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Fibrosis After Liver Transplantation. Amany A.Maqsod Sholkamy Professor of Internal Medicine &Hepatology Faculty of Medicine Cairo University Consultant Liver Transplantation Kasr AlAiny H Supervisor of the Liver ICU French H Cairo University.

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fibrosis after liver transplantation

Fibrosis After Liver Transplantation

Amany A.MaqsodSholkamy

Professor of Internal Medicine &Hepatology Faculty of Medicine Cairo University

Consultant Liver Transplantation Kasr AlAiny H

Supervisor of the Liver ICU French H

Cairo University

slide2

NAFLD and HCV are the most common indications of liver transplantation worldwide.

Amany A.Maqsoud APASL 2014

post transplant hcv related fibrosis
Post transplant HCV related fibrosis

Amany A.Maqsoud APASL 2014

the problem
The problem:
  • Recurrence of HCV in the graft occur immediately after its implantation.
  • Studies showed that approximately 10–30% of HCV patients develop cirrhosis within 5y post transplant.
  • The majority of HCV patients develop graft cirrhosis by 9–12 years post transplant.

Amany A.Maqsoud APASL 2014

risk factors
Risk factors:
  • Metabolic syndrome
  • Type of immunosuppressive drugs
  • High viral load
  • Advanced donor age
  • Prolonged warm ischemia time

Modifiable factors such as donor age metabolic syndrome…. etc should be avoided whenever possible.

Amany A.Maqsoud APASL 2014

when to treat
When to treat….?

Amany A.Maqsoud APASL 2014

when to start ttt
When to start ttt ?
  • Pre-emptive treatment is not recommended because of the side effects of antiviral drugs and drug-drug interactions with the immunosupressives.
  • So, ttt should be for selected patients. Those showing fibrosis progression, choestasis or significant necroinflammation. Specially in the first post Tx year.

Amany A.Maqsoud APASL 2014

to biopsy or not that is the question
To biopsy or not? …That is the question!
  • The issue is when to biopsy and what to interpret as an indication to start ttt before loosing the graft.
  • Scheduled annual, every 2y, or on demandbiopsyprotocols ??. The rate of progression.
  • The ideal surveillance interval is not known.
  • Complexities of biopsy interpretation is a major issue of concern. And hence the looking for another “non invasive” tool.

Amany A.Maqsoud APASL 2014

non invasive tools lab
Non invasive tools/lab.:
  • Traditional indirect markers: platelets, albumin, GGT, and liver enzymes.
  • Combinations of serologies and markers of extracellular matrix turnover.
  • However, all showed variable accuracy in determining the stage of disease or predicting progression. None of these are routinely used.

Amany A.Maqsoud APASL 2014

non invasive tools elastography
Non invasive tools/elastography:
  • US and MRI elstography have been studied in the post transplant (HCV/NASH) settings for assessment of fibrosis progression and deciding ttt.
  • Many post transplant graft copathologies (inflammation, steatosis, B obstruction) can interfere with their accuracy.

Amany A.Maqsoud APASL 2014

what findings indicate ttt
What findings indicate ttt ?
  • Clinically, the occurrence of signs of portal hypertension in the subsequent postTx year is a grave sign indicating significant graft fibrosis demanding urgent ttt.
  • However, this may occur so far after fibrosis/cirrhosis are advanced.
  • Earlier interference is shown to be better by many researches.

Amany A.Maqsoud APASL 2014

what findings indicate ttt1
What findings indicate ttt:
  • Treatment is currently recommended only for patients with histologically significant recurrence, who are generally defined as individuals with:
  • At least grade 2 of 4 necroinflammation.
  • Stage F0-1 or 1-2/4 fibrosis. ???
  • The cholestatic variant of HCV.

Amany A.Maqsoud APASL 2014

to my opinion
To my opinion, …
  • The presence of one or more of the risk factors, the alteration of graft functions, the cumulative dose of steroids used and biopsy results each should have a certain weight in decision to start ttt.
  • Elstography may come as a complementary step in follow up of borderline histologic findings.

Amany A.Maqsoud APASL 2014

slide15

Post liver transplantation NAFLD may be a recurrence of the pretransplant NAFLD or may occur de novo, even after Tx of other organs.

  • Post Tx NAFLD imposes no effect on allover mortality or graft related deaths.
  • Cirrhosis estimated to be 5% 5y after Tx.

Amany A.Maqsoud APASL 2014

risk factors for development
Risk factors for development:
  • Metabolic syndrome “the coming pandemic”.
  • Type and dose of immunosupressives
  • Donor steatosis.
  • The steatogenic, and cytotoxic effect of HCV.

Amany A.Maqsoud APASL 2014

aasld 2009 reported
AASLD 2009 reported:
  • The prevalence of postTx metabolic syndrome (PTMS) and its individual components has been found to be higher post-LT versus a comparable population without LT.
  • The development of NAFLD after liver transplantation for non-NAFLD cirrhosis is also being increasingly recognized.

Amany A.Maqsoud APASL 2014

risk factors in ptms
Risk factors in PTMS:

Amany A.Maqsoud APASL 2014

donor s steatosis
Donor’s steatosis:
  • One of the adverse impacts of the world epidemic of obesity/MS is the limited availability of suitable donors.
  • Studies showed that steatosis of 30% (15% in LDLT) are not accepted and carries the danger of early graft loss. ??? fibrosis
  • Again, studies showed that biopsy is the gold standard in assessing donor’s steatosis.

Amany A.Maqsoud APASL 2014

diagnosis
Diagnosis:
  • Clinically; the presence of one or more of the risk factors should raise a high index of suspicion.
  • NAFLD may be clinically silent.
  • Alteration of liver enzymes (if present) may occur in the posttransplant setting due to many factors.

Amany A.Maqsoud APASL 2014

diagnosis1
Diagnosis:
  • Biopsy protocol:

No standard posttransplant interval biopsy protocol.

Amany A.Maqsoud APASL 2014

biopsy protocol
Biopsy protocol
  • The variability in the time points at which postTx biopsy procedures were performed makes comparisons across studies more difficult. Furthermore, NAFLD is usually

asymptomatic and may be clinically silent, and a biopsy sample taken at a single point in time may not be representative of the spectrum of fatty liver disease. Moreover, ……

Amany A.Maqsoud APASL 2014

diagnosis biopsy protocol
Diagnosis: biopsy protocol
  • Moreover, a patient’s metabolic profile can change over time, and this may be reflected in the histological findings encountered at different time intervals.
  • This brings us to the 2 immortal “till now” questions:
  • Biopsy schedule
  • Efficacy of non-invasive tools of diagnosis.

Risk factors tailored

Amany A.Maqsoud APASL 2014

slide25

Hematoxylin and eosin–stained liver biopsy section demonstrating macrovesicularsteatosis with foci of lobular inflammation.

H&E stained liver allograft biopsy section 2.5 years after transplantation for NASH-related cirrhosis. Hepatocytes show ballooning degeneration and Mallory hyaline inclusions.

Trichrome-stained liver allograft

biopsy sample highlighting foci of

perisinusoidal fibrosis

Amany A.Maqsoud APASL 2014

treatment
Treatment:
  • Medical:
  • Prophylaxis
  • Definitive
  • Surgical

Amany A.Maqsoud APASL 2014

treatment1
Treatment:
  • Prophylaxis is of utmost importance.
  • Scheduled biopsy protocol can also identify pts with steatosis that impose critical control of metabolic risk factors and modification of type/dose of immunosupressives.
  • Until now, no specific trials assessed a specific drug therapy for post Tx steatosis.

Amany A.Maqsoud APASL 2014

surgical treatment
Surgical Treatment:
  • Bariatric surgery through limited series and case reports studies showed good results.
  • Risks of exacerbation of NASH after bariatric surgery due to excessive weight loss as well as risks of impaired drug absorption and bacterial overgrowth that can impact post-transplant outcomes.

Amany A.Maqsoud APASL 2014

consensus
Consensus:
  • Avoidance of the risk factors for RFP in post transplant HCV is important in the management of these patients. (1A)

Amany A.Maqsoud APASL 2014

c onsensus
Consensus:
  • Data regarding relative risk of different immunosuppressive drugs remain conflicting, and further studies are required before current protocols are modified. (2c)

Amany A.Maqsoud APASL 2014

consensus1
Consensus:
  • Liver biopsy is the \'gold standard\' for diagnosis and follow up of fibrosis and implementing specific antiviral therapy. Protocol liver biopsy is of utmost importance in the posttransplant care of these patients. (1A)

Amany A.Maqsoud APASL 2014

consensus2
Consensus:
  • Significant fibrosis or portal hypertension one year after transplantation predict rapid disease progression and graft loss, and indicate more urgent antiviral treatment. (1B)

Amany A.Maqsoud APASL 2014

consensus3
Consensus:
  • Transient elstography for replacing biopsy in the assessment and diagnosis of fibrosis progression still needs validation through large scale clinical studies. (2C)

Amany A.Maqsoud APASL 2014

consensus statements
Consensus statements:
  • Diagnosis depends mainly on liver biopsy. However, the alteration in liver enzymes, plus the imaging modalities and the presence of risk factors are all collectively important (beside liver biopsy) for making the diagnosis and assessing the degree of inflammation and fibrosis. (1B)

Amany A.Maqsoud APASL 2014

consensus statements1
Consensus statements:
  • Prophylaxis is important to avoid progression of fibrosis and graft dysfunction. This is confirmed through scheduled liver biopsy and follow up program tailored according to the presence of risk factors. (1A)

Amany A.Maqsoud APASL 2014

consensus statements2
Consensus statements:
  • For the treatment of post liver Tx NAFLD, Vit. E as recommended for the non transplant situation is also applied. (C2)
  • Insulin sensitizers need further clinical studies. (2C)

Amany A.Maqsoud APASL 2014

consensus statements3
Consensus statements:
  • Weight loss and treatment of metabolic syndrome and its individual components are the definite treatment available till now. (1A).
  • Modification of the type and dose of immunosuppressives is important although data are still lacking (1B)

Amany A.Maqsoud APASL 2014

consensus statements4
Consensus statements:
  • Although data supporting a role for the metabolic syndrome in post transplantation HCV-mediated RFP are preliminary, current data suggest that strict strategies to reduce weight gain and the adverse metabolic profile post-transplant should be implemented. (1B)

Amany A.Maqsoud APASL 2014

consensus statements5
Consensus statements:
  • Biopsy is the gold standard for assessing the presence and degree of steatosis in the donor graft. (1C)
  • Steatosis of more than 30% of the donor graft is associated with high risk of primary non-function.(1A)

Amany A.Maqsoud APASL 2014

slide40

Mother to Daughter

Brother to Brother

Brother to Brother

Mother to Son

Mother to Son

Father to Son

Son to Father

Mother to Daughter

Son to Mother

slide42

Annual Conference

Amany A.Maqsoud 2014

slide43

Thank you

Amany A.Maqsoud 2014

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