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Cholestatic Hepatitis C in Liver Allografts 98 - University of California ...

Cholestatic Hepatitis C in Liver Allografts

Scott A. Taga,* M. Kay Washington,† Norah Terrault,‡ Teresa L. Wright,‡

Kenneth A. Somberg,§ and Linda D. Ferrell‡

Some liver allograft recipients with hepatitis C

virus (HCV) infection develop hyperbilirubinemia,

which might be the result of a cholestatic variant

of hepatitis C. We evaluated all liver biopsy

samples from 6 liver transplant recipients who

had polymerase chain reaction–positive HCV infection

and histologic evidence of hepatitis and

jaundice and compared them with liver biopsy

samples from a control group of transplant recipients

with HCV hepatitis without jaundice. Patients

with known ductopenic rejection, biliary obstruction,

or co-infection with hepatitis A or B were

excluded from the study. Measurement of viral

titers and genomic typing were performed when

possible. Six patients developed hepatitis and

jaundice, with maximum bilirubin levels ranging

from 5.8 to 47.6 mg/dL. In this group, 5 (83%) had

moderate interface hepatitis (control group, 15%),

6 (100%) had confluent necrosis (control group,

12%), 5 (83%) had bridging fibrosis (control group,

18%), 4 (67%) had significant hepatocyte swelling

(control group, 9%), 4 (67%) had prominent ductular

proliferation (control group, 3%), and 6 (100%)

had mild duct damage and inflammation (control

group, 53%). All 6 of the patients with cholestasis

had allograft failure. Of these, three allografts

were available for review, which did not reveal

occult obstruction, rejection, or duct loss. All

patients in the control group have retained their

allografts. In 4 patients with cholestasis, the median

HCV RNA titer was 93.97 mEq/mL, with a

mean of 54.19 mEq/mL (control mean 5.2 mEq/

mL). Five patients also underwent viral genomic

typing: 2 with type 1a, 2 with type 1b, and 1 with

mixed type 1a and 1b. Cholestasis in patients with

posttransplantation hepatitis C may be caused by

an aggressive HCV infection that exhibits histologic

features of confluent necrosis, hepatocyte

swelling, and/or ductular proliferation. Viral titers

are often increased in such patients.

Copyright 1998 by the American Association for

the Study of Liver Diseases

Hepatitis C virus (HCV) infection is a leading

cause of sporadic non-A non-B hepatitis and

liver disease that requires liver transplantation. 1-3

HCV is also a common cause of chronic hepatitis

after liver transplantation. 4 In patients undergoing

orthotopic liver transplantation as a result of HCV

infection, persistent or recurrent infection is nearly

universal. Viremia can be detected by polymerase

chain reaction (PCR) amplification methods in

95% or more of these patients. 5,6 Approximately

half of transplant recipients with either recurrent

or acquired HCV infection will develop histopathologic

evidence of hepatitis within 1 to 2 years. 3,5,7

The course of HCV in liver transplant recipients

has been considered relatively indolent compared

with hepatitis B virus infection and often results in

a stable, chronic hepatitis that evolves over months

to years after transplantation. 3,7

From *Hilo Medical Center, Hilo, HI; †Vanderbilt University,

Nashville, TN; ‡the University of California, San Francisco, CA;

and §Novartis Pharmaceuticals, Randolf, NJ.

Address reprint requests to Scott A. Taga, MD, Department of

Pathology, M580, University of California San Francisco Medical

Center, 505 Parnassus Ave, Box 0102, San Francisco, CA 94143.

Copyright 1998 by the American Association for the Study of

Liver Diseases

1074-3022/98/0404-0010$3.00/0

Some patients with posttransplantation HCV

infections, however, develop cholestasis and progressive

hepatitis, which frequently results in rapidly

progressive liver failure. 8-10 Such cases of

aggressive hepatitis C have been compared with

liver transplant cases involving an aggressive, cholestatic

variant of hepatitis B, which is characterized

by periportal fibrosis, prominent cholestasis,

and hepatocyte swelling with only mild or minimal

inflammation. 8,11,12 We reviewed the liver biopsy

specimens, virologic studies, and clinical data from

a group of liver transplant recipients with documented

HCV infection and hepatitis to determine

whether a cholestatic variant of hepatitis C may

also exist, and if so, to further characterize its

histologic and virologic features.

Materials and Methods

From 518 orthotopic liver transplantation procedures

performed between 1989 and 1993 at the University of

California San Francisco (UCSF) Medical Center, we

identified 6 patients who developed progressive hepatitis

C. All 6 patients had documented HCV infection after

transplantation determined by serum antibody positivity

and/or HCV RNA positivity by PCR. These patients

developed hyperbilirubinemia during the course of their

hepatitis, defined as a total serum bilirubin concentra-

304

Liver Transplantation and Surgery, Vol 4, No 4 ( July), 1998: pp 304-310


Cholestatic Hepatitis C in Liver Allografts 305

tion of greater than 3.0 mg/dL. All liver biopsy specimens

and corresponding serum bilirubin levels, as well as

available viral titers and HCV genotype studies, were

reviewed for this group. Therapy with interferon alfa and

clinical outcome were also noted. Histologic findings

from liver biopsies performed on patients with cholestasis

were compared with those from a control group

derived from 97 liver transplant recipients with recurrent

hepatitis C who satisfied the following criteria: PCRdocumented

HCV infection or presence of HCV antibodies,

histologic evidence of hepatitis in two or more liver

biopsy specimens, absence of jaundice, and transplantation

during the same time interval as the cholestatic

group (1989 through 1993). Patients with known ductopenic

rejection or biliary obstruction were excluded from

this study, as were patients who had co-infections with

hepatitis A or B virus after transplantation. Of these 97

cases, 34 patients met the criteria. These patients made

up the control group, which was used to compare

histologic findings between HCV-infected patients with

or without cholestasis. All 40 (6 cases and 34 controls)

patients were negative for serum human immunodeficiency

virus (HIV) antibodies before transplantation.

All hematoxylin and eosin–stained percutaneous liver

biopsy samples from the study group were reviewed by

pathologists (L.F. and S.T.) who were blinded to the HCV

RNA titers, genotypes, and clinical histories. All histologic

sections were fixed in formalin and embedded in

paraffin according to standard methods. 3 Histopathologic

features of hepatitis, including portal/periportal

inflammation and necrosis (interface hepatitis), lobular

activity, and fibrosis were graded on a scale of 0 to 4

based on severity as adapted from the grading scheme for

chronic hepatitis proposed by Ludwig (Table 1). 13 Periportal

inflammation and necrosis were scored as one

category in the control group but as separate categories

for the cholestatic patients to allow a more detailed

description of the histologic findings. Bile ductular

proliferation and hepatocyte swelling were also graded

on a scale of 0 to 4, and ductular inflammation and duct

loss were noted. Biopsy samples showing rejection,

either alone or with concurrent hepatitis, were not

graded.

HCV genotype and level of viremia were determined

for available specimens. HCV RNA was detected by PCR

amplification methods and quantified by branched chain

DNA assays (HCV bDNA 1.0, Chiron Corporation,

Emeryville, CA), as previously described. 6,14 Viral titers

were determined after the development of histologic

evidence of hepatitis. Genotyping was done with typespecific

primers complementary to core regions of the

NS5 region, serotype, or restriction fragment length

polymorphisms, as previously described. 14 Patients were

tested for HCV subtypes 1a, 1b, 2a, 2b, and 3a based on

the nomenclature described by Simmonds et al. 15

Results

Clinical Outcome and Biochemistry

Six patients with hepatitis developed clinical jaundice

that could not be attributed to any cause other

than HCV infection. Maximum bilirubin levels in

these patients ranged from 5.8 mg/dL to 47.6

mg/dL (mean, 24 mg/dL; median, 26 mg/dL; Table

2). The serum bilirubin levels fluctuated in the

early stages of the recurrent hepatitis but increased

as the hepatitis progressed to liver failure. Three of

the patients (patients 3 to 5) had serum antibodies

Table 1. Histopathologic Grading Scheme

Portal/Periportal

Hepatocyte Bile Ductular

Grade Activity Lobular Activity Fibrosis

Swelling

Proliferation

0 None or minimal None Not present None None

1 Portal zone inflammation

only

2 Mild piecemeal

necrosis

3 Moderate piecemeal

necrosis

4 Severe piecemeal

necrosis

Focal inflammation,

no necrosis

Focal necrosis

Severe focal

necrosis

Bridging necrosis

Portal tracts focally

or slightly

enlarged

Periportal fibrosis or

portal-portal

septa; intact

architecture

Septal fibrosis with

architectural distortion

Probable or definite

cirrhosis

NOTE. Adapted from the grading scheme proposed by Ludwig. 13

Focal, spotty cell

ballooning

Mild-to-moderate

zonal or mild diffuse

cell ballooning

Severe zonal or

moderate diffuse

cell ballooning

Diffuse cell ballooning

Occasional portal

zone

Few ducts, every

portal zone

Several ducts, every

portal zone

Marked proliferation,

every portal

zone


306

Taga et al

Table 2. Clinical Summary for Cholestatic Patients 1 to 6

Patient

Cause of

Native Liver

Disease

Age at

Time of First

Transplantation (y)

Serum

Bilirubin

Range* (mg/dL)

First Hepatitis

Diagnosis After

Transplantation (mo)

Allograft

Failure After

Transplantation (mo)

1 Sclerosing cholangitis 30 1.1-8.5 6 19

2 Cryptogenic liver failure 55 1.6-5.8 4 13

3 HCV 38 3.8-26.0 3 49

4 HCV 42 0.5-30.6 7 8

5 HCV 43 2.9-47.6 1 9

6 Hemochromatosis 36 11.8-26.0 3 11

*Range of serum bilirubin levels during hepatitis.

to HCV or HCV RNA in serum before transplantation

and were, therefore, considered to have had

recurrent hepatitis C. The serum samples from the

remaining 3 patients were HCV RNA and HCV

antibody–negative before transplantation; therefore,

these patients were considered to have acquired

HCV infections posttransplantation.

The processes that caused the failure of the

patients’ original livers and led to the need for

transplantation are listed in Table 2. After transplantation,

all 6 of these patients developed a particularly

aggressive form of hepatitis that resulted in

liver failure in 5. Hepatitis developed 1 to 7 months

after transplantation (mean, 4.0 months; median,

4.0 months). Allograft failure developed from 8 to

49 months after transplantation in 5 patients (mean,

18.2 months; median, 11 months; Table 2). The

allografts in these patients survived from 1 to 46

months after the onset of hepatitis. Three patients

died before they could receive second organs, and 3

patients received a second organ. One died in the

perioperative period, and another died of vascular

thrombosis in the new allograft. The third patient is

still alive with cholestatic hepatitis C and receiving

interferon therapy 5 years after receiving the second

transplant. Only patient 5 was tested for HIV

status after the development of posttransplant

hepatitis (results were negative). None of the

patients in the cholestatic group had evidence of

hypersensitivity reactions (eg, rash, peripheral eosinophilia)

during the course of their hepatitis

infection.

The 34 patients in the control group were

infected by HCV and developed hepatitis, but they

did not develop jaundice. Follow-up for these

patients was over the same time period as for

patients in the cholestatic group. Thirty-three of

these patients had recurrent HCV infections; they

were seropositive for HCV antibodies or had detectable

HCV RNA before transplantation. Pretransplantation

data for the remaining patient were not

available, but the patient had a clinical diagnosis of

non-A non-B hepatitis. The mean time between

liver transplantation and the first onset of hepatitis

for the control group was 7.5 months (range, 2 to

32 months). All patients in the control group have

retained their liver allografts.

Histologic Analysis

The patients with cholestasis each had between

four to nine liver biopsies, yielding histologic

evidence of hepatitis. For the biopsy results reviewed

from this group, histopathologic grades

ranged from 0 to 4 for all features of hepatitis.

Although the initial grades for any one feature

varied from patient to patient, the severity of all

histologic grades progressed during the course of

the hepatitis. Lobular activity, as indicated by

inflammation and/or necrosis, was the most consistent

feature, with a maximum score of 3 to 4 for all

6 patients. Each patient developed areas of confluent

necrosis (Fig. 1). Portal/periportal activity

ranged from grades 0 to 4 in individual biopsy

specimens, and 5 patients (83%) developed at least

moderate interface hepatitis with piecemeal necrosis

(Fig. 2). The degree of periportal inflammation

paralleled the severity of periportal necrosis. Both

lobular and portal inflammatory infiltrates consisted

of lymphocytes with occasional eosinophils.

Neutrophils were occasionally seen in areas of

necrosis. Prominent periportal lymphoid aggregates

were identified only in specimens from patient

3. Fibrosis developed late in the course of


Cholestatic Hepatitis C in Liver Allografts 307

Table 3. Significant Histopathologic Changes in

Cholestatic Versus Noncholestatic Patient Groups

Figure 1. Liver biopsy sample showing confluent

necrosis of hepatocytes in cholestatic hepatitis C.

hepatitis but became a prominent feature (grades 3

to 4), with 5 of the 6 patients (83%) developing

bridging fibrosis (Table 3). Four patients (67%)

developed significant hepatocyte ballooning (grades

3 to 4; Fig. 3). The hepatocyte swelling was patchy

and predominantly seen in a centrilobular distribution.

Bile ductular proliferation was identified to

some degree in all cases and became quite prominent

in 4 patients (Fig. 3). P values, as determined

by Fisher’s exact test, were found to be significant

between the cholestatic and control groups for the

histologic feature scores of interface hepatitis, confluent

necrosis, bridging fibrosis, hepatocyte swelling,

and bile ductular proliferation (Table 3). Only

minimal bile duct damage was noted in any of the

biopsy specimens, and interlobular bile ductules

remained intact. Despite the development of jaundice,

only 2 of the patients had visible intracellular

or intracanalicular cholestasis on liver biopsy (patients

3 and 6). There was no clinical or histologic

evidence of rejection or biliary obstruction in any

Cholestatic

Group

(%)

(n 6)

Noncholestatic

Group

(%)

(n 34) P *

Moderate interface

hepatitis 5 (83) 5 (15) .002

Confluent

necrosis 6 (100) 4 (12) .001

Bridging fibrosis 5 (83) 6 (18) .004

Significant hepatocyte

swelling 4 (67) 3 (9) .005

Bile ductular proliferation

4 (67) 1 (3) .001

Mild duct

damage and

inflammation 6 (100) 18 (53) .064

*P determined by Fisher’s exact test.

of the cases during the course of hepatitis, and no

granulomas were present.

Two explants from the 6 cases were available for

histologic review after retransplantation, and one

graft (from patient 5) was available postmortem.

Each of these grafts showed severe chronic hepatitis

consistent with results of liver biopsy performed

before retransplantation or patient death, although

the graft from patient 5 showed marked autolysis.

None of the grafts had evidence of ductopenic

rejection, vascular rejection, or obstruction.

The patients in the control group had various

histopathologic features, with the degree of severity

for each feature reviewed ranging from grades 0

to 3 and lobular activity ranging from 0 to 4.

Figure 2. Periportal/portal inflammation and

piecemeal necrosis due to cholestatic hepatitis C.

Note uninjured interlobular bile ductules.

Figure 3. Liver biopsy sample showing marked

hepatocyte swelling due to cholestatic hepatitis

C.


308

Taga et al

Fibrosis was negligible (grade 0) in most of the

biopsies, with only 6 of the 34 patients (18%)

developing moderate-to-severe fibrosis. Likewise,

only 3 patients (9%) developed significant cell

swelling, and 5 (15%) had interface hepatitis.

Moderate-to-severe lobular activity with confluent

necrosis was present in 4 cases (12%). Moderate to

marked ductular proliferation was present in only

1 of the patients (3%). Mild duct damage was

present in 18 of the patients without jaundice

(53%; Table 3).

Virologic Studies

HCV genotype studies were available for 5 of the 6

cholestatic patients (Table 4). Of these, 2 had an

HCV genotype of 1a, 2 had 1b, and 1 (patient 4)

had a probable mixed infection with subtypes 1a

and 1b. Viral titers of 4 of the 6 patients from the

cholestatic group ranged from 2.88 to 93.97

mEq/mL (median, 54.19 mEq/mL). Viral titers

were obtained after the development of chronic

active hepatitis for patients 2, 4, and 5, and after

the development of acute hepatitis for patient 6.

Only a single titer was available for each of these

patients. The average viral titer for the control

group was 5.2 mEq/mL (median, 5.5 mEq/mL;

range, 0.35 to 69.9 10 3 mEq/mL). Three of the

patients with cholestasis had markedly elevated

viral titers compared with the average titer of

patients in the noncholestatic group.

Four of the cholestatic patients received interferon

alfa therapy during the course of their

hepatitis (Table 5) without any apparent effect on

the overall histopathologic findings or clinical

outcome. In all 5 cases, the severity of periportal

inflammation seemed to decrease slightly (usually

by one grade) after administration of interferon,

but the therapy did not affect other histopathologic

Table 4. Virologic Results for Cholestatic Patients

Patient

Viral RNA Titer

(mEq/ml)

HCV

Genotype

Duration of

Interferon

Therapy (mo)

1 N/A N/A None

2 27.55 1b 6

3 N/A 1b None

4 2.88 1a 1b 10

5 92.37 1a 3

6 93.97 1a 3

findings nor did it prevent the eventual progression

of hepatitis. All 5 patients who received interferon

developed graft failure; 3 patients died and 2

required retransplantation. The patient with cholestatic

hepatitis who retained the allograft (patient

3) did not undergo interferon therapy.

Discussion

We reviewed 40 patients who developed hepatitis

C after orthotopic liver transplantation to find

evidence of the existence of an aggressive variant of

HCV infection similar to that described for hepatitis

B. 11,12 We identified 6 patients who developed

jaundice in association with rapidly progressive

hepatitis that resulted in graft failure. Because of

the poor outcome of these 6 patients with cholestatic

hepatitis, and with no other cause identified

to explain the liver failure, we speculate that an

aggressive variant of HCV infection may exist.

Only a few published reports have described the

histologic features of cholestatic hepatitis C in liver

allografts. One report described ballooning degeneration,

bridging fibrosis, and cholestasis, features

similar to those described with the fibrosing cholestatic

variant of hepatitis B. 8 Our study demonstrates

considerable histologic overlap between the

features of this variant of hepatitis B and those of

cholestatic hepatitis C. However, we identified

additional features of confluent hepatocyte necrosis,

interface hepatitis, and bile ductular proliferation

in our cases of hepatitis C. These features

varied in severity among the patients in the group

with cholestasis but were more profound than

those seen in the control group without cholestasis.

Confluent necrosis is a distinguishing feature between

the aggressive forms of hepatitis C and

hepatitis B. Such necrosis was described in a

previous study of cholestatic hepatitis C 10 and was

the most consistent feature present in our cases.

Mild duct damage was present in all patients with

cholestasis but also in a significant number of

patients without cholestasis; thus, most likely, it is

not a specific finding nor an obvious cause of

cholestasis in this aggressive hepatitis.

Of the 6 patients with cholestatic hepatitis, the

grafts of 3 were available for review; none showed

evidence of superimposed problems such as biliary

obstruction or ductopenic rejection. After review of

the clinical histories, no single drug was identified

as a cause of cholestatic hepatitis for the 6 patients

with cholestasis. In addition, none experienced


Cholestatic Hepatitis C in Liver Allografts 309

hypersensitivity-type reactions or developed granulomas,

both of which are common findings in

drug-related hepatidites. However, it would be

difficult to completely exclude the possibility of a

drug reaction as contributing to the process of

hepatitis. Aggressive viral hepatitis and/or cholestasis

have been associated with various medications,

including trimethoprim/sulfamethoxazole and immunosuppressive

therapy with corticosteroids and

OKT3. 8,9

In previous studies of HCV infection in liver

transplant recipients, correlation between serum

RNA levels and the development of hepatitis has

been inconsistent, although some authors have

found more severe disease to be associated with

higher serum viral titers. 5,7 Recently, it was documented

that markedly elevated viral titers were

present in liver transplant recipients with cholestatic

HCV infections. 8 In our study, assays were

conducted with viral titers from 4 of the 6 transplant

recipients who developed cholestatic hepatitis

C. Three of these patients with aggressive

disease had elevated viral titers in comparison with

the patients without cholestasis. Only 1 of the

patients (patient 3) with jaundice had viral RNA

levels less than the mean viral titer of the patients

without cholestasis. Because only one viral titer

was available, the lower value for this titer may

have been due to fluctuations in circulating viral

load. If serial measurements had been taken, viral

titers may have been found to be higher. Alternatively,

because this patient’s allograft survived longer

than those of the other 5 cholestatic patients, the

patient may have had a milder form of the cholestatic

disease.

In addition to determining serum viral titers,

HCV genotyping was performed on 5 of the patients

with cholestasis. We did not find a definite

correlation between genotype 1b and aggressive

disease as previously reported by others. 8,9,16 However,

our cholestatic group demonstrated infection

by HCV genotypes 1a and/or 1b. This is in agreement

with previous reports in which transplant

recipients who developed chronic active hepatitis

as a result of HCV infection were infected by

subtypes 1a and/or 1b, but not by other HCV

genotypes. 5,9,14,16

Four of the 6 patients with jaundice and hepatitis

had received interferon alfa therapy during the

course of their disease. The therapy did not significantly

alter the histopathologic appearance of the

liver of the hepatitis except for a slight reduction of

the periportal inflammation seen in the results of

subsequent biopsies. Interferon did not affect disease

progression or clinical outcome, because all 4

patients who received interferon therapy eventually

developed liver failure.

The nature of this progressive variant of hepatitis

C is unknown. A previous study reported that

primary immunosuppressive therapy or the extent

of HLA mismatching between donor and recipient

did not significantly affect the severity of the HCV

infection. 9 Previous studies regarding cholestatic

hepatitis C have been based on cases of recurrent

hepatitis C only. 8-10 Our study group consisted of 3

patients with recurrent HCV infection and 3 with

acquired infection who developed cholestasis. Our

study demonstrates that cholestatic hepatitis C is

not limited to patients with recurrent infection. A

case report has also described organ-transmitted

cholestatic hepatitis C in a heart transplant recipient.

17 In this case, the virus was presumed to be

carried in the donor organ. Histologic features of

liver biopsy specimens from this patient included

periportal fibrosis, ductular proliferation, and diffuse

hepatocyte degeneration, features similar to

those seen in our patients with cholestasis. Rapidly

progressive non-A non-B hepatitis has also been

reported in elderly patients and in patients with

HIV. 2,18 Hyperbilirubinemia developed in the cases

that were associated with HIV infection. It was

speculated that the effects of age and HIV infection

on the immune system allowed for increased viral

replication, which may have contributed to the

progression of the hepatitis. The histopathologic

changes in these cases have not been described in

detail.

In summary, we have identified a group of liver

Figure 4. End-stage liver disease due to cholestatic

hepatitis C showing marked fibrosis and

bile ductular proliferation.


310

Taga et al

transplant recipients with documented HCV infection

who developed a progressive hepatitis associated

with jaundice. Although histopathologic features

for this aggressive disease are not always

consistent, confluent necrosis, significant hepatocyte

swelling, and bile ductular proliferation seem

to be prominent features, and serum HCV RNA

levels are often markedly elevated. Because patients

with clinical or histologic evidence of confounding

diagnoses such as ductopenic rejection, co-infections

with hepatitis A or B virus, or biliary obstruction

were excluded from the study, we speculate

that the 6 cases of hepatitis C with cholestasis were

caused by an aggressive, cholestatic variant of

hepatitis C.

Acknowledgment

The authors thank David Geller for editorial assistance.

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