respond to, or refused glucocorticoid therapy. DESIGN: Prospective case study. SETTING: Academic medical center hospital. PATIENTS: Seven patients with biopsy-proven, idiopathic granulomatous hepatitis who could not tolerate or were unresponsive to glucocorticoid therapy. INTERVENTION: Low-dose oral pulse methotrexate, 15 mg/wk. MEASUREMENTS: Temperature, symptoms, dose of concurrent glucocorticoids, biochemical tests of liver function, side effects of methotrexate, and assessment of liver biopsy specimens. RESULTS: All six febrile patients became afebrile within 3 months of starting methotrexate. Fatigue and anorexia improved in all patients. Glucocorticoid therapy was successfully discontinued within 6 months of starting methotrexate in four patients receiving prednisone at entry. Liver biopsy specimens were obtained again after methotrexate therapy and showed absence of granulomas in four of four patients. The minimum effective dose of methotrexate was 0.20 mg/kg body weight per week. No serious adverse effects and no failures to respond to methotrexate therapy were noted in this group of patients. In three patients, methotrexate therapy has been successfully tapered without signs or symptoms of recurrent disease. CONCLUSIONS: Low-dose oral pulse methotrexate was effective in treating patients with granulomatous hepatitis.

Administration, Oral↗
PubMed1995

Alternate-day prednisone in the maintenance immunosuppressive therapy after orthotopic liver transplantation.

Glucocorticoids have been an important part of maintenance immunosuppressive therapy following orthotopic liver transplantation (OLT). However, long-term daily glucocorticoid use is associated with a high incidence of unpleasant side effects. In an effort to minimize side effects while maintaining adequate immunosuppression, we have treated 48 adult patients with low dose alternate-day prednisone, 15 mg q.o.d. Pre-OLT diagnoses included primary biliary cirrhosis (16 patients), alcoholic liver disease (8 patients), sclerosing cholangitis (8 patients), cryptogenic cirrhosis and/or non-A, non-B hepatitis (11 patients), acute hepatic failure (3 patients), and hepatocellular carcinoma and bile duct carcinoma (1 patient each). Conversion to alternate-day prednisone was attempted when patients were clinically stable and the daily prednisone dose was 15 mg. The average interval between OLT and beginning of the conversion to alternate-day prednisone was 38 weeks. The mean time for conversion to alternate-day prednisone was 35 weeks, but decreased as more experience was gained. The mean follow-up was 106 weeks. Cushingoid side effects diminished in all. In 47 of the 48 patients, there were no clinical laboratory or histologic changes suggestive of rejection after the initiation of alternate-day prednisone. A single episode of rejection occurred during the taper. This episode responded promptly to increased glucocorticoid therapy, and the patient was easily converted to alternate-day prednisone at a later date. There was no increase in concurrent immunosuppressives dosage after the conversion. Alternate-day prednisone is effective and safe for chronic immunosuppression after OLT in patients receiving cyclosporine and azathioprine.

Adolescent↗