Liver disease in renal transplant recipients.

Significant liver disease developed in 14 patients after renal transplantation. Nine patients had morphologic and functional evidence of chronic active hepatitis. In general, these patients had few symptoms of liver disease, even though the course of chronic active hepatitis was progressive. Despite large doses of prednisone, cirrhosis ultimately developed in five patients. The cause of chronic active hepatitis could not be related to azathioprine or methyldopa therapy because there was no perceptible change in the course of liver disease after treatment with these drugs was stopped. Three patients were persistently positive for hepatitis B surface antigen. Isolated instances of granulomatous hepatitis (Mycobacterium kansasii) and of prolonged intrahepatic cholestasis were encountered in patients with chronic active hepatitis. Two patients had acute cytomegalovirus hepatitis. There was one episode each of fulminant herpes simplex hepatitis and severe fatty metamorphosis.     

Chronic hepatitis in carriers of hepatitis B surface antigen, with intrahepatic expression of the delta antigen. An active and progressive disease unresponsive to immunosuppressive treatment

To assess the characteristics of chronic hepatitis in hepatitis B surface antigen (HBsAg) carriers with intrahepatic delta antigen, the hepatic histologic findings of 137 patients were reviewed; 101 patients were followed for 2 to 6 years. The predominant liver disease was chronic active hepatitis in 93 patients or cirrhosis in 32; minor forms of chronic persistent or lobular hepatitis were seen in 12 patients. Eight of the 26 patients with an initial diagnosis of cirrhosis died during the follow-up period. Cirrhosis developed in 31 of 75 patients (41%) without nodular regeneration seen in the first biopsy specimen; 5 of these patients died. Treatment with prednisone or azathioprine did not induce histologic amelioration of delta hepatitis or prevent cirrhosis. Chronic HBsAg hepatitis with intrahepatic expression of the delta antigen is an active, progressive disease unresponsive to conventional immunosuppressive treatment.     

Carcinoma of the Cervix After Treatment with Prednisone and Azathioprine for Chronic Active Hepatitis

A 24-year old woman with chronic active hepatitis developed carcinoma of the cervix, in situ , after receiving 1,000 gm. of azathioprine and 250 gm. of prednisone during a period of 5½ years. This occurrence emphasizes one of the risks of immunosuppressive therapy and we recommend careful surveillance for cancer in patients so treated. The evidence that hepatitis may be associated with an increased incidence of cancer of the cervix is reviewed.     

Granulomatous lipophagic panniculitis and temporal arteritis in a patient with cryptogenic chronic active hepatitis.

An elderly woman receiving long term treatment with prednisone and azathioprine for cryptogenic chronic active hepatitis developed granulomatous lipophagic panniculitis and temporal arteritis. The lymphoplasmahistiocytic inflammatory reaction pattern is common to this patient's three diseases. It is suggested that an aberration of the defence mechanisms, immunological or otherwise, is responsible for this unusual occurrence. The triple association of chronic active hepatitis, granulomatous panniculitis and temporal arteritis has not been reported previously.     

Autoimmune pancreatitis with evolution to cholangitis: a case report

We report the case of a 47-year-old Caucasian male patient who presented with obstructive jaundice and mild epigastric pain. Autoimmune pancreatitis was diagnosed based on magnetic resonance imaging, biopsy and clinical evolution, and the patient was successfully treated with corticosteroids. However, a few months later ERCP showed an image compatible with sclerosing cholangitis. Again, treatment with corticosteroids was given, after which the bile ducts became normal. A few months later, again there was a relapse and azathioprine was started. After decreasing the dose of immunesuppression, we saw relapses of cholangitis and pancreatitis, with eventually evolution to chronic calcifying pancreatitis. The aim of this report is to describe autoimmune pancreatitis as a cause of obstructive jaundice, and to illustrate that evolution to an immunesuppression-responsive cholangitis, with evolution to chronic calcifying pancreatitis is possible. Also, our patient had a small fluid collection, possibly a pseudocyst, an unusual finding in autoimmune pancreatitis, which disappeared during treatment.     

Therapy of chronic hepatitis (author's transl)]

The favorable effect of glucocorticoids on the development of the chronic active hepatitis is statistically proved on the basis of the amelioration of the survival rate in controlled studies. The so-called lupoid hepatitis is significantly better influenced than the HBs-Ag positive chronic hepatitis. By additional therapy with azathioprine it is possible to reduce the dose of glucocorticoids. Therefore it is better to combine glucocorticoids and azathioprine in some cases, especially in those with a high dosed glucocorticoid therapy. Further prospective studies are necessary to check more precisely the therapeutic effect of the different remedies. The effect of D-penicillamine is vague. A treatment with chloroquine is indicated in cases with contraindications again glucocorticoids and azathioprine.     

Azathioprine treatment in a patient with HBsAg-positive acute viral hepatitis complicated by bridging necrosis

A patient with HBsAg-positive subacute hepatitis who presented a progressively deteriorating clinical condition was treated with azathioprine (100 mg/day) for eight months. Although the clinical symptoms disappeared and the biochemical abnormalities decreased, the disease nevertheless progressed to chronic active hepatitis. Moreover, azathioprine favoured hepatitis B virus replication since titers of HBsAg, HBeAg and Dane-particle-associated core-antigen, as detected by radioimmunoassay, increased during treatment. In all, this drug was only of moderate use to our patient.     

A Complex Case of Hepatitis in a Patient with Systemic Lupus Erythematosus

Liver involvement in patients with systemic lupus erythematosus (SLE) is considered rare. Previous treatment with potentially hepatotoxic drugs or viral hepatitis have usually been implicated as the main causes of liver disease in SLE patients. On the other hand, even after careful exclusion of these aetiologies, the problem remains whether to classify the patient as having a primary liver disease with associated autoimmune clinical and laboratory features resembling SLE, such as autoimmune hepatitis, or as having liver disease as a manifestation of SLE.  We report the case of an elderly woman who presented with acute hepatitis, who had been diagnosed with SLE 14 years ago and who also had Sjo¨gren’s syndrome and anti-phospholipid’s syndrome for several years. The histology depicted chronic active hepatitis and, after drug-induced hepatitis and viral hepatitis were excluded, the serological and clinical features were shown to be typical of liver damage caused by SLE. The patient was treated with azathioprine 100mg/d and prednisone 30 mg/d. The clinical symptoms resolved in 10 days and the laboratory values were normal at the end of the first month of therapy. Prednisone was progressively reduced, during a period of 4 months, to 10 mg/d but azathioprine was kept to the same dose. One year after the diagnoses the patient is still in remission.  Although uncommon, hepatic involvement is well recognised in SLE. The interest of this case lies in the differential diagnosis and recognition of this condition, which deserves an agressive treatment. Received: 8 March 1999 / Accepted: 8 March 1999     

Controlled trial of a thymic hormone extract (Thymostimulin) in 'autoimmune' chronic active hepatitis.

A randomised controlled trial of thymic hormone extracts (Thymostimulin) (1 mg/kg/day for seven days; 1 mg/kg/weekly thereafter) was undertaken in 30 patients (21 women, nine men) with treated, apparently inactive 'autoimmune' chronic active hepatitis during withdrawal of maintenance corticosteroid and azathioprine therapy. Reactivation of disease occurred in 26 patients (86%) during or after treatment withdrawal and was as frequent in the Thymostimulin treated (11 of 13; 84%) and untreated (15 of 17; 88%; p greater than 0.05) groups. Reactivation of disease was accompanied by a severe defect in concanavalin A induced suppressor cell activity, the magnitude of which was similar in the Thymostimulin treated and untreated groups (mean % suppression = 16.4 and 3.2 respectively; p greater than 0.05 vs 84.4 in control subjects). Further studies assessing the optimal dose, duration of treatment, and mode of administration are required to establish a therapeutic role for thymic hormone extracts in 'autoimmune' chronic active hepatitis.     

Acute myelogenous leukemia in two patients treated with azathioprine for nonmalignant diseases

Two patients receiving long-term azathioprine therapy for immunosuppression of nonmalignant conditions (chronic active hepatitis and renal transplantation) were admitted to Stanford University Hospital with acute myelogenous leukemia. Possible mechanisms of leukemogenesis are discussed. A review of the literature reveals these to be the first reported instances of acute myelogenous leukemia occurring after azathioprine immunosuppression for nonmalignant illness.     

Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn's disease

BACKGROUND: Crohn's disease is a chronic inflammatory disease of the alimentary tract. Azathioprine is an effective agent in the management of chronic active Crohn's disease leading to long term remission of disease activity. Such treatment leads to limited efficacy or side effects in a small subset of patients. AIMS: To compare efficacy and side effects of treatment with azathioprine plus corticosteroids versus mycophenolate mofetil (MMF) plus corticosteroids in patients with chronic active Crohn's disease. METHODS: Seventy patients with chronic active Crohn's disease (Crohn's disease activity index (CDAI) greater than 150) were randomised for treatment with azathioprine/cortisone or MMF/cortisone. Corticosteroid dosage was tapered according to a standard protocol. Disease activity was monitored by clinical scores after one, two, three, and six months. RESULTS: Treatment of patients with moderately active (CDAI 150-300) Crohn's disease with MMF/cortisone led to a significant reduction in clinical activity scores comparable to treatment with azathioprine/cortisone. Treatment of patients with highly active Crohn's disease (CDAI greater than 300) with MMF/cortisone caused significant suppression of clinical activity earlier than azathioprine/cortisone treatment. Treatment with MMF/cortisone was associated with few adverse effects. CONCLUSION: Treatment of chronic active Crohn's disease with MMF plus cortisone appears to be effective and well tolerated and should be considered in patients allergic to azathioprine or in whom azathioprine has failed.     

Persistent elevation of the aminoterminal peptide of procollagen type III in serum of patients with acute viral hepatitis distinguishes chronic active hepatitis from resolving or chronic persistent hepatitis

We measured the serum concentration of the aminoterminal propeptide of collagen type III (PIIIP) in 22 patients with acute viral hepatitis (19 hepatitis B, 3 hepatitis non-A, non-B). Nine patients showed persistent biochemical remission, 13 patients developed chronic active hepatitis (CAH); 6 of those underwent therapy with methylprednisolone and azathioprine. Thirteen patients with chronic persistent viral hepatitis (CPH) and 38 healthy individuals were also investigated. In the control group, PIIIP values were 9.5 +/- 2.25 ng/ml (chi +/- SD; range 4-14 ng/ml). All patients with acute hepatitis showed elevated PIIIP values (range 20-125 ng/ml). In the 9 patients with biochemical resolution, PIIIP normalized after a maximum of 6.5 months (range 7.5-14 ng/ml). In CAH, PIIIP was persistently elevated on the day of the diagnostic biopsy (range 15.6-35.7 ng/ml). In comparison, the patients with chronic persistent hepatitis showed a range of 5.0-15.4 ng/ml. Differences between controls and CAH and CPH/CAH were statistically highly significant (P less than 0.001). Treatment of patients with CAH by immunosuppression resulted in normal PIIIP values in 3 and persistently elevated values in 3. One additional patient had normal PIIIP after treatment with an increased dose of methylprednisolone of 16 mg p.d. Serum concentrations of PIIIP offer a non-invasive index for the development of chronic active hepatitis from acute viral hepatitis. This blood test may also be useful for monitoring immunosuppressive treatment in CAH.     

Outcomes in pediatric autoimmune hepatitis

Autoimmune hepatitis (AIH) is a common cause of acute and chronic hepatitis in childhood. Once the diagnosis is established, treatment with corticosteroid or corticosteroid and azathioprine is indicated. Most children with AIH respond to such therapy and experience remission from active disease. Eliminating drug therapy while maintaining remission is the ultimate goal of therapy. The optimal duration of therapy before drug elimination is unclear. Relapse rate is inversely related to therapy duration before drug withdrawal; thus, discontinuing immunosuppressive treatment is considered only after at least 1 to 2 years of complete remission. When applying a slow and systematic approach, many children with AIH can successfully be weaned off immunosuppression completely. Even patients presenting in acute liver failure may avoid liver transplantation with early medical therapy. In about 10% of patients, treatment fails, requiring alternative therapies and/or liver transplantation as liver disease progresses. Less than 10% of children with autoimmune hepatitis die during 10 years of follow-up.     

The effectivity of immunosuppressive therapy on chronic aggressive (active) hepatitis and on chronic nonsuppurative destructive cholangitis (PBC)

ABSTRACT— Morphometric investigations were carried out on liver biopsies of chronic aggressive (active) hepatitis (CAH), type IIa, chronic aggressive (active) hepatitis, type IIb, and on chronic nonsuppurative destructive cholangitis (CNDC) (primary biliary cirrhosis (PBC)) in the second and third stages. The goal of the histometric analysis was a comparison of the portal tracts before and after immunosuppressive therapy with azathioprine and corticosteroids as well as with azathioprine alone. The volume and surface measurements of the portal tracts and their components showed that for an evaluation of the effectivity of the immunosuppressive therapy on CAH, along with a division into HBsAg-positive and -negative cases, a histologically determined degree of the severity of the inflammatory activity is extremely significant. The therapeutic effect is significant for all cases of CAH IIb, evident for HBsAg-negative cases of CAH IIa and slight for HBsAg-positive cases of CAH IIa. Immunosuppressive therapy of CNDC has no effect on the characteristic destruction process of the bile ducts and ductule proliferation.     

HBsAg clearance in patients with long-standing chronic active hepatitis B and hepatitis B virus-induced liver cirrhosis

During a period of 3 years we observed 5 patients with chronic active hepatitis B and 2 with hepatitis B virus-induced liver cirrhosis who cleared HBsAg from their sera after 2-14 years of HBsAg carriership. 4 of them developed anti-HBs. After HBsAg clearance there was no evidence of persisting inflammatory activity within their livers. 5 of the 7 patients had been treated for 1-39 months with prednisolone, sometimes in combination with azathioprine. This therapy, however, had been stopped more than 3 years before these patients terminated their HBsAg carriership. Our observations indicate that even after long-standing chronic active hepatitis B or hepatitis B virus-induced liver cirrhosis HBsAg may be eliminated in a considerable number of patients.     

Treatment of Posttransfusion Non-A, Non-B Acute and Chronic Hepatitis with Human Fibroblast β-Interferon: A Preliminary Report

We treated five patients with posttransfusion non-A, non-B chronic active hepatitis and six patients with posttransfusion non-A, non-B acute hepatitis with 3 million units of human fibroblast beta-interferon three times weekly for 4 wk. Initiation of interferon therapy was followed by a prompt and marked decrease in serum aminotransferase activity in five patients with chronic active hepatitis and five patients with acute hepatitis; the exception was one patient with acute hepatitis in whom serum aminotransferase levels fluctuated during treatment. Biopsy specimens obtained immediately after therapy showed improvement in hepatic histology in two of four patients with chronic active hepatitis and three of four patients with acute hepatitis. Cessation of interferon therapy was followed by a prompt increase in serum aminotransferase levels in five patients with chronic active hepatitis and in one patient with acute hepatitis, although re-elevated serum aminotransferase levels returned gradually to the normal range in the patient with acute hepatitis, but did not do so in five patients with chronic active hepatitis. In another patient with acute hepatitis whose serum aminotransferase levels fluctuated during interferon therapy, serum aminotransferase levels reached normal range after discontinuation of therapy. At 6 months and 12 months after discontinuation of interferon therapy, all five patients with chronic active hepatitis showed elevated serum aminotransferase levels, and all six patients with acute hepatitis showed normal serum aminotransferase levels. These results suggest that short-term and low doses of beta-interferon therapy has an only temporal effect on controlling the disease activity in patients with posttransfusion non-A, non-B chronic active hepatitis, and it might become an effective therapy for posttransfusion non-A, non-B acute hepatitis.     

Chronic pancreatitis associated with systemic lupus erythematosus in a young girl

Systemic lupus erythematosus (SLE) is an uncommon etiology of pancreatic disease. Up to now, only 3 cases of chronic pancreatitis associated with SLE have been reported in adults. We report the case of a 14-year-old girl with SLE and calcifying chronic pancreatitis. At the age of 4 she was diagnosed with SLE. She presented with several acute exacerbations of SLE that were managed with prednisone and azathioprine. At the age of 9, she was admitted with abdominal pain and elevation of serum amylase and lipase levels; no gallstones were found on ultrasound, and treatment with azathioprine was withdrawn. Thereafter, she developed numerous episodes of acute pancreatitis. Later, an ERCP showed pancreatic calcifications and distortion of the main pancreatic duct, both findings consistent with established chronic pancreatitis. At the age of 14, her condition worsened progressively, and a surgical procedure (corporo-caudal spleno-pancreatectomy) was performed. The pathology specimen showed acinar atrophy and intense fibrosis. After surgery, the patient has remained pain-free and is enjoying a normal life.     

Cyclosporin in the treatment of corticosteroid resistant autoimmune chronic active hepatitis.

A 17 year old Asian patient with autoimmune chronic active hepatitis resistant to treatment with high dose corticosteroids and azathioprine was given cyclosporin at a dose of 5 mg/kg/day. Within two weeks of starting the cyclosporin treatment a favourable clinical and biochemical response was obtained and by one month serum aminotransferase activities were within normal limits. An attempted reduction in the daily dose of cyclosporin resulted in a relapse of the patient's disease. Remission was again attained by returning the dose of cyclosporin to 5 mg/kg/day. No significant side effects of the treatment have been shown. Cyclosporin seems to have a role in the treatment of corticosteroid resistant autoimmune chronic active hepatitis and its further evaluation is warranted.     

Long-term immunosuppressive treatment in Crohn's disease

We studied the clinical effects of long-term immunosuppressive treatment in 42 patients with severe Crohn's disease and extensive colonic involvement. Mean observation period before and after start of therapy exceeded 5 years. All but one of the patients receiving azathioprine or 6-mercaptopurine improved, and 11 of 42 attained complete remission during therapy. Cyclophosphamide was substituted for azathioprine with inferior results in four patients with pancreatitis soon after initiation of azathioprine therapy. The frequency of both local and systemic complications decreased significantly during the period of therapy. Prednisolone could be withdrawn in 25 patients and reduced to less than 7.5 mg every other day in the others. The average remission period after withdrawal of all drugs in 10 patients was 40 months. The results were superior to those in a surgical series with comparable observation time drawn from the same background population. Aside from pancreatitis in four patients, no serious side effects were seen. Fertility was unaffected. The data demonstrate the feasibility of long-term azathioprine (6-mercaptopurine) treatment in extensive Crohn's disease.     

Increase of sulfated ursodeoxycholic acid in the serum and urine of patients with chronic liver disease after ursodeoxycholic acid therapy

The present study was undertaken in order to investigate the influence of ursodeoxycholic acid (UDCA) on the composition of sulfate-conjugated bile acids in the serum and urine of patients with chronic active hepatitis and compensated liver cirrhosis. After a 12 week UDCA treatment (600 mg/day), total serum bile acid concentration increased two-fold in patients with compensated liver cirrhosis and increased slightly in patients with chronic active hepatitis. The percentage of sulfated bile acids significantly increased in patients with both compensated liver cirrhosis and chronic active hepatitis. UDCA made up 63% of the total serum bile acids in compensated liver cirrhosis and 61% in chronic active hepatitis after UDCA treatment. Of the serum bile acids after UDCA treatment, 35.2 and 53.9% of UDCA was sulfate conjugated in compensated liver cirrhosis and chronic active hepatitis, respectively. Urinary excretion of total bile acid and UDCA after UDCA treatment in compensated liver cirrhosis were higher than in chronic active hepatitis. UDCA made up 68% of the total urinary bile acids in compensated liver cirrhosis and 64% in chronic active hepatitis after UDCA treatment. Of the urinary bile acids after UDCA treatment, 51.8 and 54.8% of UDCA was sulfate conjugated in compensated liver cirrhosis and chronic active hepatitis, respectively. UDCA treatment for compensated liver cirrhosis was less effective than for chronic active hepatitis. We found that sulfate conjugation is one of the major metabolic pathways for UDCA after UDCA treatment in chronic liver diseases.