Correspondence

How to Diagnose Autoimmune Hepatitis in Systemic Lupus Erythematosus?

TABLE 2. Diagnosis of AIH in Our
To the Editor: Patient According to
Systemic lupus erythematosus (SLE) is an autoim- Scoring System
mune disorder affecting multiple organs, including the Required parameters Score*
liver; the co-occurrence of autoimmune hepatitis (AIH)
and SLE is considered to be rare.1,2 The International Female /2
Ratio of serum alkaline phosphatase to aminotransferase
Autoimmune Hepatitis Group has recently presented activities (IU/L) õ3.0 /2
a scoring system for the diagnosis of AIH,3 which may Total serum globulin, gammaglobulin, or IgG: times upper
serve as a tool to differentiate between SLE-associated limit Å 1.0-1.5 /1
hepatitis and AIH in SLE. Based on these defined crite- Autoantibodies (titers ANA/SMA/LKM-1); adults ú1:80;
ria, we considered the diagnosis of AIH in a patient children ú1:20 /3
with SLE, and discuss the value and possible refine- Seronegative for markers hepatitis A, B, and C /3
ment of the scoring system for AIH in autoimmune No recent history of hepatotoxic drug usage or parenteral
diseases with hepatic involvement. exposure to blood products /1
Case report. A 20-year-old woman presented with a Average alcohol consumption õ25 g/day /2
Other autoimmune disease in patient /1
3-week history of fatigue, malaise, myalgias, episodic
fever, and weight loss (6 kg). Complaints of alopecia, Additional parameters
arthralgias, and a positive Raynaud’s phenomenon al- Complete response to therapy /2
ready existed, with pigmented macules successively
Total aggregate score†
arising on the palms, soles, and face. There was no Before treatment 15
history of recent hepatotoxic drug usage or parenteral After treatment 17
exposure to blood products. No family history of liver
disease existed. Abbreviations: IgG, immunoglobulin G; ANA, antinuclear anti-
On physical examination, her temperature was body; SMA, smooth-muscle antibody; LKM-1, liver and kidney micro-
407C. Pigmented macules and erythematous lesions some antibodies.
* Scoring system for AIH recently defined by the International
were prominent on the hands, feet, and nose. Fur- Autoimmune Hepatitis Group.3
ther examination revealed no joint swelling, and † Interpretation of scores before and after treatment: before, ú15;
neither hepatomegaly nor stigmata of chronic liver after, ú17; definite AIH; before, 10-15; after 12-17; probable AIH.
disease.
We considered the diagnosis of AIH in view of raised
serum aminotransferases, hypergammaglobulinemia,
antinuclear antibodies (titer: 1:10,240), seronegativity
TABLE 1. Laboratory Data of markers for viral hepatitis, and absence of hepato-
Before During toxic drug usage (Tables 1 and 2). The diagnosis of AIH
Treatment Treatment Normal Values was supported by using the scoring system mentioned
ESR (mm/h) 74 12 õ10 above and the excellent response to treatment with
Hemoglobin (mmol/L) 6.5 7.9 7.3-9.3 prednisone. Liver histology, however, showed no char-
Leukocyte count (1109/L) 2.3 5.9 4.0-10.0 acteristic features of AIH, especially no piecemeal ne-
Total bilirubin ( mmol/L) 16 8 4-14 crosis or rosetting of liver cells (Fig. 1). The specimen
Alkaline phosphatase 106 50 25-75 had been obtained by percutaneous liver biopsy and
(U/L) measured 12 mm 1 2 mm 1 2 mm, containing nine
g-glutamyl 138 29 5-35 portal tracts.
transpeptidase (U/L)
Discussion. A patient is described with active SLE4
AST (U/L) 293 21 5-30
and hepatic involvement without characteristic histo-
ALT (U/L) 84 21 5-30
LDH (U/L) 1,463 274 160-320 logical findings for AIH. Nevertheless, AIH could be
Complement C3 (g/L) 0.37 0.79 0.80-1.60 considered very probable by using the scoring system
Complement C4 (g/L) õ0.08 0.08 0.15-0.40 for this diagnosis.3 The absence of piecemeal necrosis
Total complement (U/mL) 71 239 101-300 and the rosetting of liver cells in the present case, how-
IgG (g/L) 24.8 19.7 8.0-18.0 ever, point to SLE-associated hepatitis rather than to
ANA titer 1:10, 240 early detection of AIH. Therefore, in the AIH scoring
Anti-Sm/SS-A/RNP positive system, more importance should be given to histologi-
Abbreviations: ESR, erythrocyte sedimentation rate; AST, aspar- cal findings to differentiate between AIH and other (au-
tate transaminase; ALT, alanine transaminase; LDH, lactic dehy- toimmune) causes of liver disease, such as SLE-associ-
drogenase; IgG, immunoglobulin G; ANA, antinuclear antibody; ated hepatitis. We think that the diagnosis of AIH
Anti-Sm, anti-Smith antibodies; SS-A, anti-Sjogren Syndrome-A an- cannot be characterized as ‘‘definite’’ by the currently
tibodies; RNP, anti-ribonucleoprotein antibodies. proposed diagnostic scheme without the histology de-

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HEPATOLOGY Vol. 23, No. 4, 1996
FIG. 1. Liver biopsy specimen shows only a limited portal infil-
trate (open arrow) and isolated degeneration of hepatocytes (solid
arrow) in a patient with SLE.
fined as showing moderate or severe activity with
piecemeal necrosis. In this respect, further refinement
of the scoring system for AIH appears desirable.
ADRIAAN KOOY, M.D., Ph.D.
Department of Internal Medicine
Bethesda Hospital
Hoogeveen, The Netherlands
How to Diagnose Autoimmune Hepatitis in Systemic Lupus Erythematosus?
Reply:
The provisional criteria for diagnosis of autoim-
mune hepatitis (AIH) proposed by the International
Autoimmune Hepatitis Group in 19931 comprised a
set of descriptive criteria to define patients as having
‘‘definite’’ or ‘‘probable’’ AIH, and a scoring system to
be used mainly as an adjunct to the descriptive crite-
ria either for difficult cases or where a more objective
assessment is required. The scoring system was
based on retrospective analysis of large numbers of
patients with various chronic liver diseases, and the
points allocated for each feature (and cutoffs for in-
terpretation of aggregate scores) were determined by
trial-and-error; however, it was recognized that the
system would require validation by prospective eval-
uation and will undoubtedly undergo refinements as
experience with its use accumulates. In this regard,
the letter from Dr. Kooy et al. is a welcome contribu-
tion.
The scores obtained by their patient with systemic
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CORRESPONDENCE 937
LOEK J. M. DE HEIDE, M.D.
Department of Internal Medicine
Medical Center Leeuwarden
Leeuwarden, The Netherlands
HERMAN J. H. ENGELKENS, M.D., Ph.D.
Department of Dermatology
ANDRIES H. MULDER, M.D., Ph.D.
Department of Clinical Pathology
MARTIN VAN HAGEN, M.D., Ph.D.
Department of Immunology
SOLKO W. SCHALM, M.D., Ph.D.
Department of Hepatology
University Hospital Rotterdam
Rotterdam, The Netherlands
REFERENCES
1. Matsumoto T, Yoshimine T, Shimouchi K, Shiotu H, Kuwabara
N, Fukada Y, Hoshi T. The liver in systemic lupus erythematosus:
pathologic analysis of 52 cases and review of Japanese autopsy
registry data. Hum Pathol 1992;23:1151-1158.
2. Hall S, Czaja AJ, Kaufman DK, Markowitz H, Ginsburg WW.
How lupoid is lupoid hepatitis? J Rheumatol 1986;13:95-98.
3. Johnson PJ, McFarlane IG. Meeting Report: International Auto-
immune Hepatitis Group. HEPATOLOGY 1993;18:998-1005.
4. Tan EN, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield
NF, Schaller JG, et al. The 1982 revised criteria for the classifica-
tion of systemic lupus erythematosus. Arthritis Rheum
1982;25:1271-1277.
lupus erythematosus (SLE) are at the upper limit of
the ranges suggested for the diagnosis of ‘‘probable’’
AIH. However, the patient’s liver biopsy showed no
evidence of the periportal hepatitis with a predomi-
nantly lymphoplasmacytic infiltrate that is consid-
ered characteristic (although not pathognomonic) of
AIH.1 This would have excluded a diagnosis of AIH on
the basis of the descriptive criteria,1 and, normally,
there would have been no need to apply the scoring
system.
Nevertheless, their letter does raise several im-
portant points. The relatively high scores of 15 and
17 (before and after treatment, respectively) in their
patient are due partly to the International Autoim-
mune Hepatitis Group’s attempt to cover every even-
tuality by assigning positive scores for the absence
of a history of recent hepatotoxic drug usage or paren-
teral exposure to blood products, and for low alcohol
consumption; these may need to be adjusted. Second,
the system specifies a score of 03 for histological fea-
tures suggestive of a different etiology.1 This proba-
bly should also apply to cases (such as the present
WBS: Hepatology
938 CORRESPONDENCE
one) with no specific morphological features to sug-
gest the etiology of the liver disease. This would re-
duce the above scores to 12 and 14, respectively, and
increase doubt about a diagnosis of AIH. Most impor-
tantly, their observations highlight the need for liver
histology in making the diagnosis, which was
stressed by the International Autoimmune Hepatitis
Group.1
Subcutaneous Octreotide for the Prevention of Early Variceal Rebleeding
To the Editor:
We read with interest the article by Primignani et
al.1 on the use of octreotide to prevent early rebleeding
in patients undergoing endoscopic sclerotherapy of
esophageal varices. The authors did not demonstrate
any beneficial effect of subcutaneous injections of oc-
treotide (100 mg three times a day) given during the 29
days after variceal bleeding. However, the dose used
should be seriously questioned. In a previous study,2
we indeed observed early rebleeding when octreotide
was given subcutaneously (100 mg at 12 and 18 hours)
after a 12-hour intravenous infusion. As stated by
Primignani et al.,1 few studies deal with portal hemo-
dynamic effects of such a drug regimen, and pharmaco-
kinetic data are not available in cirrhotic cases. Herein
we report the results of a pharmacokinetic study com-
paring plasma octreotide levels obtained after intrave-
nous infusion and subcutaneous injection in patients
with cirrhosis.
Informed consent was obtained from all patients. The
study protocol was approved by our institution’s human
research review committee.
FIG. 1. Plasma octreotide concentrations obtained in six cirrhotic
patients after 500-mg subcutaneous injection (curves) and 25-mg/h
intravenous infusion (horizontal line corresponding to mean steady-
state concentration derived from mean plasma concentration ob-
tained at 16 hours).
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HEPATOLOGY April 1996
IAN G. MCFARLANE, D. SC. MED.
Institute of Liver Studies
King’s College Hospital
Denmark Hill
London, England
REFERENCE
1. Johnson PJ, McFarlane IG. Meeting Report: International Auto-
immune Hepatitis Group. HEPATOLOGY 1993;18:998-1005.
Six male patients (Pugh’s grade A Å 2, B Å 2, C Å 2)
with alcoholic cirrhosis received a 25-mg/h intravenous
infusion of octreotide for acute variceal bleeding.
Plasma octreotide concentrations were measured at 12
and 16 hours after infusion. Intravenous infusion was
then stopped during a 24-hour washout period, after
which the patient received a 500-mg subcutaneous oc-
treotide injection. Plasma octreotide concentrations
were measured at 0, 1.5, 8, and 14 hours after dosing.
Plasma octreotide concentrations were determined by
radioimmunoassay (Sandoz Laboratory, Rueil Malmai-
son, France). Data are shown in Fig. 1. Mean plasma
concentrations obtained at 12 and 16 hours after intra-
venous infusion were 5,212 pg/mL (range, 3,095-8,361
pg/mL) and 4,622 pg/mL (range, 3,112-7,858 pg/mL), re-
spectively, the latter representing steady-state octreo-
tide concentration. In most patients, plasma octreotide
concentrations remained above steady-state octreotide
concentrations for the first 8 hours. The main pharmaco-
kinetic parameters extrapolated from plasma octreotide
concentrations were: the mean half-life was 5.08 hours
(range, 2.94-6.97 hours), the mean total clearance/abso-
lute availability was 4.9 L/h (range, 4.0-6.2 L/h), and
the mean volume of distribution at steady state was 34
L (range, 23-45 L). Assuming that a linear pharmacoki-
netic model could be applied to octreotide, theoretical
mean plasma octreotide concentrations after 100- and
200-mg subcutaneous injections would be 2,610 and
5,221 pg/mL at 90 minutes, respectively (921 and 1,842
pg/mL at 8 hours, respectively).
Few pharmacodynamic studies using subcutaneous
octreotide have previously been reported. Octreotide
(200 mg) blunted the increase of the hepatic venous
gradient normally observed after ingestion of a meal;
however, this study was limited to the first 60 minutes
after dosing.3 Navasa et al.,4 using the same dose,
showed that the beneficial effects on portal and collat-
eral blood flows persisted for 60 minutes and gradually
returned toward control values at 180 minutes. Assum-
ing that a 25-mg/h intravenous infusion is the minimal
dose required to control variceal bleeding, our results
suggest that 100 mg, and even 200 mg, of subcutaneous
octreotide would have limited effects lasting less than
2 hours. The optimal dose should be 500 mg every 8
hours to obtain plasma octreotide concentrations above
those obtained with intravenous infusion. In our opin-
WBS: Hepatology