Nonalcoholic steatohepatitis: An expanded clinical entity

GASTROENTEROLOGY 1994;107:llO3-1109

Nonalcoholic Steatohepatitis: An Expanded Clinical Entity BRUCE R. BACON,* MOHAMMAD J. FARAHVASH,* and BRENT A. NEUSCHWANDER-TETRI*

CHRISTINE

G. JANNEY,?

*Division of Gastroenterology and Hepatology, Department of Internal Medicine, and ‘Department of Medicine, St. Louis, Missouri

Background/Aims: In the past, nonalcoholic steatohep atitis has been described mostly in obese women with diabetes. The aim of this study was to describe a series of patients with nonalcoholic steatohepatitis with a different clinical profile. Methods: The clinical, biochemical, and histological features of 33 patients with nonalcoholic steatohepatitis seen from July 1990 to June 1993 were analyzed. Results: The mean age was 47 years. All patients were antibody to hepatitis C virusnegative. Nineteen of 33 (58%) were men, 20 of 33 (61%) were nonobese, 26 of 33 (79%) had normal glucose levels, and 26 of 33 (79%) had normal lipid levels. Fourteen of 33 (42%) had normal glucose and lipid levels and were not obese. Thirteen of 33 (39%) had pathological increases in fibrosis, 5 of whom had micronodular cirrhosis. Of these 13 with severe, progressive disease, 8 (62%) were women, 8 (62%) were obese, 4 (31%) were diabetic or had an elevated glucose level, and 3 (23%) had hyperlipidemia. Although serum iron studies (transferrin saturation and ferritin) were abnormal in 18 of 31(58%), no patient had hemochromatosis. Conclusions: Nonalcoholic steatohepatitis can be a severe, progressive liver disease leading to the development of cirrhosis. It should no longer be considered a disease predominantly seen in obese women with diabetes.

of these other conditions, acterized

a “typical”

or without other

overt

medical

roidism,

ingly

recognized

alcoholic and

the description

holic steatohepatitis clinical

Laennec’s,

diabetic

hepatitis)

by Ludwig

(NASH) entity.

fatty

Several

liver

have

et al,’ nonalco-

has become hepatitis,

been

other

an increasterms

(non-

steatonecrosis,

used to describe

this

condition,2m5 but NASH is the term most frequently used today. Diagnosis is confirmed by liver biopsy specimens in which macrovesicular steatosis and parenchymal inflammation with or without fibrosis, cirrhosis, and Mallory bodies are shown in the absence of a history of excessive ethanol ingestion.“6’7 Several series of patients with NASH have included individuals receiving various medications, including corticosteroids, patients after jejunoileal bypass, patients who were morbidly obese, or patients who had other medical conditions known to be associated with hepatic steatosis.‘-’ After excluding some

and/or (e.g.,

as a middle(with

hyperlipidemia

hypertension,

with

hypothy-

artery disease) often requiring

medications.‘.“-”

as clinically hepatic

NASH

The condition

use

has been

mild with little progression.798 Al-

steatosis

is now recognized

to be a com-

mon histological finding in hepatitis C infection,“’ none of the earlier series of patients with NASH have excluded hepatitis

C virus serologically.

During

from July 1990 to June

a 3-year period,

we have seen and cared for 33 patients ologic

diagnosis

of NASH.

clinical

profile considerably

before

has been observed.

women,

and obesity,

1993,

with a clinicopath-

In this series of patients, different There

diabetes,

a

than that described

were more

men

and hyperlipidemia

than were

not prominent features, serving to expand the previously narrow spectrum of this clinical entity.

Materials and Methods Patients From July 1990 to June NASH

versince

diabetes)

and coronary

though

with

have char-

who often has hyperglycemia

conditions

of long-term described

more recent studies

patient

aged, obese woman

of the authors

E

of Pathology, St. Louis University School

(B.R.B.)

were reviewed.

ingestion

was provided

Evidence

Patients

at time of presentation,

phyhis-

(2 20 g ethanol/

from this series. Age, sex, height,

of ideal body weight,

of

and confir-

with a questionable

to excessive ethanol ingestion

day) were excluded calculation

with the primary

at the time of referral,

by family members.

tory of moderate

seen by one diagnosis

for a lack of excessive alcohol

by consultation

sician, careful questioning mation

1993, all patients

with a clinicopathologic

weight,

reason for refetral, symptoms

other medical

problems,

and medica-

tions were all documented.

Laboratory Laboratory and included

Evaluation

studies wete obtained

at the time of referral

serum liver tests (alanine aminotransfetase,

aspat-

Abbreviations used in this paper: NASH, nonalcoholic steatohepa titis. 0 1994 by the American Gastroenterological Association OOIG-5085/94/$3.00

1104

GASTROENTEROLOGY Vol. 107, No. 4

BACON ET AL.

tate aminotransferase, bumin,

alkaline phosphatase,

and total protein

(hepatitis

B surface antigen,

antigen,

antibody C virus),

antibody,

antinuclear

metabolism

iron,

glucose,

obtained. clinical

phosphate,

cholesterol,

transferrin

All laboratory

of iron

saturation,

and a,-antitrypsin

and levels.

urea nitrogen,

and triglyceride

additional referred

of abnormal

creati-

pain,

fatigue,

tension,

Liver Biopsy

had had a percutaneous

for cholecystec-

7 years earlier, and another biopsy performed

were fixed in formalin,

with H&E for routine

blue for storage

had a

also had a wedge biopsy performed

time of a cholecystectomy

and stained

percutaneous

One patient

at the time of laparotomy

tomy. One patient

opsy specimens

underwent

as an outpatient.

at the patient

4 years earlier.

embedded

Bi-

in paraffin,

histology,

Perls’ Prussian

trichrome

for connective

iron, and Masson’s

tissue. Five patients

were referred

hemochromatosis, iron

studies

>55%).

for consideration

and an additional

(elevated

ferritin

of nonheme chromatosis performed

and in five additional

of Torrance

patients.

laboratory.

and Bothwell.”

iron concentrations

transferrin

saturation

determination

being evaluated

were dried in

and assayed using the

Normal

in our laboratory

for hemo-

This analysis was

Samples

an oven at 70°C for 24 hours, weighed, method

had abnormal

for biochemical

iron in all five patients in our research

of hereditary

13 patients

and/or

Tissue was submitted

hepatic

nonheme

are < 1500 pg/g

(dry

weight). Liver biopsy samples were evaluated (C.G.J.)

without

findings.

Histological

the presence without

knowledge criteria

Qualitative methodology

of the clinical

or biochemical

in this study were

of fatty change and lobular inflammation

hepatocyte

The grading

by a single pathologist

for inclusion

necrosis,

regimen hepatic

Mallory’s

described

hyaline,

by Diehl

iron determinations

that we have previously

upper quadrant

malaise).

(36%)

patients

to liver disease abdominal

Twenty-one

(64%)

were

were being treated for hyper-

2 for hypothyroidism,

and 1 for

(type IV). Six had prior cholecystectomy.

with or

and fibrosis.

liver

enzymes

aminotransferase, and albumin

aspartate

alanine

phosphatase),

bil-

aminotransferase

and/or

The aspartate

amino-

level.

aminotransferase

Two of the three

aminotransferase/alanine

ratio was < 1 .O in 30

patients

with

aminotransferase

found to have cirrhosis

on biopsy.

with normal aminotransferase bilirubin

aminotransferase,

are shown in Table 1. Thirty patients

aminotransferase

transferase/alanine patients.

(alanine

and alkaline

(91%) had an abnormal

level (caused

an aspartate ratio > 1 were

Of the three patients

levels, one had an elevated

by Gilbert’s

syndrome)

and an

elevated ‘y-glutamyl transpeptidase level, and two had an elevated alkaline phosphatase level and had been referred for evaluation

for hemochromatosis.

rant ultrasonography

was negative

ties in all three patients.

Right

upper

quad-

for biliary abnormali-

Two patients

had an elevated

transferrin saturation, and 17 of 31 (55%) had elevated ferritin levels (Table 2). All patients

were negative

virus and hepatitis antibody Two

patients

to hepatitis

One patient

B core antigen-positive,

to hepatitis had positive

2 1:16O; in both,

for antibody

B surface antigen.

to hepatitis

were antibody

C was

and two

B surface antigen-positive. antinuclear

antibody

a brief trial of corticosteroid

titers therapy

was ineffective in reducing serum aminotransferase levels. Only two patients had low titer antinuclear antibody positivity

(I 1:80), and the remaining

patients

had nega-

No. abnormal

Range of abnormal

et al9 was used.

were assessed

using

described.‘*

Table1. Serum Liver Tests in NASH

Results Patient Demographics 26-69

Twelve

Laboratory Evaluation

irubin,

liver biopsy performed

and

specifically on the basis

by standard Serum

of 33 patients

studies.

Six patients

hyperlipidemia

were

could be attributed

5 for diabetes,

aspartate Thirty-two

Five patients for hemochromatosis

iron

that

asymptomatic.

laboratories.

biopsy performed

serum

had symptoms

levels were also

analyses were performed

life insurance. for evaluation

at the time of referral (right

muscle antibody, studies

calcium,

to

(antimitochondrial

antibody),

levels), and ceruloplasmin

Serum electrolytes, nine,

serum

B surface

and antibody

antismooth

microsomal

(fasting

to hepatitis

serology

antibody,

al-

B and C serology

B core antigen,

autoimmune

and anti-liver/kidney ferritin

antibody

to hepatitis

hepatitis

total bilirubin,

levels), hepatitis

The mean (+SEM) age was 47 ? 2 years (range, years). There were 14 women (42%). Only 13 of

33 (39%) were considered obese (> 10% above ideal body weight using Metropolitan Life Insurance Standards).” Reasons for referral included evaluation of abnormal liver enzymes with or without hepatomegaly in 30 of 33 (91%). These were incidental findings in 29; in 6 they were actually identified only at the time of application for

Normal range Alanine

aminotransferase (U/U Aspanate aminotransferase (U/L) Alkaline phosphatase

3-55

(W 29/33

(88)

12-50

29/33 (88)

33-133

10/33

(30)

64-224

52-122

139-205

(U/L) Bilirubin (mg/dL) Albumin (g/dL)

0.2-1.2 3.5-5.5

4/33 o/33

(12) -

1.5-2.3 -

October 1994

NONALCOHOLIC STEATOHEPATITIS

Table 2. Serum and Liver iron Studies in NASH

Normal range Transferrin saturation (%) Ferritin (ng/mL) Hepatic iron concentration (KY&Z dry W Hepatic iron index (pmo//g + age)

10-55 10-195

had abnormal

No. abnormal

Range of abnormal

(%) 2/31 (6) 17/31(55)

t1500

4/10

<1.9

58-78 218- 1060

(40)

serum

iron

tests.

Results

dicative

of homozygous

four had mild

hereditary

increases

hemochromatosis,

in hepatic

Discussion

1608-2230

This series of 33 patients

sin, serum

electrolytes,

gen, and creatinine Random

glucose

phosphate,

a,-antitryp-

calcium,

levels were all normal levels were elevated

urea nitro-

in all patients. mg/dL)

(141-277

in seven patients (2 1%); five of these were known co be diabetic. Evidence of hyperlipidemia (hypercholesterolemia

and/or

patients

hypertriglyceridemia)

was found

one of these was known

(21%);

in seven

to have severe

but

(> 1500 pg/g dry wt).

0

Ceruloplasmin,

in

iron concentration

clinical

with NASH

and pathological

posed to what has been described were more men than women, hyperlipidemia

atic, and recognition evaluation

(including

incidental

liver

other

studies,

considered.

and obesity,

enzyme

and

condi-

were asymptom-

only came about after full

liver biopsy)

hepatitis

As op-

diabetes,

underlying

of patients

of NASH

of this

in other series, there

were not prominent

tions (Table 4). Two thirds

shows im-

characteristics

disease that have not been previously markers.

are shown

Table 2. None of these individuals had hepatic iron concentrations, including calculated hepatic iron index, in-

portant tive autoimmune

1105

of what were usually

abnormalities. C infection

In contrast was ruled

to

out

by

type IV hyperlipidemia.

Liver Biopsy Findings Liver biopsy findings and characteristic All patients

findings

inflammation

consisted

of predominantly Lipogranulomas

Steatosis

zones in 30 patients

in 28 (85%)

polymorphonuclear

and

inflamma-

polymorphonuclear

infiltration

leukocyte

and consisted

leukocytes

in five.

were found in two. All but one patient

had glycogen nuclei. Thirteen (39%) had pathological two had increased

severity.

increases

in fibrosis;

portal fibrosis, six had bridging

sis, and five had established were found

micronodular

in 23 (70%),

fibro-

cirrhosis.

Mal-

were often

small

and infrequent, and were mainly present in patients with more severe disease. Hepatic iron staining was 2+ in eight patients and l+ or less in the others. When present, hepatic

iron was found

both

in Kupffer’s

Findings in NASH No. (%)

l-3.

degrees and

(zone 3) in three. Lobular

of a mixed

and lymphocyte

lory bodies

in Figures

of varying

in all parenchymal

was only pericentral tion

are shown

in Table 3,

had hepatic steatosis to different

parenchymal was found

Table 3. Histological

are summarized

cells and

hepatocytes. Of the 13 patients with more severe disease, evidenced by increased fibrosis and/or cirrhosis, eight (62%) were women, eight (62%) were obese, four (3 1%) were diabetic or had an elevated blood glucose level, and three (23%) had hyperlipidemia. Of the two patients who had had biopsies performed 4 and 7 years previously, one showed no histological progression of bridging fibrosis (4 years), whereas the other had progressed from bridging fibrosis to micronodular cirrhosis (7 years). Hepatic biochemical iron determination was obtained on biopsy specimens from 10 patients, seven of whom

Microvesicular steatosis

o

1+ 2+ 3+ Macrovesicular steatosis 0

1+ 2+ 3+ Lobular inflammation 0 1+ 2+ 3+ Portal inflammation 0 If 2+ 3+ Mallory bodies 0 1+ 2f 3+ Fibrosis/cirrhosis None Trivial Portal Bridging Cirrhosis Iron staining (n = 28) None 1+ 2+ 3+/4+

o12 (36) 8 (24) 13 (39) o12 (36) 4 (12) 17 (52)

o18 (55) 12 (36) 3 (9) 12 (36) 16 (48) 5 (15) o10 (30) 18 (55) 3 (9) 2 (6) 12 (36) 8 2 6 5

(24) (6) (18) (15)

10 (36) 10 (36) 8 (29) O-

1106

GASTROENTEROLOGY Vol. 107. No. 4

BACON ET AL.

Figure 1. Mild NASH. (A) Note the mild degree of hepatic steatosis and small foci of inflammation (H&E; original magnification 200x). (6) Mild macrovesicular and microvesicular steatosis and mixed mononuclear-polymorphonuclear cell infiltrate (H&E; original magnification 400x).

negative

hepatitis

individuals

with

intolerance

while possibly These

other

known (31%)

contributory,

observations

of NASH

had increased

However,

need

possibility

with abnormal

have concluded

disorder.‘-*

the

(men or women,

nign and nonprogressive,

The presence

were not uniformly

emphasize

tive serological workup. Earlier reports describing

and

causes of steatohepatitis or hyperlipidemia

NASH as a definite diagnostic group of patients or euglycemic)

in all patients,

b ypass) were also excluded.

(e.g., jejunoileal of glucose

C virus serology

to

found.

of significant

consider

in an expanded

the risk factors and outcome was largely a be-

or only very slowly progressive,

fibrosis or cirrhosis

series, 39% already

on initial

and cirrhosis

biopsy. This

was found

in 30 of 199 (15%)

evidence

liver disease at the time of initial

to fibrosis and/or cirrhosis patients.

However,

at

(36%) with

tion. Specific risk factors for the progression

evalua-

of NASH

could not be identified

in our

we did observe that the 13 individuals

with the most histologically advanced form of the disease characterized by increased fibrosis and cirrhosis were predominantly

women

(62%) and often obese (62%). Thus,

sex and body habitus, with NASH

while

as a clinical

not particularly

entity,

associated

did appear to be linked

to the more severe forms of the disease, Only two previous provided

shown in Table 4, ‘J-’ increased

4.5 years was provided

patho-

in 42 of 199

in these studies had histological

observation is corroborated by the findings of others. When our series is combined with the previous series fibrosis (without

was identified

the time of biopsy. Thus, 72 of 199 patients NASH reported

liver enzymes and a nega-

in the present

(21%)

for cirrhosis)

(23%),

lean or obese, diabetic

that NASH

logical criteria

series of patients

any degree of histological

series reported

by Powell

with NASH follow-up.“,’

et al.,’ median

in 42 patients.

have In the

follow-up

Thirteen

of

had serial

Figure 2. Moderate NASH. (A) Moderate steatosis with lobular disarray, multifocal inflammatory infiltrates (arrows), and Mallory bodies (H&E; original magnification 200x). (6) Ballooned hepatocytes, Mallory bodies (arrows), and lobular inflammation (H&E; original magnification 400x).

October 1994

NONALCOHOLIC STEATOHEPATITIS

cation

of the etiology

of chronically

elevated

1107

liver en-

zymes in the absence of a history of excessive alcohol use can be inaccurate without a biopsy specimen up to 44% of the time.14 The observation with

a high

frequency

histologically

evident

vides an additional the evaluation

that NASH

of clinically and significant

impetus

but

liver disease pro-

to perform

of unexplained

is associated

unrecognized

a liver biopsy in

aminotransferase

eleva-

tions. In our series of patients,

five patients

referred for further evaluation sis. Nearly of their which Figure 3. Severe NASH. Moderate steatosis with cirrhosis (Masson trichrome; original magnification 40X).

all patients

iron status identified

ferritin

in our series had serum

performed

abnormal

or transferrin

saturation)

biopsies

during

a 1-9-year

period;

to either

worse fibrosis

one improved.

Similarly,

Lee’ reported

pathology

in 13 patients

of 3.5 years changed,

(range,

patients

cirrhosis.

follow-up Eight

progression

In the present

and 12 of 28 (43%)

of fibrosis.

This

NASH

accumulating

is not a benign

progress

to irreversible

liver

developed evidence

disorder

of is

chromatosis

during

The importance

of performing

that

iron could contribute NASH

relatively

been questioned tomatic

patients

serological

a liver biopsy

aminotransferase

in the past. When with an unrevealing

evaluation

evaluating

has

Ludwig et a1.l (1980) ltoh et al.* (1987) Diehl et al.9 (1988) Lee7 (1989) Powell et aL6 (1990) Bacon et al. (1994)

25%

studies

of

to the liver injury As in chronic

in patients

viral hepatitis,i2

serum iron and ferritin

with it is

levels in

into the blood.

The pathogenesis of fatty liver is multifactorial, and the relationship between triglyceride accumulation within the hepatocyte and infiltration of the liver paren-

and metabolic

studies), some investigators have considered liver biopsy unnecessary. However, others have shown that identifi-

Table 4. Comparison

is unknown.

and ferritin

asymp-

history and negative

(viral, autoimmune,

in serum

these patients with NASH result from the underlying necroinflammatory condition with release of tissue iron

during

levels

when the ratio is > 1 .9.15-*”

have abnormalities

likely that the increased

of elevated

age and

of homotygous

iron metabolism and mild nonprogressive increases in hepatic iron.*’ Whether this mild increase in hepatic

progression confirms

the ratio of

to the patient’s

because it is known that approximately

of heterozygotes

short time periods. the evaluation

by calculating

iron concentration hemochromatosis

and

It may be that these four patients with slightly elevated hepatic iron concentrations are heterozygotes for hemo-

cirrhosis

but one that can clearly disease

hemochromatosis,

series, only two

hereditary

hepatic iron con-

iron index > 1.9. The he-

has been shown to be a useful indicator

(3%), 15 of 28 (54%) were

unchanged,

hereditary hepatic

the hepatic

with one unchanged

his-

on liver

in four, none were in the range

patic iron index is determined

un-

iron staining

showed that, although

in homozygous

serum

iron determinations

were elevated

none had a calculated

(elevated

in 18 of 31 patients

had >2+

of fibrosis with

of 4 years and one developing

only one improved

found

period

were

during a period of 7 years. Combining the results these three series for which follow-up histopathology available,

centrations

and histo-

a mean follow-up

had repeat histopathology a period

or cirrhosis,

years).

but five developed

two developing during

during 1.2-6.9

biopsy specimens

six were unchanged,

six progressed

Biochemical

studies

as part of their workup,

iron studies

(58%). No biopsy specimen tochemically.

were actually

of possible hemochromato-

chyma

with

inflammatory

cells characteristic

of NASH

of Studies of Patients With NASH

Mean age

Female

Obesity

n

(Yb

(%)

(%)

20 16 39 49 42 33

54 52 52 53 49 47

65 75 81 78 83 42

90 100 71 69 95 39

Diabetes, elevated glucose (%) 50 75 55 51 36 21

Hyperlipidemia 67 63 20 81 21

(%)

No symptoms of liver disease (%) 77 100 48 64

Increased fibrosis/cirrhosis 15 19 39 34 50 39

(%)

1108

GASTROENTEROLOGY Vol. 107, No. 4

BACON ET AL.

is unclear.

Fatty liver alone (without

common

histological

disparate

causes such as protein

acute starvation, roid therapy. hypothesis mulation

finding

carbohydrate

Despite

explain

malnutrition,

ously cycles between any relatively stantially

hepatic

triglyceride

mulation

minor perturbation

in this process can sub-

of fat

aberrations

in

It is now apparent the

liver

can

un-

that the accu-

be

attributed

to

in at least one of four basic processes as fat

is cycled between

hepatocytes

and adipocytes:“‘,”

(1) in-

creased free fatty acid delivery

to the liver, (2) increased

free fatty acid synthesis

the liver, (3) decreased

oxidation

within

of fatty acids, and (4) decreased

sity lipoprotein

synthesis

or secretion.

into very low density

p

very low den-

of newly formed

lipoprotein

steatosis,

accumulation

inflammation,

and secre-

earlier,

described

and

and fi-

of NASH.

the need to consider

NASH

patients

with

biochemical

here, together

shows the diversity

causes and outcomes

abnormal

with

of potential

This series emphasizes

in an expanded

liver enzymes

and serological

workup.

group

of

and a negative

Before this study,

female sex, obesity, diabetes, and hyperlipidemia were thought to be prominent risk factors for NASH.‘.‘.“-’ These considerations histologically the association

The weakest links

of this cycle seem to be the incorporation triglyceride

those reported

knowledge Fat continu-

stores and the liver, and

conditions.

between

The series of patients

accu-

established

of triglyceride

the pathological sequelae of the resulting increase in constitutive lipid peroxidation and also to better understand brogenesis.

peripheral

equilibrium

define the contribution

the relationship

of causes, a unifying

metabolism.“’

alter the dynamic

der normal

obesity,

and corticoste-

is now possible based on our current

of fatty acid and triglyceride

is a

with seemingly

overload,

the multitude

that might

inflammation)

associated

may still be important

advanced

are essential

and determine

with respect to fibrosis. NASH sidered

in the more

of the disease;

is not as straightforward

Liver biopsy specimens nosis of NASH

forms

to establish

the severity should

a disease found predominantly

however,

as once thought. the diag-

of the disease

no longer be conin obese women

with diabetes.

References

tion

of very low density lipoprotein from the hepatocyte. 23m25This complex process requires a fully functioning protein synthetic capacity in addition to intact mechanisms for exocytosis. 24 Any defect in this multistep

1. Ludwig J, Viggiano TR, McGill DB, Ott BJ. Nonalcoholic steatohep

process results in accumulation

2.

hepatocyte,

which presents

of triglyceride

clinically

within

the

as fatty infiltration

of the liver.23 Whether

3.

the accumulation

of triglyceride

in the liver

is responsible for the subsequent inflammatory cell infiltration characteristic of NASH or whether an inflamma-

4. 5.

tory response in the liver evoked by some other stimulus causes steatosis

sufficient

hepatocyte

dysfunction

has not been established

to result

in NASH.

in

On the one

hand, there is evidence to suggest that increased triglyceride in the liver provides increased substrate for lipid peroxidation with the consequent generation tially reactive and cytotoxic intermediates.12

of potenIt would

not be unreasonable to suppose that such intermediate products of lipid peroxidation could induce an inflammatory rectly”

response either by causing or by recruiting inflammatory

6.

cellular injury dicells into the liver

7. 8.

9. 10.

parenchyma.” However, the greater prevalence of fatty liver without any inflammatory response would suggest that other factors might be important. If the initial inciting event is an inflammatory response to a heretofore unrecognized stimulus, the accumulation of triglyceride may only be a “symptom” of inflammation-induced disruption of hepatocyte metabolism. The early observation that a-tocopherol could prevent ethanol-induced fatty liver provides evidence for a mechanism of injury-induced fatty liver.” Additional research is needed to better

11

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Received January 17, 1994. Accepted June 13, 1994. Address requests for reprints to: Bruce R. Bacon, M.D., Division of Gastroenterology and Hepatology, 3635 Vista Avenue at Grand Boulevard, P.O. Box 15250, St. Louis, Missouri 63110-0250. Fax: (314) 577-6125. Presented in part at the annual meeting of the American Assock+ tion for the Study of Liver Diseases, Chicago, Illinois, in November 1993 (Hepatology 1993;16:174A).