Corticosteroid therapy of alcoholic hepatitis

001&5085/78/7502-0193$02.00/O

Vol. 75, No. 2

GASTROENTEROL~GY 75:193-199, 1978 Copyright 0 1978 by the AmericanGastroenterological Association

CORTICOSTEROID

THERAPY

Printed in U.S.A.

OF ALCOHOLIC

WILLIS C. MADDREY, M.D.,

HEPATITIS

JOHN K. BOITNOTT, M.D.,

FREDRICK L. WEBER, JR., M.D.,

MARSHALL S. BEDINE, M.D.,

ESTEBAN MEZEY, M.D.,

AND

ROBERT I. WHITE, JR., M.D. Departments of Medicine, Pathology and Radiology, The Johns Hopkins Hospital, Baltimore, Maryland

The Johns Hopkins University School of Medicine, and

Fifty-five patients with alcoholic hepatitis were studied in a 2% to 32-day randomized double blind treatment trial comparing prednisolone (40 mg per day) with placebo therapy. Of 31 placebo-treated patients, 4 died during the study interval and 2 more died within 5 days of study completion. Only 1 of 24 prednisolone-treated patients died during the same interval (Fisher exact test; P = 0.10). Stepwise discriminant analysis of laboratory factors associated with death revealed independently significant associations with prolongation of prothrombin time and height of serum bilirubin at the initiation of the study. When treatment was included as a variable in this discriminant analysis, it was found that corticosteroid therapy significantly decreased mortality (P < 0.05). The corrected wedged hepatic venous pressure decreased to a similar extent in the two groups. These studies suggest that corticosteroid therapy does decrease early mortality in patients with severe alcoholic hepatitis, but has no short term effect on the development of portal hypertension. Alcoholic hepatitis is an important clinical entity associated with a significant early mortality and with the subsequent development of cirrhosis in survivors. l, 2 Conventional management emphasizes abstinence from alcohol, correction of dietary deficiencies, and general supportive care. The inflammatory component to the hepatic injury and the possible role of immunological factors in its perpetuation have suggested that corticosteroid therapy might be of benefit in reducing initial mortality and subsequent progression to cirrhosis.3 Reported trials comparing corticosteroid to placebo therapy have been inconclusive, with some investigators reporting improved survival, whereas others found either no ‘effect or even an increased mortality.4-13Part of the discrepancy in results may reflect differing criteria for inclusion, with some series weighted toward less severely ill patients but others include many with such advanced disease that treatment stood little chance of success. To study this problem further, we initiated a randomized double blind trial of prednisolone versus placebo therapy in patients with moderate to severe alcoholic hepatitis. Our major objectives were to define Received December 8, 1977. Accepted March 4, 1978. Address requests for reprints to: Willis C. Maddrey, M.D., Associate Professor of Medicine, The Johns Hopkins Hospital, 601 North Broadway, Baltimore, Maryland 21205. This study was supported by Research Grant AA00201 from the National Institute of Alcohol Abuse and Alcoholism of the National Institutes of Health, and by Grant RR-35 from the Clinical Research Centers Program, United States Public Health Service. The authors wish to acknowledge the expert technical assistance provided by Mr. David Schaefer, Ms. Victoria Frazier, and Ms. Christine Comely.

factors important in determining outcome in alcoholic hepatitis and to evaluate further the effects of corticosteroid therapy on early mortality and on the progression to cirrhosis, as reflected by histological changes and wedged hepatic venous pressure. Materials and Methods Patientselection. Patients admittedto The Johns Hopkins Hospitalwith a historyof long-standingand recentalcoholism who were referred to the Liver Service were evaluated by the

Principal Investigator within 5 days of admission. The protocol was explained to candidate patients and their families and informed consent was obtained. Sixty-four patients met the criteria for admission to the study. Seven patients declined to enter the study and were not evaluated further. Patients with active gastrointestinal hemorrhage, pancreatitis, history of peptic ulcer disease, active infection, presence of hepatitis B antigen (HBsAg), or history of previous viral hepatitis were excluded. A percutaneous liver biopsy was performed unless precluded by coagulation abnormalities (prothrombin time > 3.5 set over control or platelets less than 75,000 per mm3). Alcoholic hepatitis was defined histologically as an inflammatory hepatic disease with cell swelling and hydropic change, cell necrosis, and polymorphonuclear leukocytic infiltration. The presence of Mallory’s alcoholic hyaline, although supportive of the diagnosis, was not required. Patients with clinical and laboratory manifestations suggesting severe alcoholic hepatitis with clotting abnormalities that prevented liver biopsy entered the study in a separate group (group C below). The investigations from entrance into the study were carried out on the Osler 5 Clinical Research Unit (52 patients) or on the general medical units under the direction of the Principal Investigator (3 patients). Treatment regimens. All patients were offered a 3000 calorie diet. Protein (1 to 1.5 g per kg) was provided for patients with no evidence of hepatic encephalopathy. Protein restric193

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tion to 20 g per day or less and lactulose therapy were

instituted in patients with signs of hepatic encephalopathy. Ascites was managed with sodium restriction alone or with the addition of spironolactone in those who did not respond with diuresis in 5 days. All patients initially received 100 mg of thiamine intramuscularly. B-complex multivitamins and folic acid (1 mg) were given each day. Randomization procedures. The study was conducted in a randomized double blind fashion. Patients were randomized for treatment within three groups based on apparent severity of disease. Group A (moderately ill), serum bilirubin > 3 mg per dl; hepatomegaly; and clotting factors adequate to allow liver biopsy. Group B (more severely ill), hyperbilirubinemia and hepatomegaly as in A with additional presence of ascites and/or hepatic encephalopathy, but coagulation studies adequate for liver biopsy. Group C (severely ill), hyperbilirubinemia and hepatomegaly as in A and B, with or without ascites and/or hepatic encephalopathy, but coagulation abnormalities precluded liver biopsy. Random drug sequences were arranged within each group. Prednisolone (5 mg) or identical placebo tablets were given in a single dose of 8 pills each morning for 28 to 32 days. (Prednisolone (5 mg) and identical placebo tablets were provided by the Division of Steroid Research, The Upjohn Company, Kalamazoo, Mich.) The investigators were not aware of which regimen the patient was receiving until the completion of the study.

Procedures and Methods After acceptance into the study and before initiation of treatment, all patients had biochemical and hematological tests, urinalysis, determination of stool guaiac, and determination of HBsAg. In addition, all had hepatic venous catheterization with determination of wedged hepatic venous pressure, free hepatic venous pressure, and inferior vena cava pressure.14

Results Patients studied. Fifty-five patients with alcoholic hepatitis have completed the study. No patient withdrew and all who survived completed 28 to 32 days of therapy with prednisolone (40 mg per day) or placebo. Two additional patients were removed from the study after randomization. One patient who was randomized to the placebo group bled from esophageal varices before receiving the study drug. He subsequently stopped bleeding and survived. Another patient had an episode of upper gastrointestinal hemorrhage presumably from esophageal varices after receiving prednisolone for 9 days and the drug was stopped. This patient subsequently survived but has not been included in analysis because the study drug was discontinued. In table 1 are presented the data regarding the age, sex, historical features, and clinical findings for the combined groups.

The 24 prednisolone- and 31 placebo-treated patients were similar in age, physical findings related to liver disease, and mean hospital days before study onset. The prednisolone-treated group did include proportionately more females and fewer patients with hepatic encephalopathy at initiation of the study, but these differences did not achieve statistical significance. Results of the initial laboratory studies are included in tables 2 and 3. The prednisolone-treated patients did have a higher white blood cell count (P < 0.01) and lower mean

corrected wedged hepatic venous pressure than did the placebo-treated patients (P < 0.05).

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TABLE1. Clinical features of 55 patients with alcoholic hepatitis Preclnisolone Placebo therapy therapy No. of patients Sex Male Female Mean age (yrs) Mean hospital days before onset of study Spiders Palmar erythema Fever more than 100°F Fever more than 102°F Hepatic tenderness Ascites Encephalopathy with asterixis Splenomegaly Clinical groups A I3 C

24 12 12 40.0 2 8.5 SD” 8.8 ? 2.6 SD

31 23 8 42.3 + 11.1 SD 9.5 k 2.1 SD

50% 50% 70% 20% 79% 67% 21%

35% 29% 77% 16% 77% 58% 32%

17%

27%

7W 4 (3) 13 (7)

8 (7) 5 (4) 18 (12)

” SD,standard deviation. b Numbers in parentheses, number of males.

Survival. Of 31 placebo-treated patients, 4 died during the study period and 2 more who were mortally ill at the termination of the study died within 5 days of completion. All died of hepatic failure with terminal coma and hepatorenal syndrome. Only 1 of 24 corticosteroid-treated patients died during the same time interval (Fisher exact test; P = 0.10). All deaths occurred

in the group C (severely ill) patients. Six of 18 placebotreated (group C) patients died (33%) compared to 1 of

13 in the (group C) corticosteroid-treated group (8 %) (Fisher exact test; P = 0.10). Furthermore, all patients

who died had hepatic encephalopathy with asterixis upon admission to the study. Of patients with hepatic encephalopathy, 6 of 10 in the placebo-treated group died as compared to 1 of 5 in the prednisolone-treated group (Fisher exact test; P = 0.18). Two additional corticosteroid-treated patients died during the hospitalization (26 and 48 days after completion of the study). Both died of hepatic failure and hepatorenal syndrome and in one, complicating infections were found at autopsy (see below). Complications of therapy. Of the 24 patients receiving prednisolone, 3 developed diabetes mellitus, requiring insulin. In no patient was there continued need for insulin once the corticosteroids were discontinued after the study. There were no instances of diabetes in the placebo group. No patient developed an infection during the study. One patient died of hepatic failure 26 days after the completion of the study and was found at postmortem examination to have pulmonary cytomegalic inclusion disease, Pneumocystis carinii pneumonia, and monilial esophagitis. No patient receiving either treatment developed psychosis. Liver function and hematological tests (table 2). The

results of selected liver, renal, and hematological tests before and after therapy for the two treatments are presented in table 2. Differences between treatment

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TABLE 2. Laboratory

CS Globulin (mgidl) PL cs Renal function Serum urea nitrogen (mg/dl) PL cs Serum creatinine tmg/dl) PL cs Hematological tests Hematocrit (%‘o) PL cs WBC ( x 103/mm3) PL cs Platelets (X 103/mm”) PL cs Prothrombin time (set) PL cs

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features in 55 patients with alcoholic hepatitis” Adjusted A at 4 wk’ -

Values at 4 weeks

Onset of study

Tests”

________~ -__. Liver function Total bilirubin (mg/dl) PL CS SGOT (III/liter) PL cs SGPT (IU/liter) PL CS Alkaline phosphatase tIU/liter) PL cs Albumin (mg/dl) PL

THERAPY

SEM ~-

N

SEM

___

N

Mean

SEM

11.2 11.8

1.8 2.2

31 24

3.9 3.8

1.2 1.4

27 23

-5.8 -7.7

0.7 0.8

15.3 73.9

5.8 8.2

31 24

41.7 34.5

4.1 4.0

27 23

-32.4 -39.7

3.8 4.1

24.8 22.0

3.6 5.1

31 24

19.4 29.7

1.6 4.8

27 23

-5.2 +5.9

83.4 79.4

8.0 7.1

31 24

60.7 60.4

5.6 6.4

27 23

-22.8 -22.6

5.8 6.3

2.4 2.6

0.2 0.2

31 24

3.0 3.3

0.2 0.2

27 23

+0.5 10.7

0.2 0.2

4.2 4.2

0.2 0.2

31 24

3.9 3.3

0.2 0.2

27 23

-0.2 -0.9

0.1’ 0.1

15.4 16.5

3.5 3.1

31 24

15.2 17.2

3.2 2.2

27 23

+3.3 +3.1

2.4 2.6

1.6 1.2

0.3 0.2

29 22

1.4 1.0

0.3 0.1

27 23

+0.2 -0.2

0.2 0.2

28.6 29.8

1.1 1.2

31 24

30.4 32.4

1.1 1.5

27 23

+1.5 i2.7

1.0 1.0

9.9 13.7

0.8 1.3

31 24

7.6 12.3

0.7 0.6

27 23

-3.2 +0.1

0.6’ 0.6

225 231 15.8 15.5

29 23 0.7 0.7

31 24 31 24

201 225 15.5 14.0

24 15 0.9 0.5

27 23 27 23

-39 -12 +0.5 -1.0

3.1” 3.4

17 18 0.6 0.6

’ Abbreviations are: PL, placebo; CS, corticosteroid; SEM, standard error of the mean; N, number of patients. h Normal laboratory values: total bilirubin 0.3 to 1.1 mg per dl; SGOT 0 to 19 IU per liter; SGPT 0 to 17 IU per liter; alkaline phosphatase 10 to 32 IU per liter; albumin 3.5 to 5.5 g per dl; globulin 2.6 to 3.1 g per dl; serum urea nitrogen 8 to 23 mg per dl; serum creatinine 0.7 to 1.5 mg per dl; hematocrit 40 to 54% (males), 37 to 47% (females); WBC 5,000 to 10,000 per mm3; platelet count 150,000 to 300,000 per mm3; prothrombin time 11.5 to 12.0 sec. c Mean change from onset values adjusted by analysis of covariance. ‘I P <. 0.05. ’P < 0.005. ’ P ‘z 0.0005.

groups were studied by analysis of covariance using the onset values for the given tests as the control value (covariant).‘” To facilitate comparison at various intervals, the data presented in figures 1 to 6 were adjusted to the common mean at onset, using the separate regression lines for the two treatments. There was a rapid decrease in serum bilirubin in both treatment groups (fig. 1). The bilirubin fell more rapidly in the prednisolone-treated group. The differences between the therapies were statistically significant at 1, 2, and 3 weeks. However, by 4 weeks the serum bilirubin levels were no longer significantly different, having returned

to normal in many patients. The prothrombin time fell in the prednisolone-treated patients (fig. 2) during the 1st week of therapy and remained lower than in the placebo-treated patients throughout the study. There was a fall of SGOT of similar magnitude in both prednisolone- and placebo-treated patients (fig. 3). The SGPT remained essentially unchanged in the placebo group but increased promptly in the prednisolone group (P < 0.0001 at 1 week) and remained significantly higher throughout the study. The alkaline phosphatase levels fell to an equal extent in both treatment groups. The serum albumin increased in both prednisolone- and

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3. Hepatic venous catheterization

studies”

Pressure readings(mmHg) at Pressure@

Onset of study

Wedged hepatic venous ( WHVP) PL cs Inferior vena cava (IVCP) PL cs Corrected WHVP (WHVP - IVCP) PL cs

Adjusted A at 4 wk’ 4 weeks

Mean

SEM

26 22

-1.8 -3.0

1.0 1.1

0.7 0.7

26 22

-0.4 -1.2

0.7 0.7

1.4 1.2

26 22

-1.8 -1.4

0.9 1.0

Mean

SEM

N

Mean

SEM

N

27.4 24.3

1.3 1.6

31 24

24.5 21.1

1.7 1.4

10.1 11.0

0.6 0.9

31 24

9.8 9.2

17.3 13.3

1.1 1.0

31 24

14.7 11.9

(1Abbreviations are: SEM, standard error of the mean; N, number of patients; PL, placebo; CS, corticosteroid. b Normal values: WHVP up to 10 mm Hg; IVCP less than 5 mm Hg; corrected WHVP less than 5 mm Hg. c Mean change from onset values adjusted by analysis of covariance. 14.0-

120-

12.0 -

IOO-

10.0 80-

Serum Bilirubin mg/dl 6.O-

1.u.

GO-

6.0404.0 -

20-

FIG. 1. Serum bilirubin at weekly intervals in prednisolone (solid line) and placebo (broken line) treated patients. In this and subse-

quent figures the values on admission and at weekly intervals after onset of therapy have been adjusted to a common onset mean (see text). Bars represent * 1 SEM.

nl ”

Admission Onset

I wok

2

weeks

3

weeks

4

woks

FIG. 3. Serum transaminases at weekly intervals for the two treatment groups.

4.0-

IB-

3.5 Prothrombin Time Seconds

Albumin

If5

g’d’

3.0 -

2.ot I”

Adrniwrm

Onset

I week

2 weeks

tdks

4 rwkr

Admission

onwt

I week

u&&s

w&s

bi&

FIG. 4. Serum albumin at weekly intervals for the two treatment

FIG. 2. Prothrombin time at weekly intervals for the two treatment groups.

groups.

placebo-treated groups (fig. 4). There were significantly greater increases in albumin in the prednisolonetreated group at 2 weeks (P < 0.05) and 3 weeks (P < 0.005). However, at 4 weeks, the differences in albumin concentrations were no longer significant. There was a

decrease in serum globulins in the prednisolone-treated patients by 3 weeks in the study (P < O.OOOl>, and this difference persisted at 4 weeks. There was no significant change in serum globulins in the placebo-treated patients. The serum urea nitrogen and significant

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cv-

Admission

FIG. 5. Hematocrit ment groups.

16 -

Onset

I

week

2 weeks

(Hct) at weekly intervals

THERAPY

3 weeks

4 weeks

for the two treat-

0

CWHVP mmHg

,4-

IL

Onset

4 weeks

FIG. 6. Changes in corrected wedged hepatic venous pressure (CWHVP) after 4 weeks of therapy adjusted to a common mean at onset.

serum creatinine were comparable in the two groups throughout the study. There was a rapid increase in hematocrit in the prednisolone-treated patients (fig. 5) which was highly significant at 2 weeks, as compared to the placebo-treated group (P < 0.0005). The hematocrit gradually increased in the placebo-treated group so that the differences at 4 weeks were no longer significant. There was an increase in white blood cell count in both groups during the 1st week of the study with the greatest increase in the prednisolone-treated patients. The white blood cell count subsequently fell with the greatest fall in the placebo-treated patients so that at 4 weeks of therapy the differences between the two groups was highly significant (P < 0.0005). There were no statistically significant differences in platelet count between the two groups throughout the study. Wedged hepatic venous pressure. In table 3 are presented the results of hepatic-venoug catheterization studies. There was a fall in wedged hepatic venous pressure and corrected wedged hepatic venous pressure in both the corticosteroid- and placebo-treated groups, and when both treatment groups are considered together, the fall is statistically significant (P < 0.05). There were no differences in the decreases in pressure with the two treatments (fig. 6). Factors associated with a fatal outcome. Statistically significant differences of clinical and laboratory features at the onset of the study between survivors and nonsurvivors included, in the nonsurvivors: more hepatic encephalopathy with asterixis (P < 0.001); more prolonged prothrombin time (P < 0.001); lower serum albumin (P < 0.01); higher total bilirubin (P < 0.001); higher serum urea nitrogen (P < 0.001); and higher serum creatinine (P < 0.05). There were no significant differences between survivors and nonsurvivors as re-

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gards age, presence of ascites, hematocrit, white blood cell count, and platelet count. The mean corrected wedged hepatic venous pressure was slightly higher among those who died (18.6 mm Hg) than in the survivors (15.1 mm Hg), but this difference was not statistically significant. It is also of note that 4 of the 7 patients who died (57 %) were females, although females comprised only 36% of the entire series. The fatality rate in females was 20% as compared to 9% in males. However, this sex difference in survival was not statistically significant. Discriminant function analysis. Stepwise discriminant analysis of laboratory tests was performed to determine those laboratory tests most associated with death. ‘;, Independently significant associations were found with prolongation of prothrombin time and the height of the serum bilirubin at the initiation of the study. All patients who died had an initial serum bilirubin of greater than 20 mg per dl or a prothrombin time of greater than 8 set over control. The discriminant function (DF) formula which best predicted survival was DF = 4.6 x prothrombin time (set) + serum bilirubin (mg per dl) (fig. 7). When treatment was considered as a variable in the discriminant analysis, its effect on mortality was found to be significant (P < 0.05). All deaths occurred in patients whose initial DF was >93; among these patients, 6 of 8 placebo-treated patients died as compared to only 1 of 7 prednisolonetreated patients (Fisher exact test; P = 0.03). There were three clinical factors which were likely to be of significance in determining outcome which were not evenly distributed between the two treatment groups sex, hepatic encephalopathy, and portal hypertension as measured by the corrected wedged hepatic venous pressure. When these factors were included as forced variables in the discriminant analysis, the effect of treatment on survival became even more highly significant (P < 0.01). 170

0

160

140 130D.F.

120 -

*

0

??

IIO100 90 8070605oA

Placebo

Predntsolone

0 = death FIG. 7. Discriminant function (D.F.) (4.6 x prothrombin time (set) + serum bilirubin (mg per dl) at onset in two treatment groups.

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MADDREY

Discussion These studies suggest that there are severely ill patients with alcoholic hepatitis in whom corticosteroid therapy decreases early mortality. Our analysis of features which characterize this subgroup indicate that a very prolonged prothrombin time and pronounced elevation of serum bilirubin were the most significant. Among our most severely ill patients with discriminant function >93 (DF = 4.6 x prothrombin time (set) + serum bilirubin (mg per dl), there was a 75% mortality in the placebo-treated patients (6 of 8) as compared to 12% in the prednisolone-treated group (1 of 8). Our results are thus in agreement with those of Helman et al.” who reported that prednisolone therapy improved survival in patients with severe alcoholic hepatitis. Eight of their 9 prednisolone-treated patients who manifested hepatic precoma or coma within the first 10 days after admission survived compared to none of 6 control patients. This group conducted a second trial in patients with alcoholic hepatitis and encephalopathy comparing prednisolone with a 1600~cal diet.13 Again, a favorable corticosteroid effect was observed, with all 7 patients given calorie supplementation alone dying as compared to only 2 of 7 prednisolone-treated patients (P < 0.01). A similar trend toward improved survival was reported by Porter et a1.6 Six of 11 patients with severe alcoholic liver disease treated with prednisolone survived as compared to only 2 of 9 in a placebo group. This difference, however, was not statistically significant. In apparent contrast, Campra et alY reported no benefit from prednisone therapy in a prospective study of 45 patients with severe alcoholic hepatitis. Mortality was 36% in the 20 prednisone-treated patients and 35% in the 25 placebo-treated patients. However, among their smaller group with hepatic encephalopathy, 8 of 10 placebo-treated patients died compared to 4 of 8 who received prednisone. Blitzer et al. I2reported no significant difference in survival in 28 patients with alcoholic hepatitis treated with prednisolone or placebo. Five of 16 (31%) died in the placebo group and 6 of 13 (50%) in the prednisolone-treated group. All of their patients were males and only 5 had encephalopathy at the onset of the study. Other studies comparing corticosteroid and placebo therapy in patients with alcoholic liver disease have used less rigid criteria for inclusion. In 1960, Wells4 reported an over-all reduction in mortality in a group of patients with alcoholic cirrhosis who received prednisolone plus adrenocorticotropic hormone. Schlichting et al.,” however, reported no difference in long term survival between patients with cirrhosis and alcoholic hepatitis treated with prednisone or placebo. In agreement with the findings of Helman et al.,j all of our patients who died did have hepatic encephalopathy at the initiation of the study and it appears reasonable to select patients for corticosteroid therapy on this basis. However, early hepatic encephalopathy may be difficult to detect in severely ill alcoholics. Our discriminant function analysis of laboratory factors suggests that a combination of initial prolongation of

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the prothrombin time and marked elevation of serum bilirubin may provide a more objective basis for selection. It should be noted that this discriminant function was based on laboratory data at the time the patient entered the study 7 to 12 days after admission to the hospital. We excluded extremely ill patients by requiring survival in the hospital for at least 5 days without evidence of gastrointestinal hemorrhage or active infection. Helman et al.” further limited inclusion into their study by requiring that the patient have a liver biopsy. The mechanisms by which corticosteroid therapy favorably affects the outcome in severely ill patients with alcoholic hepatitis are unknown. Prednisolone therapy did improve a number of laboratory values, including serum bilirubin, prothrombin time, albumin, and hematocrit. However, our analysis of liver biopsies revealed no differences in histological changes after 1 month of therapy.‘” The most effective corticosteroid compound and its dosage remain uncertain. Prednisolone was selected for our studies instead of prednisone because of the known requirement for hepatic metabolism of prednisone to the biologically active steroid prednisolone. Powell and Axelsen17 have demonstrated incomplete conversion of prednisone to prednisolone in patients with liver disease. Whether this impairment of conversion is of clinical importance in treatment is uncertain.lx We found no evidence that short term prednisolone therapy retarded the development of hepatic fibrosis and portal hypertension. ItiThere was an over-all fall in portal pressure as measured by corrected wedged hepatic venous pressure in our patients, confirming the reversibility of at least part of the portal hypertension associated with acute alcoholic hepatitis.‘s, 2o This decrease in portal pressure may reflect reduction in cell swelling attributable to fluid and fat accumulation. We believe that an over-all analysis of reported results of trials of corticosteroids versus placebo in the management of severe alcoholic hepatitis supports the use of these agents in selected severely ill patients. Such therapy is employed in the hope that it will allow survival until resolution of the acute component of the alcoholic liver disease. There is no evidence from our studies that corticosteroid therapy prevents the progression to cirrhosis or influences changes in portal pressure over those found in placebo-treated patients. Therefore, the long term prognosis in patients who survive the acute illness may not be altered. In fact, 2 of our corticosteroid-treated patients died of severe liver disease well after completion of the study without leaving the hospital. In these patients corticosteroid therapy may only have served to delay their demise. It is important to identify the subgroup of patients who might benefit. On the one hand, some patients with only mild to moderate alcoholic hepatitis are at little risk of dying acutely from their liver disease and the use of corticosteroids does not appear warranted. Our results indicate that readily available laboratory studies such as bilirubin and prothrombin time may adequately distinguish these patients from those at serious risk of dying. However, the usefulness of a

August 1978

CORTICOSTEROID

THERAPY

discriminant function based on these tests needs to be confirmed. On the other hand, there are patients who present at such an advanced stage of cirrhosis that there is scant expectation of improvement. Use of corticosteroids in these may merely increase the risk of complications. Unfortunately, there is no sure way to distinguish this group from those in whom the severe clinical illness is attributable primarily to alcoholic hepatitis. Percutaneous liver biopsy is often not possible in these patients and portal pressure measurements may be misleading, because portal pressure may be acutely elevated owing to fat accumulation and hepatocellular swelling. REFERENCES 1 Schaffner FM, Popper H: Alcoholic hepatitis in the spectrum of ethanol-induced liver injury. Stand J Gastroenterol7 (suppl1:6978, 1970 2 Galambos JT: Alcoholic hepatitis: its therapy and prognosis. In Progress in Liver Disease, vol. IV. Edited by H Popper, FM Schaffner. New York, Grune & Stratton, 1972, p 567-588 3. Leevy CM, Zetterman R, Smith F: Newer approaches to treatment of liver disease in the alcoholic. Ann NY Acad Sci 252:135144. 1975 4. Wells R: Prednisolone and testosterone propionate in cirrhosis of the liver. A controlled trial. Lancet 2:1416-1419, 1960 5. Helman RA, Temko MH, Nye SW, et al: Alcoholic hepatitis: natural history and evaluation of prednisolone therapy. Ann Intern Med 74:311-321, 1971 6. Porter HP, Simon FR, Pope CE II, et al: Corticosteroid therapy in severe alcoholic hepatitis, A double-blind drug trial. N Engl J Med 284:1350-1355, 1971 7. Davidson CS: Alcoholic hepatitis. N Engl J Med 284:1378, 1971 8. Reynolds TB, Edmondson HA: Alcoholic hepatitis. Ann Intern

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Med 74:440-442, 1971 9. Campra JL, Hamlin EM Jr, Kirshbaum RJ. et al: Prednisone therapy of acute alcoholic hepatitis. Report of a controlled trial. Ann Intern Med 79:625-631, 1973 10. Isselbacher KJ: Metabolic and hepatic effects of alcohol. N Engl J Med 296:612-616, 1977 11. Schlichting P, Juhl E, Poulsen H, et al: Alcoholic hepatitis superimposed on cirrhosis. Clinical significance and effect of long-term prednisone treatment. Stand J Gastroenterol 11:305312, 1976 12. Blitzer BL, Mutchnick MG, Joshi PH, et al: Adrenocorticosteroid therapy in alcoholic hepatitis. Am J Dig Dis 22:477-484, 1977 13. Lesesne HR, Bozymski EM, Fallon HJ: Treatment of alcoholic hepatitis with encephalopathy: comparison of prednisolone with caloric supplements. Gastroenterology 74:169-173, 1978 14. Miller FJ, Maddrey WC, Sheff RN, et al: Hepatic venography and hemodynamics in patients with alcoholic hepatitis. Radiology 115313-317, 1975 15. Armitage P: Statistical Methods in Medical Research. New York, John Wiley & Sons, 1971 16. Boitnott JK, Maddrey WC: Histologic correlations in alcoholic liver disease (abstr). Lab Invest 34:309, 1976 17. Powell LW, Axelsen E: Corticosteroids in liver disease: studies on the biological conversion of prednisone to prednisolone and plasma protein binding. Gut 13:690-696, 1972 18. Schalm SW, Summerskill WHJ, Go VLW: Development of radioimmunoassays for prednisone and prednisolone. Application to studies of hepatic metabolism of prednisone. Mayo Clin Proc 51:761-766, 1976 19. Leevy CM, Zinke M, Baber J, et al: Observations on influence of medical therapy on portal hypertension in hepatic cirrhosis, Ann Intern Med 49837-851, 1958 20. Reynolds TB, Geller HM, Kuzma OT, et al: Spontaneous decrease in portal pressure with clinical improvement in cirrhosis. N Engl J Med 263:734-739, 1960