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Letters to the Editor

Journal of Gastroenterology and Hepatology21 (2006) 1634–1639 © 2006 The Authors

1635

Journal compilation © 2006 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd

citrulline level (764 mmol/L, normal range 19–46 mmol/L) and

liver biopsy revealed micronodular liver cirrhosis with marked

fatty infiltration. Hepatic ASS activity was markedly reduced to

4% of control. Mutation analysis of the SLC25A13

gene was

performed with informed consent of the patient and his family.

The patient was a homozygote for the mutation of

IVS11 +

1G >

A

1

and CTLN2 was diagnosed. Both his mother

and brother were heterozygotes for the mutation. In January 2000,the patient received living-related liver transplantation from his

younger brother. After liver transplantation, blood chemistry

including liver function tests and hyperlipidemia returned to nor-

mal levels without any dietary restriction (Fig. 1).

It is difficult to diagnose CTLN2 before the onset of encephal-

opathy. To make an early diagnosis, it is important to clarify the

preceding symptoms of CTLN2. Although increased serum levels

of pancreatic secretory trypsin inhibitor (PSTI) have been reported

as a diagnostic marker for CTLN2,

2

the measurement of PSTI is

not performed routinely in clinical practice. After the discovery of

the gene responsible for CTLN2, an infantile form of the disease

was elucidated in patients with neonatal cholestasis (NICCD;

MIM#605814).

3

Clinical features of NICCD patients include

cholestasis, hepatic steatosis, hypoproteinemia and hyperami-noacidemia. Among the manifestations of citrin deficiency in both

adults (CTLN2) and neonates (NICCD), steatosis is associated in

most patients.

The present patient also had fatty liver in association with idio-

pathic hypertriglyceridemia. Saheki et al

. considered that a mech-

anism of fatty liver and hypertriglyceridemia was based on the

function of citrin as the AGC.

4

A function of AGC is to transport

NADH reducing equivalent from the cytosol into the mitochondria

as a member of the malate aspartate shuttle. Citrin deficiency may

cause dysfunction of this shuttle and NADH may accumulate in

the cytosol. Conversely, two alternative NADH shuttle systems are

known, the glycerophosphate shuttle and the citrate malate shuttle.

The citrate malate shuttle, which is a part of the fatty acid synthe-sis pathway, might operate compensatory to reduce cytosolic

NADH reducing equivalent. Activation of this system leads to

production of acetylCoA in the cytosol and stimulates fatty acid

synthesis, resulting in fatty liver and hypertriglyceridemia.

4

How-

ever, it needs to be proved whether or not these compensatory

processes are taking place in each patient with citrin deficiency.

Another interesting feature is the progression of fibrosis during

the first and second liver biopsy. The pathological features resem-

bled those of nonalcoholic steatohepatitis (NASH). Although the

mechanism of inflammation and fibrosis with NASH patients is

not clear, a possible explanation for the initiation of inflammation

might be that accumulation of excessive fat may develop oxidativestress which stimulates collagen production and fibrosis.

5

Also, in

patients with CTLN2, citrin deficiency may increase cytosolic

NADH and the increased cytosolic NADH may induce reductive

stress and subsequent oxidative stress. Although the mechanism of

hypertriglyceridemia with fatty liver in CTLN2 remains to be

clarified, it might be a useful marker for the early diagnosis of

CTLN2.

Ryo Terada,* Kazuhide Yamamoto,

†

Keiko Kobayashi,

‡

Kohsaku Sakaguchi,* Yoshiaki Iwasaki,* Takeyori Saheki

‡

and

Yasushi Shiratori*

*

Department of Medicine and Medical Science, Okayama,

Okayama University Graduate School of Medicine and Dentistry,

†

Okayama Saiseikai General Hospital, Okayama, and

‡

Department of Molecular Metabolism and Biochemical Genetics,

Kagoshima University Graduate School of Medical and Dental

Sciences, Kagoshima, Japan

References

1 Kobayashi K, Sinasac DS, Iijima M et al.

The gene mutated in adult-

onset type II citrullinaemia encodes a putative mitochondrial carrier

protein. Nat. Genet.

1999; 22

: 159–63.

2 Kobayashi K, Horiuchi M, Saheki T. Pancreatic secretory trypsin inhib-

itor as a diagnostic marker for adult-onset type II citrullinemia. Hepa-

tology

1997; 25

: 1160–5.

3 Yamaguchi N, Kobayashi K, Yasuda T et al.

Screening of SLC25A13

mutations in early and late onset patients with citrin deficiency and inthe Japanese population: Identification of two novel mutations and

establishment of multiple DNA diagnosis methods for nine mutations.

Hum. Mutat.

2002; 19

: 122–30.

4 Saheki T, Kobayashi K, Iijima M et al.

Adult-onset type II citrullinemia

and idiopathic neonatal hepatitis caused by citrin deficiency: involve-

ment of the aspartate glutamate carrier for urea synthesis and mainte-

nance of the urea cycle. Mol. Genet. Metab.

2004; 81

(Suppl. 1): S20–6.

5 Sanyal AJ, Campbell-Sargent C, Mirshahi F et al.

Nonalcoholic steato-

hepatitis: association of insulin resistance and mitochondrial abnormal-

ities. Gastroenterology

2001; 120

: 1183–92.

Figure 1

Clinical course of the patient. Hypertriglyceridemia and

ammonia normalized after liver transplantation. (

᭹

) Triglyceride, left (

᭺

)

ammonia, right.

0

200

400

600

800

1000

1200

1400

1600

97/10 98/4 98/10 99/4 99/10 00/4 00/10 01/4 01/10

0

50

100

150

200

250

300

350

400

1st liverbiopsy

2nd liverbiopsy

Transplantation

T r i g l y c e r i d e

( m g / d l )

Bezafibrate 400mg

Amm oni a ( mm ol / l )

Blackwell Publishing AsiaMelbourne, AustraliaJGHJournal of Gastroenterology and Hepatology0815-93192006 Blackwell Publishing Asia Pty Ltd

200621016341639Letter to the Editor

Letters to the EditorLetters to the Editor

LETTER TO THE EDITOR

Unusual case of hepatitic cholestasisresembling fibrosing cholestatichepatitis in a dialysis patient withchronic hepatitis B infection

To the Editor,

A 48-year-old man, a non-drinker with no known history of

liver disease, presented with end-stage renal failure of unknown



1636




(a)

b

c

d

600 600

500

umol/L

400

300

200

100

0

500

400

300 I U / L

200

100

0

A u g - 9 7

F e b - 9 8

A u g - 9 8

F e b - 9 9

A u g - 9 9

F e b - 0 0

A u g - 0 0

Date

F e b - 0 1

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etiology. In August 1997, he was started on continuous ambula-

tory peritoneal dialysis (CAPD), which was subsequently

switched to hemodialysis after an episode of severe peritonitis in

2001.

Upon presentation in August 1997, the patient was found to

have acute hepatitis flare. His serum alkaline phosphatase (ALP)

level peaked at 246 IU/L; alanine transaminase (ALT) level was

294 IU/L and total bilirubin was 10 µ

mol/L during that episode

(Fig. 1a). All serology and virology markers were negative, except

for a positive hepatitis B surface antigen (HBsAg) and a hepatitisB e antigen (HBeAg). The serum HBV DNA detected by Digene

Hybrid Capture II assay (Digene, Beltsiville, MD, USA) was

69 ρ

g/mL, in which 1ñg/mL represented 2.83 ×

10

5

copies/mL.

Abdominal ultrasonography revealed a small and lobulated liver

and a normal size spleen. Histological findings in liver biopsy

were consistent with chronic hepatitis B infection with early

cirrhosis.

Effective nucleoside analogs such as lamivudine were not avail-

able at that time and the patient was kept under close observation

without antiviral therapy. The liver function then improved sponta-

neously with the ALP level returning to 117 IU/L and ALT to

40 IU/L 6 months later, and he has also been HBeAg negative

since December 1998. However, follow-up HBV DNA levels andanti-HBe antibody status were not available.

The serum ALT then stabilized below 1.5 times the upper limit

of normal (ULN) (

<

60 IU/L) over the following 4 years. Neverthe-

less, the ALP slowly increased with time and the patient was found

to have portal hypertension with esophageal varices and splenom-

egaly in March 2002. In addition, he had pancytopenia with a

normal bone marrow examination finding.

The total bilirubin level also started to increase in April 2003. At

the end of July 2003, it increased to 236 µ

mol/L while ALT

remained 41 IU/L. The patient complained of severe anorexia,

general malaise and jaundice. Physical examination revealed that

he had jaundice, hepatomegaly and bilateral ankle edema. There

was no evidence of gastrointestinal bleeding. There had been no

recent changes in his medications and he denied recent use of herbs, alcohol or over-the-counter medications. He remained

HBeAg negative and was tested negative for IgM anti-HAV, anti-

HCV, hepatitis D, and anti-HIV 1 and 2 antibodies. Liver ultra-

sonography revealed normal biliary tract with no space occupying

lesions. However, the patient’s serum HBV-DNA level was ele-

vated to 3781 ρ

g/mL. In view of his rapidly deteriorating liver

function and the high HBV-DNA level, the patient was started on

an adjusted renal dose of lamivudine 10 mg daily, during which

time his total bilirubin level had gone up to 420 µ

mol/L with

prothrombin time (PT) 2.9 International Normalized Ratio (INR).

Figure 1

(a) Serial serum alkaline phosphatase (ALP), alanine ami-

notransferase (ALT) and bilirubin levels from August 1997 to August

2003. GGT, gamma-glutamyltranspeptidase. (b) Light microscopy of

liver biopsy sections shows hepatocytes ballooning, mild chronic inflam-

matory cell infiltrate, perisinusoidal fibrosis and cholestasis (hematoxylin

and eosin stain, original magnification ×

40). (c) In immunohistochemical

study, the hepatocytes strong cytoplasmic staining to HBsAg. (d) Strong

nuclear staining to HBcAg.





1637


Nevertheless, his condition continued to deteriorate and he devel-

oped hepatic encephalopathy and died of hepatic failure 5 days

after the commencement of lamivudine.

A postmortem liver biopsy was performed. Histological exami-

nation showed severe hepatocyte injuries and dysfunction with

marked intracytoplasmic cholestasis, focal intracanalicular

cholestasis and balloon degeneration (Fig. 1b). There was only

scanty inflammatory infiltrate. Marked perisinusoidal fibrosis wasseen. In immunohistochemical studies, the hepatocytes showed

diffuse and strong reactivity to HBsAg in the cytoplasm (Fig. 1c),

and focal but strong reactivity to hepatitis B core antigen (HbcAg)

in the nuclei (Fig. 1d). The overall findings were similar to those

described for fibrosing cholestatic hepatitis.

The possible spontaneous development of fibrosing cholestatic

hepatitis (FCH)-like severe cholestatic hepatitis, as shown in our

case, represents a rare but serious and potentially fatal complica-

tion in dialysis patients with chronic HBV infection. Although

uremia is associated with a wide range of impairment in the

lymphocyte and granulocyte functions, FCH has not been reported

in this group of patients without immunosuppressive treatment.

1,2

As the entity ‘FCH’ is used to refer to the rapid evolution of severe

disease in patients without underlying cirrhosis,

3

and our patienthad been found to have liver cirrhosis several years before the

development of cholestatic hepatitis, it would be difficult to ascer-

tain the pathogenic origin of the fibrosis in the autopsy findings.

Therefore, it might not be appropriate to label our patient as a case

of FCH. Nevertheless, given its dominant hepatic cholestasis,

modest increase in hepatic transaminases, rapid clinical course,

high HBV DNA level together with prominent HBcAg cytoplas-

mic staining and histological features in the postmortem liver

biopsy, the condition occurring in our case probably shares a

similar clinical-pathological mechanism with cases of FCH, in

which the hepatic injury is related to the direct cytotoxic effects of

high viral loads and accumulation of viral antigens, in particular,

large surface protein. The possible pathogenic role of this largesurface protein was first suggested by an experimental study with

a transgenic mice model, in which hepatic overexpression of HBV

large surface protein was associated with the development of hepa-

tocellular apoptosis and chronic hepatitis.

4

It was further sup-

ported by another study, in which cultured hepatoma cells being

transfected with a plasmid selectively expressing the viral large

surface protein developed numerous large vacuoles and apoptosis

resembling findings observed in FCH.

5

However, it remains unknown whether or not there are factors

other than uremia contributing to the viral reactivation and devel-

opment of this condition in our case. Previous studies have

shown that patients with HBV precore mutants might be at a

greater risk of developing FCH as compared with those carrying

wild types, and many of the FCH cases reported in the literaturewere HBeAg negative related.

6–8

It was speculated that the lack

of HBeAg could enable the virus to escape immune recognition

and predispose to unchecked viral replication. It is interesting to

note that HBeAg negative HBV mutants also play a pivotal role

in our case. Our patient had been tested negative for HBeAg

since late 1998 following resolution of an acute hepatitis flare.

Although follow-up HBV DNA levels and anti-HBe status were

not available, the clinical course was compatible with HBeAg

seroconversion. Since then, there had not been any major

derangement in his serum ALT levels and there had been no

definite evidence to suggest an occurrence of severe flares of

hepatitis, which might be able to give rise to prolonged hepatic

cholestasis in this case. Conversely, given a common occurrence

of serum ALT depression in dialysis patients, ongoing hepatic

activity could still occur with a modest elevation of serum ALT.

9

In fact, with a high frequency of HBeAg negative mutants in the

Asian population, progressive deterioration of liver function is

commonly seen even after HBeAg seroconversion in this locality,especially in patients with advanced liver disease. In our patient,

HBeAg negative mutants probably emerged after HBeAg loss

and accounted for the progressive liver disease and subsequent

FCH-like cholestatic hepatitis. Nevertheless, the exact identity of

the responsible mutant (precore or basal core-promoter mutant)

remains undefined without performing mutation analysis and

DNA sequencing.

FCH is a rapidly fatal condition, in which successful treatment

would largely rely on early diagnosis with liver biopsy and timely

treatment with a nucleoside analog type of antiviral agent such as

lamivudine.

10

A similar clinical approach probably should also be

applied to patients with a FCH-like cholestatic hepatitis, as shown

in our case.

Ping-Nam Wong,* Tang-Tat Fung,

†

Alice NH Chan,

‡

Pak-Kwan Hui,

‡

Siu-Ka Mak,* Kin-Yee Lo,* Gensy MW Tong,*

Yuk Wong,* Ching-Kong Loo,

†

Eric KM Lam

†

and

Andrew KM Wong*

*

Division of Nephrology and †

Gastroenterology Department of

Medicine and Geriatrics, and ‡

Department of Pathology,

Kwong Wah Hospital, Hong Kong SAR, China

References

1 Kohler H. Hepatitis B immunization in dialysis patients—is it worth-

while? Nephrol. Dial. Transplant.

1994; 9

: 1719–20.2 Pesanti EL. Immunologic defects and vaccination in patients with

chronic renal failure. Infect. Dis. Clin. North Am.

2001; 15

: 813–32.

3 Davies SE, Portmann BC, O’Grady J et al.

Hepatic histological find-

ings after transplantation for chronic hepatitis B virus infection,

including a unique pattern of fibrosing cholestatic hepatitis. Hepatol-

ogy

1991; 13

: 150–7.

4 Chisari FV, Filippi P, Buras J et al.

Structural and pathological effects

of synthesis of hepatitis B virus large envelope polypeptide in trans-

genic mice. Proc. Natl. Acad. Sci. USA

1987; 84

: 6909–13.

5 Foo NC, Ahn BY, Ma X, Hyun W, Yen TS. Cellular vacuolization and

apoptosis induced by hepatitis B virus large surface protein. Hepatol-

ogy

2002; 36

: 1400–7.

6 Angus PW, Locarnini SA, McCaughan GW, Jones RM, Mcmillan JS,

Bowden DS. Hepatitis B virus precore mutant infection is associated

with severe recurrent disease after liver transplantation. Hepatology

1995; 21

: 14–18.

7 Trautwein C, Schrem H, Tillmann HL et al.

Hepatitis B virus muta-

tions in the pre-S genome before and after liver transplantation. Hepa-

tology

1996; 24

: 482–8.

8 Jung S, Lee HC, Han JM et al.

Four cases of hepatitis B virus-related

fibrosing cholestatic hepatitis treated with lamivudine. J. Gastroen-

terol. Hepatol.

2002; 17

: 345–50.

9 Wong PN, Fung TT, Mak SK et al.

Hepatitis B virus infection in

dialysis patients. J. Gastroenterol. Hepatol.

2005; 20

: 1641–51.

10 Gane E, Pilmore H. Management of chronic active hepatitis before and

after renal transplantation. Transplanatation

2002; 74

: 427–37.

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