Correspondence

Autoimmune Hepatitis

N Engl J Med 1996; 334:923-924April 4, 1996

Article

To the Editor:

Meyer zum Büschenfelde and Lohse (Oct. 12 issue)1 suggest that patients with mild autoimmune hepatitis should be treated. However, few data support the contention that such patients will benefit. Although the results of large controlled trials support the use of corticosteroids in the treatment of autoimmune hepatitis,2-4 these beneficial effects are fully established only in patients with the most severe histologic manifestations.5 The effects of corticosteroids in reducing mortality appeared to be confined to patients whose initial live biopsies revealed bridging necrosis, multilobular necrosis, or cirrhosis. There were no deaths among patients whose initial liver biopsies revealed only chronic active hepatitis. Furthermore, corticosteroid therapy does not unequivocally lower the risk of cirrhosis in patients who have only chronic active hepatitis.

Koretz et al. have shown that only a minority of patients with chronic active hepatitis appear to derive proved benefit from corticosteroid treatment.6 What, then, should be recommended for patients with mild autoimmune hepatitis? Should corticosteroids be used in an asymptomatic patient in whom the disease is manifested histologically only as periportal or piecemeal necrosis? I believe the answer is a qualified no and that the decision to treat must be made on an individual basis and be guided by the available data. Pending additional information, it may be most prudent to withhold corticosteroid or immunosuppressive therapy in patients with asymptomatic, mild, autoimmune hepatitis.

Joseph C. Yarze, M.D.
Gastroenterology Associates of Northern New York, Glens Falls, NY 12801

6 References

1. 1

   Meyer zum Buschenfelde K-H, Lohse AW. Autoimmune hepatitis. N Engl J Med 1995;333:1004-1005
   Full Text | Web of Science | Medline

2. 2

   Cook GC, Mulligan R, Sherlock S. Controlled prospective trial of corticosteroid therapy in active chronic hepatitis. Q J Med 1971;40:159-185
   Web of Science | Medline

3. 3

   Soloway RD, Summerskill WH, Baggenstoss AH, et al. Clinical, biochemical, and histological remission of severe chronic active liver disease: a controlled study of treatments and early prognosis. Gastroenterology 1972;63:820-833
   Web of Science | Medline

4. 4

   Murray-Lyon IM, Stern RB, Williams R. Controlled trial of prednisone and azathioprine in active chronic hepatitis. Lancet 1973;1:735-737
   CrossRef | Web of Science | Medline

5. 5

   Wright EC, Seeff LB, Berk PD, Jones A, Plotz PH. Treatment of chronic active hepatitis: an analysis of three controlled trials. Gastroenterology 1977;73:1422-1430
   Web of Science | Medline

6. 6

   Koretz RL, Lewin KJ, Higgins J, Fagen ND, Gitnick GL. Chronic active hepatitis: who meets treatment criteria? Dig Dis Sci 1980;25:695-699
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Yarze correctly points out that the role of immunosuppressive therapy in mild cases of autoimmune hepatitis has not yet been defined by controlled trials. Until such studies are conducted, clinical reasoning and experience should guide therapy. We believe that patients with mild autoimmune hepatitis should receive immunosuppressive therapy, albeit at lower doses than are recommended in more aggressive disease.

A large proportion of patients with autoimmune hepatitis already have cirrhosis when they come to medical attention. In most of them the cirrhosis has developed in the absence of clinical symptoms. In many, mild elevations of aminotransferase levels have been documented without a definite diagnosis being made or therapy commenced. Furthermore, the majority of patients with cryptogenic cirrhosis have features of autoimmune hepatitis, suggesting that subclinical hepatitis has led to their cirrhosis.1 Most important, in many patients untreated disease has a spontaneously fluctuating course. If liver biopsies are performed in these patients during a phase of spontaneous remission, little inflammation will be observed. However, when the patients are left untreated, reactivation is likely to occur, usually within one year, and it may go undetected, because the only symptom, if any are present, may be fatigue.2 The only justifiable alternative, we believe, would be very close follow-up. However, regular biopsies would need to be included in such an approach, because fibrosis may develop rapidly.

The rate at which cirrhosis develops in untreated patients with autoimmune hepatitis is not well documented.3 The therapeutic trials cited by Yarze have not included sufficiently long observation periods or sufficient numbers of patients with milder disease to show a survival benefit in this subgroup. Another study whose follow-up period lasted at least 10 years (or until death, in the case of 44 patients) found a marked survival benefit that was independent of the patients' aminotransferase levels at the start of immunosuppressive therapy.4 That report concluded, “This study confirms the well-established fact that steroid therapy is mandatory, and suggests that the required duration of treatment is about five years.” In addition, since all these studies were undertaken before the hepatitis C virus was discovered, patients with viral hepatitis who do not benefit from immunosuppressive therapy were included.

Autoimmune hepatitis often occurs in young patients. It is a chronic disease that has been shown to be progressive in many, if not most, cases. In the more aggressive form of the disease, the survival benefit of therapy is dramatic. Therefore, it makes good sense to treat milder disease as well.

K.-H. Meyer zum Büschenfelde, M.D., Ph.D.
Ansgar W. Lohse, M.D.
Johannes Gutenberg University, D-55101 Mainz, Germany

4 References

1. 1

   Czaja AJ, Carpenter HA, Santrach PJ, Moore SB, Homburger HA. The nature and prognosis of severe cryptogenic chronic active hepatitis. Gastroenterology 1993;104:1755-1761
   Web of Science | Medline

2. 2

   Czaja AJ, Ludwig J, Baggenstoss AH, Wolf A. Corticosteroid-treated chronic active hepatitis in remission: uncertain prognosis of chronic persistent hepatitis. N Engl J Med 1981;304:5-9
   Full Text | Web of Science | Medline

3. 3

   Thaler H. The natural history of chronic hepatitis. In: Schaffner F, Sherlock S, Leevy CM, eds. The liver and its diseases. New York: Stratton Intercontinental Medical, 1974:207-15.
   

4. 4

   Kirk AP, Jain S, Pocock S, Thomas HC, Sherlock S. Late results of the Royal Free Hospital prospective controlled trial of prednisolone therapy in hepatitis B surface antigen negative chronic active hepatitis. Gut 1980;21:78-83
   CrossRef | Web of Science | Medline

Citing Articles (4)

Citing Articles

1. 1

   Omer Junaidi, Adrian M. Di Bisceglie. (2007) Aging Liver and Hepatitis. Clinics in Geriatric Medicine 23:4, 889-903
   CrossRef

2. 2

   Michael A Heneghan, Thawab Al-Chalabi, Ian G McFarlane. (2006) Cost-effectiveness of pharmacotherapy for autoimmune hepatitis. Expert Opinion on Pharmacotherapy 7:2, 145-156
   CrossRef

3. 3

   Jasmina Simonovic-Babic, Dragan Delic, Neda Svirtlih, Marija Djordjevic. (2004) Elevated aminotransferase levels: Diagnostic approach. Medicinski pregled 57:9-10, 429-433
   CrossRef

4. 4

   Ivica Stankovic, Marija Zlatkovic, Dragan Prokic, Pavle Plamenac. (2002) Histologic variant form of autoimmune hepatitis with prominent zonal necrosis. Srpski arhiv za celokupno lekarstvo 130:3-4, 103-106
   CrossRef