Nodular regenerative hyperplasia with portal hypertension in patients with inflammatory bowel disease treated with azathioprine

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Nodular regenerative hyperplasia with portal
hypertension in patients with inflammatory bowel
disease treated with azathioprine Gwenola
Vernier-Massouille (1), Jacques Cosnes (2), Marc
Lemann (3), Philippe Marteau (4), Walter Reinisch
(5), David Laharie (6), Guillaume Cadiot (7),
Yoram Bouhnik (8), Martine de Vos (9), Arnaud
Boureille (10), Bernard Duclos (11),
Jean-Frédéric Colombel (1) 
Department of Hepato-Gastroenterology (1)
Hôpital Huriez, CH et U Lille, France(2) Hôpital
Saint Antoine, Paris, France(3) Hôpital Saint
Louis, Paris, France(4) Hôpital Européen Georges
Pompidou, Paris, France(5) University of Vienna,
Austria(6) Hôpital Haut-Leveque, Bordeaux,
France(7) Hôpital Robert Debré, Reims,
France(8) Hôpital Lariboisière, Paris,
France(9) University of Gand, Belgium(10) Hôtel
Dieu, Nantes, France(11) Hôpital Universitaire
de Hautepierre, Strasbourg, France.
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INTRODUCTIONNodular regenerative hyperplasia

• Nodular regenerative hyperplasia (NRH) is a rare
  hepatic lesion defined by diffuse nodulation of
  the hepatic parenchyma, without annular fibrosis,
  corresponding to the alternating of atrophic and
  hyperplastic areas.
• Among drugs likely to cause NRH are the purine
  analogues azathioprine (AZA), 6-mercaptopurine
  (6-MP) and 6-thioguanine (6-TG).
• Drug surveillance data have revealed several
  cases of NRH following renal, hepatic and bone
  marrow transplantation.
• Nevertheless, an adverse role for AZA remains
  subject to caution because of the existence of
  other causes associated with hepatopathy.

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Nodular regenerative hyperplasia and thiopurine
therapy

• The onset of NRH in patients treated with
  AZA/6-MP for inflammatory bowel disease (IBD)
  would appear to be a rare event
• 7 cases have been reported up to now.
• This low number of NRH cases is surprising given
  the higher number of cases reported in renal
  transplant patients treated by AZA.
• Concern about this complication in IBD has been
  rekindled following recent experiments with 6-TG
  in the treatment of Crohns disease (CD).

Duvoux et al. GCB 1991 Arnott et al. Eur J G H
2000 Rusmann et al. Eur J G H 2001 Daniel et
al. GCB 2005
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Hepatotoxicity of 6-thioguanine therapy
111 IBD patients receiving 6TG therapy
Dubinsky M et al. Gastroenterology 2003
29/111 (26.1) abnormal liver chemistry and/or
evidence of hematologic toxicity attributable
to 6-TG therapy
9/82 patients without AE elected to undergo liver
biopsy
17/29 underwent liver biopsy

• 5/9 (55)specimens showed
• abnormal liver histology
• 3/9 NRH
• 2/9 early periportal fibrosis

13/17 (76) NRH by reticulin silver impregnation
method
9/17 electron microscopy evaluation
7/9 electron microscopy evaluation
4/9 collagen deposition in the space of Disse
5/7 collagen deposition in the space of Disse
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AIM
To carry out a multi-centric survey of reported
cases of NRH occurring under AZA/6-MP treatment
in IBD patients, in order to elucidate their
characteristics, fate and eventual risk factors.
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METHODS

• Retrospective study
• Information related to clinical history,
  biological, morphological and histological data
  were reported in a standardized questionnaire
  using the medical records.

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METHODS

• Patients were classified as having either
  confirmed or suspected NRH

• Confirmed NRH 
• Histopathological study of liver biopsies
  showing hyperplastic parenchymatous nodules
  without extensive fibrosis on silver reticulin
  staining, with compressed and atrophic
  internodular parenchyma.

Suspected NRH A battery of clinical,
biological and morphological (non-cirrhotic PHTN)
arguments, associated with anatomopathological
study of the liver compatible with NRH
diagnosis In these cases, the biopsy was
assigned by the pathologist the nomenclature
equivocal pathohistological findings possibly
related to NRH
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RESULTSPatient characteristics

• 11 centers
• 36 NRH 31 CD / 5 UC
• Gender 29 men / 7 women
• Location of CD small bowel only (n18), small
  bowel and colon (n9), colon only (n4)
• Ileal resections 21 / 31 CD including multiple
  resections
• in 14
• Significant past histories 1 melanoma, 1
  Hodgkins disease treated with radiochemotherapy,
  1 chronic hepatitis C virus, 1 large B-cell
  lymphoma treated with anthracyclines and which
  caused cardiac insufficiency.
• Patients presented with past histories of
  thrombotic events confirmed on imaging 6
• Thromboembolic risk factor 10 / 15 patients
  studied
• 6 hyperhomocysteinemia (MTHFR gene mutations,
  n2)
• deficit in protein C and/or S (n5)

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RESULTSAZA treatment

• Median time between the beginning of AZA
  treatment and the discovery of NRH 48.5 months
  (6-187 months)
• AZA was stopped in 35/36 patients before or at
  the time of suspected diagnosis of NRH
• Median dose of AZA 2 mg/kg/day (1.5-3 mg/kg/day)
  
• Median duration of treatment 35.5 months (3-165
  months)
• TPMT genotyping (n6) all homozygous for a
  functional allele
• 6 TGN levels (n7) 274.7 pmol/8.108 RBC (68-625)

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RESULTSCircumstances leading to discovery of NRH

• Portal Hypertension (n16)
• 12 clinical symptoms of PHTN Rupture of
  varices (n6),ascites (n2), splenomegaly (n2),
  edema of the lower limbs (n2)
• For 4 other patients, circumstances included
  PHTN observed upon imaging performed for other
  reasons
• Biological abnormalities(n20)
• - Hepatic biological abnormalities
  (n15)
• - And/or thrombopenia (n15)

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RESULTScharacteristics of NRH

• Mean age at diagnosis of NRH 41 yrs (18-70)
• Biological abnormal liver function tests (n28)
  
• platelet levels lt 150x109/L (n29)
• Non-cirrhotic portal hypertension 31 / 36
• with varices (n25)
• The median duration of treatment prior to
  diagnosis of NRH
• for patients with PHTN
• 34 months (3-159)
• for patients without PHTN
• 37 months (16-165)

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RESULTSliver biopsies

• Confirmed NRH 28
• Suspected NRH 8

• Associated Hepatic vascular lesions 28
• 11 perisinusoidal fibrosis
• 12 sinusoidal dilatations
• 4 portal venopathies
• 1 peliosis

All eight patients with suspected NRH had
non-cirrhotic PHTN ( rupture of esophageal
varices (n3) and ascites (n3) ).
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RESULTSFollow-up after NRH diagnosis
- Among the five patients without PHTN at
diagnosis no complications during follow-up
- Among the 31 patients presenting with PHTN at
diagnosis

• median follow-up of 15 months (1 138)
• complication from PHTN (n14)
• rupture of esophageal varices (n9), ascites
  (n5)
• 2 TIPS
• 1 liver transplantation
  
• No deaths
• No hepatocellular carcinomas

Figure 1. Cumulative risk of complication due to
portal hypertension after diagnosis of HNR
of patients free of complications
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DISCUSSION

• this is the largest series of cases of NRH in
  IBD reported in the literature up to now
• the frequency of this complication remains
  unknwown

C
only patients presenting with clinical and/or
biological symptoms were reported
PHTN
autopsy series P 0.6 2.6

• biological
• abnormalities

asymptomatic
Wanless IR. Hepatology 1990
clinical complications of PHTN
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DISCUSSION

• 31 NRH presented with portal hypertension
• Severity of PHTN associated with NRH has already
  been reported
• in patients treated with AZA following renal
  transplantation
• in the 3 other reported literature cases of NRH
  during the course of AZA treatment for IBD
• 5 NRH presented without portal hypertension
• No signs of PHTN were observed during the course
  of follow-up.
• These patients did not differ from the others in
  terms of doses of AZA or length of treatment.
  

Duvoux et al. GCG 1991 Arnott et al. Eur J G H
2000 Rusmann et al. Eur J G H 2001
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DISCUSSION NRH plurifactorial disease

• When observing our patients, several possible
  risk factors for NRH could be suspected
• - male gender (n29)
• - CD (n31) of ileal topography (n27)
  having necessitated surgical
  resections (n21)
• - hypercoagulable
  states (n10)
• - past history of thrombotic events (n7)
• - other diseases associated with the risk
  of NRH

NRH observed in the course of AZA treatment of
IBD is likely a plurifactorial disease, the
frequency of which could be augmented by the
coexistence of several vascular risk factors
Gender Ileal CD Ileal resections
AZA
Vascular disorders
Antecedents
HYPERHOMOCYSTEINEMIA B12, folate
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CONCLUSION

• Treatment with AZA might be associated with the
  onset of NRH in the course of IBD.
• The frequency of this complication is unknown,
  but it is probably underestimated due to its
  non-specific mode of discovery and the frequency
  of asymptomatic forms.
• Because it is poorly understood, NRH is most
  often diagnosed following severe PHTN, which
  could have been avoided by early diagnosis.

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CONCLUSION

• Our series illustrates the importance of regular
  monitoring of functional liver tests and platelet
  counts in patients under AZA treatment for CD,
  especially in the presence of other associated
  risk factors
• Antecedents
• Coagulopathies
• Deficit in vitamin B6, B12,folates

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