Hepatitis azathioprine

Pol S, Cavalcanti R, Carnot F, Legendre C, Driss F, Chaix ML, Thervet E, Chkoff N, Brechot C, Berthelot P, Kreis H. Azathioprine hepatitis in kidney transplant recipients. A predisposing role of chronic viral hepatitis. Transplantation 1996 61(12) 1774-6. 

Agents targeting the excessive immune response or cytokines involved in IBD are potential treatment options (Table 16-3). Azathioprine and its active metabolite 6-mercaptopurine (6-MP) are inhibitors of purine biosynthesis and reduce IBD-associated GI inflammation. They are most useful for maintaining remission of IBD or reducing the need for long-term use of corticosteroids. Use in active disease is limited by their slow onset of action, which may be as long as 3 to 12 months. Adverse effects associated with azathioprine and 6-MP include hypersensitivity reactions resulting in pancreatitis, fever, rash, hepatitis, and leukopenia.25,26... 

Several types of immunosuppression have also been tried. Azathioprine alone was found to have no effect on PBC [82], but additional benificial effects were found in combination with ursodeoxychohc add and corticosteroids [78]. Cyclosporin showed some success, espe-dally in corticosteroid-resistant autoimmune hepatitis [83], but its use is generally considerably hmited by severe side-effects. Corticosteroids were effective in the management of several types of autoimmune chronic active hepatitis [84,85] and in the management of acute al-cohohc hepatitis [86]. Their use, however, has to be brief hi order to minimize side-effects. In the treatment of PBC, corticosteroids alone were found to be toxic and had only limited efficacy [77]. 

Mycophenolate mofetil is used together with cyclosporine and corticosteroids for the prophylaxis of acute organ rejection in patients undergoing allogeneic renal, or hepatic transplants. Compared with azathioprine it is more lymphocyte-specific and is associated with less bone marrow suppression, fewer opportunistic infections and lower incidence of acute rejection. More recently, the salt mycophenolate sodium has also been introduced. Mycophenolate mofetil is rapidly hydrolyzed to mycopheno-lic acid, its active metabolite. Mycophenolic acid is a reversible noncompetitive inhibitor of inosine monophosphate dehydrogenase, an important enzyme for the de novo synthesis of purines. As lymphocytes have little or no salvage pathway for purine... 

Corticosteroids, often given in conjunction with azathioprin, improve hepatic function and may reduce the risk of advancing autoimmune disease-associated cirrhosis. 

For auto-immune hepatitis relatively low doses of oral corticosteroids are effective, and concurrent azathioprin (2 mg/kg) is steroid sparing. Those in remission for two years can stop treatment, but relapse is common. 

Since allopurinol is metabolized by the hepatic microsomal drug-metabohzing enzymes, coadministration of drugs also metabohzed by this system should be done with caution. Because allopurinol inhibits the oxidation of mercaptopurine and azathioprine, their individual administered doses must be decreased by as much as 75% when they are given together with allopurinol. Allopurinol may also increase the toxicity of other cytotoxic drugs (e.g., vidarabine). The actions of allopurinol are not antagonized by the coadministration of salicylates. 

The chief toxic effect of azathioprine and mercaptopurine is bone marrow suppression, usually manifested as leukopenia, although anemia and thrombocytopenia may occur. Skin rashes, fever, nausea and vomiting, and sometimes diarrhea occur, with the gastrointestinal symptoms seen mainly at higher dosages. Flepatic dysfunction, manifested by very high serum alkaline phosphatase levels and mild jaundice, occurs occasionally, particularly in patients with preexisting hepatic dysfunction. 

A patient developed atorvastatin-induced severe autoimmune hepatitis and a lupus-like syndrome. Although the drug was immediately withdrawn, the disease persisted and deteriorated to a fulminant form with acute hepatic failure. There was no response to conventional immunosuppression with glucocorticoids and azathioprine. Only the introduction of intense immunosuppressive therapy, as used in solid organ transplantation, led to a complete and sustained recovery. The patient had the HLA haplotypcs DR3 and DR4, which are well-known genetic factors associated with autoimmune diseases. 

Clinical Use. Azathioprine (Imuran) is a cytotoxic agent that is structurally and functionally similar to certain anticancer drugs, such as mercaptopurine.22,30 Azathioprine is primarily used to prevent the rejection of transplanted organs, especially in patients with kidney transplants. Azathioprine may also be used to suppress immune responses in a wide range of other conditions, such as systemic lupus erythematosus, dermatomyositis, inflammatory myopathy, hepatic disease, myasthenia gravis, and ulcerative colitis. As presented in Chapter 16, azathioprine is also used as an antiarthritic disease-modifying agent. 

Adverse Effects. The primary side effects of azathioprine are related to suppression of bone marrow function, including leukopenia, megaloblastic anemia, and similar blood dyscrasias. Other side effects include skin rash and gastrointestinal distress (appetite loss, nausea, vomiting) hepatic dysfunction can also occur when higher doses are used. 

Comparisons with azathioprine in the renal transplantation literature show that MMF and azathioprine have similar gastrointestinal, hematopoietic, and hepatic toxicity profiles, with a possibly decreased incidence of fungal infections among patients treated with MMF. Hepatic toxicities are infrequent but must be monitored. 

Dose-related toxicities of azathioprine or 6-mercaptopurine include nausea, vomiting, bone marrow depression (leading to leukopenia, macrocytosis, anemia, or thrombocytopenia), and hepatic toxicity. Routine laboratory monitoring with complete blood count and liver function tests is required. Leukopenia or elevations in liver chemistries usually respond to medication dose reduction. Severe leukopenia may predispose to opportunistic infections leukopenia may respond to therapy with granulocyte stimulating factor. Hypersensitivity reactions to azathioprine or 6-mercaptopurine occur in 5% of patients. These include fever, rash, pancreatitis, diarrhea, and hepatitis. 

The special risk is observed in patients with hepatic or renal impairment. It is not advised to use allopurinol in acute attacks of gout, but it is useful in chronic gout. Excretion of allopurinol and its active metabolite oxypurinol is primarily via the kidneys and therefore the dosage should be reduced if renal function is impaired. The adverse effects have been reported in patients receiving allopurinol with thiazide diuretics, particularly in patients with impaired renal function. The metabolism of azathioprine and mercaptopurine is inhibited by allopurinol and their doses should be reduced to one-quarter to one-third of the usual dose when either of them is given with allopurinol to avoid potentially life-threatening toxicity.27-29... 

Autoimmune hepatitis If single drug therapy then start with 60 mg p.o. q.d. and taper over 4 weeks to 20 mg q.d. maintenance dose until end point. If combination therapy with azathioprine, then start with 30 mg q.d. and taper over 4 weeks to 10 mg q.d. maintenance dose until endpoint... 

Hepatitis with cholestasis Chlorpromazine, tricyclics, erythromycin, flucloxacillin, co-amoxiclav, ACE inhibitors, phenytoin, NSAIDs, ranitidine, propafenone, ketoconazole, azathioprine, gold salts, penicillamine... 

Autoimmune hepatitis typically occurs in females, at puberty and between the ages of 40 and 70. It can also occur in males at any age. It may present in a number of ways as a mild hepatitis, as a severe acute hepatitis or as established cirrhosis. The functioning capacity of the liver will vary depending on the stage of disease. The diagnosis of AIH is based on serum biochemistry, liver histology, and the presence of certain autoantibodies in the serum. Exclusion of other potential causes of hepatitis, e.g. hepatitis B or C, alcohol consumption, is needed before a definitive diagnosis can be made. There are no featnres that are specifically indicative of AIH, but it usually responds to treatment with corticosteroids. Once remission is indnced azathioprine or... 

MERCAPTOPURINE ANTIGOUT DRUGS -ALLOPURINOL t mercaptopurine levels with risk of toxicity (e.g. myelosuppression, pancreatitis) Azathioprine is metabolized to mercaptopurine. Allopurinol inhibits hepatic metabolism of mercaptopurine 1 doses of azathioprine and mercaptopurine by up to three-quarters and monitor FBC, LFTs and amylase carefully... 

Methotrexate can be helpful in controlling relapses of Crohn s disease unresponsive to corticosteroid or azathioprine. It has also been used with benefit in ulcerative colitis. Its short- and long-term use are limited by a wide profile of adverse effects including bone marrow suppression and pulmonary and hepatic fibrosis (see p. 291). 

Veno-occlusive disease (VOD) describes the occlusion of small hepatic veins and is defined as a radicular form of the Budd-Chiari syndrome. A variety of endotheliotoxic noxae, particularly phytotoxins, are responsible for this clinical picture. In 1951 reports were simultaneously published for the first time both in South Africa (G. Selzer et al.) and Jamaica (K. R. Hill) dealing with this disease of the small venous branches, which results from chronic intoxication with pyrrolizidine alkaloids, (s. pp 548, 571) Similar morphological and clinical effects can also be caused by cytostatic agents (6-mercaptopurine, dacarbazine, thioguanine), azathioprine, contraceptives and exposure to X-rays. Since 1957, the term Stuart-Bras syndrome has also been used to describe the occlusion of the small hepatic veins, (s. p. 832)... 

Medicinal agents (such as contraceptives) may result in proliferations of the intima in the hepatic artery and its branches. In some cases, these arterial alterations were associated with thrombosis in the hepatic veins. Phar-macons can trigger three different forms of damage to the sinusoids (7.) dilation of the sinusoids (e.g. by contraceptives), (2.) perisinusoidal fibrosis (e.g. by azathio-prine, vitamin A and cytostatic agents), and (i.) peliosis hepatis (e. g. by contraceptives, anabolic and androgenic steroids, azathioprine, chenodesoxycholic acid). (13, 28, 130) (s. p. 398) (s. fig. 21.8)... 

Occlusion of the small hepatic veins is called veno-occlu-sive disease (VOD) (G. Bras et al., 1954 K.L. Stuart et al., 1957). It is identical to the radicular type of the Budd-Chiari syndrome, (s. p. 249) Cytostatics and azathioprine are among the alleged causal agents. (I2l, 130) Diagnosis is based on imaging techniques (ultrasound, CEDS, CT), and sometimes on liver biopsy, (s. fig. 29.10) (see chapter 39)... 

A female patient between 35 and 40 years of age with confirmed (in line with the methods of the time, including laparoscopy and biopsy) autoimmune hepatitis (ANA ++, SMA+, LMA +, LE factor+, IgG++, y-globulin++, GPT, GOT80-100 Utl, GDH ca. 12 UH, no cholestasis) had been undergoing treatment with prednisolone I azathioprine and had been in constant remission for over 3 years (maintenance dose of 4—6 mg prednisolone and 50 mg azathioprine for over 2 years). Physically and mentally stable, engaged in her profession, she had placed great confidence in us. Approximately 3 days after a sudden, severe emotional trauma with mental breakdown, the AlH deteriorated on a massive scale, and about 3 weeks later, the patient died in a coma hepaticum from acute liver failure. 

Bellary, S., Schlano, T., Hartman, G., Black, M. Chronic hepatitis with combined features of autoimmune chronic hepatitis and chronic hepatitis C favorable response to prednisone and azathioprine. Ann. Intern. Med. 1995 123 32-34... 

Johnson, P.J., McFarlane, I.G., Williams, R. Azathioprine for longterm maintenance of remission in autoimmune hepatitis. New Engl. J. 72... 

Rerson, J.L., McHutchison, J.G., Fong, T., Redeker, A.G. A case of cyclosporine-sensitive, steroid-resistant autoimmune chronic active hepatitis. J. Clin. Gastroent. 1993 17 317-320 Rratt, D.S., Flavin, D.R., Kaplan, M.M. The successful treatment of autoimmune hepatitis with 6-mercaptopurine after failure with azathioprine. Gastroenterology 1996 110 271-274 Rahaman, SM., Chira, R, Koff, R.S. Idiopathic autoimmune chronic hepatitis triggered by hepatitis A. Amer. J. Gastroent. 1994 89 106-108... 

R. Maintenance of remission in autoimmune chronic active hepatitis with azathioprine after corticosteroid withdrawal. Hepatology 1988 8 781-784... 

Mackay, I.R., Weiden, S., Ungar, B. Treatment of active chronic hepatitis with 6-mercaptopurine and azathioprine. Lancet 1964/1 899-902... 

Pratt, D.S., Flavin, D.P., Kaplan, MM. The successful treatment of autoimmune hepatitis with 6-mercaptopurine after failure with azathioprine. Gastroenterology 1996 110 271-274... 

---