|Year : 2017 | Volume
| Issue : 3 | Page : 138-142
Retrospective analysis of post-transplant liver biopsies – From diagnosis to therapy – Can we guide further? Experience from a tertiary care center in India
Nalini Bansal1, Mukul Rastogi2, Manav Wadhawan3, Vivek Vij4, Ajay Kumar5
1 Department of Histopathology, SRL Limited, Fortis Escorts, New Delhi, India
2 Department of Hepatology, Fortis Hospital, Noida, Uttar Pradesh, India
3 Department of Hepatology, Fortis Escorts Liver and Digestive Institute, New Delhi, India
4 Department of Liver Transplant Surgery, Fortis Hospitals, New Delhi, India
5 Department of Gastroenterology, Fortis Escorts Liver and Digestive Institute, New Delhi, India
|Date of Web Publication||20-Dec-2017|
Dr. Nalini Bansal
SRL Ltd, Fortis Escorts, New Delhi
Source of Support: None, Conflict of Interest: None
Background and Aim: Post-transplant liver biopsies form a critical part of management of complications arising post-transplant. The objective of this study was to analyze the Indian experience in pathologic diagnosis of liver biopsies after orthotopic liver transplantation (OLT) with special emphasis on cases presenting with intrahepatic cholestasis (IHC). Type, incidence, and timing of major complications were analyzed. All cases with IHC were retrospectively analyzed with clinical inputs to look for cryptic clues in subclassifying such cases. Materials and Methods: Forty-five post-transplant liver biopsies from 39 OLT patients were retrospectively analyzed from May 2015 to May 2016. All biopsies were stained with hematoxylin and eosin and Masson's Trichrome, and other stains were performed as required. Results: The number of liver biopsies performed for each patient ranged from 1 to 3. The timing of these biopsies varied from 5 days to >4 years post-transplant. Of the 39 patients who underwent post-transplant liver biopsies, most common etiology of a liver transplant was hepatitis C virus (HCV)-related chronic liver disease in 66.6% cases. The common complications post-transplant were acute cellular rejection (ACR) (33.3%), biliary stricture (13.3%), HCV recurrence (11.1%), plasma cell hepatitis (4.4%), chronic hepatitis (4.4%), IHC (22.2%), and others. On analysis of post transplant biopsy cases with IHC, we found that patients with high baseline HCV RNA levels had recurrences presenting only with prominent IHC without fibrosis and ballooning of hepatocytes. These changes might represent early stages of fibrosing cholestatic hepatitis (FCH). Conclusions: This study evaluated the types, incidence, and timing of major complications occurring after OLT. ACR remains major complication following transplant. The presence of IHC on biopsy, especially in HCV-positive patients, should prompt anti-HCV therapy even if other features of FCH were not found.
Keywords: Intrahepatic cholestasis, orthotopic liver transplantation, post-transplant liver biopsies
|How to cite this article:|
Bansal N, Rastogi M, Wadhawan M, Vij V, Kumar A. Retrospective analysis of post-transplant liver biopsies – From diagnosis to therapy – Can we guide further? Experience from a tertiary care center in India. Indian J Transplant 2017;11:138-42
|How to cite this URL:|
Bansal N, Rastogi M, Wadhawan M, Vij V, Kumar A. Retrospective analysis of post-transplant liver biopsies – From diagnosis to therapy – Can we guide further? Experience from a tertiary care center in India. Indian J Transplant [serial online] 2017 [cited 2019 Oct 19];11:138-42. Available from: http://www.ijtonline.in/text.asp?2017/11/3/138/221183
| Introduction|| |
Post-transplant liver biopsies form a cornerstone in management of transplant cases. They provide critical information regarding rejection or recurrence of diseases. However, data are still sparse on the interpretation of cases where no definite etiological findings are identified on biopsy tissue. We conducted this retrospective study to analyze the spectrum of findings on post-transplant liver biopsies, to correlate them with patient's follow-up, and to specifically study cases which showed intrahepatic cholestasis (IHC). These cases of IHC were evaluated further for guiding therapy in future.
| Materials and Methods|| |
The study was a retrospective observational study of 45 cases of post-transplant liver biopsy specimen received at histopathology from May 2015 to May 2016.
Details of all histopathology reports were retrieved using hospital information system and central laboratory information management system and were computerized using a Microsoft ® Excel database. Each diagnosis was entered accompanied by the patient's age, etiology of transplant, timing of biopsy, gender, and clinical details. The data were sorted according to pathology category and diagnosis. Most common cause of primary explant liver pathology was hepatitis C virus (HCV)-related chronic liver disease (CLD) seen in 66.6% cases. The diagnosis was sorted into 10 categories. Cases with IHC were evaluated in detail for assessing the final diagnosis of the patient [Table 1] and [Table 2].
Acute cellular rejection
There were 15 cases of acute cellular rejection (ACR). Age of the patients ranged from 21 to 68 years. Cases with moderate rejection with rejection activity index (RAI) of 6 or more were treated with pulse steroid intravenous methylprednisolone, and cases of mild rejection were treated with mild oral steroid escalation. Timing of rejection ranged from 2 months to 2 years post-transplant with maximum number of cases (46%) seen between 4 and 8 months post-transplant. Biopsy in 14 cases showed moderate-to-severe rejection with mild rejection seen only in one case. There were less cases of mild rejection as most cases were managed without the need for biopsy based on clinical picture. Moderate rejection was taken as RAI of ≥6. Biopsy tissue in these cases showed moderate mixed inflammatory infiltrate comprising of mainly lymphocytes and occasional eosinophils. Lymphoblasts were seen only in one patient who did not take immunosuppression for 2 months. Endotheliitis and bile ductulitis were also noted. There were four cases of late acute rejection which showed features of central perivenulitis seen as perivenular hepatocyte dropout and necrosis. There were associated portal tract changes of mixed inflammatory infiltrate [Figure 1].
|Figure 1: (a) Showing ductulitis, (b) showing endotheliitis, (c) showing mixed inflammatory infiltrate (H and E, ×40)|
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There were 22.2% (10/45) cases of IHC on biopsy, and bilirubin of these patients ranged from 2.9 mg/dl to 50 mg/dl. Timing of biopsy was 15 days to 3 year post-transplant. Biopsy tissue showed perivenular to panlobular cholestasis without significant portal inflammation/ductulitis/endotheliitis/ductular reaction and ballooning degeneration of hepatocytes. Of these 10 cases, 4 had a transplant for HCV cirrhosis. All these 4 patients had high baseline HCV-RNA levels [Table 2]. RNA quantitative analysis in these patients following biopsy report revealed very high HCV-RNA in 3 patients favoring a diagnosis of fibrosing cholestatic hepatitis (FCH) though no fibrosis or significant ballooning was seen on biopsy tissue. Sepsis was the second common cause for IHC, seen in two patients with positive blood cultures, one of these (10-year-old child) patients responded to escalated antibiotic therapy and other died after 3 months. One patient of Wilson's disease with IHC on biopsy done 5 months after transplant responded to methylprednisolone initially but later bilirubin become static at 5–6 mg/dl. Endoscopic retrograde cholangiopancreatography (ERCP) was also performed but did not respond. The patient is alive and on follow-up. One patient of PBC, PTLB biopsy showed marked IHC but no ductular reaction or duct loss. Differentiation of recurrence from biliary cholangiopathy could not be made further, however patient responded to stenting. One patient of primary sclerosing cholangitis, 2 years post-transplant with IHC on biopsy, did not respond to repeated ERCP and stenting and underwent retransplantation. Explant liver showed a traumatic neuroma at porta and features of sclerosing cholangitis. The patient is doing well after retransplantation. There was one patient with primary hepatitis B virus-related CLD, 3 years post-transplant with IHC on biopsy. He had a history of repeated episodes of ACR previously. He underwent ERCP followed by hepaticojejunostomy, but bilirubin remained high though enzymes initially came down. The patient finally died after 6 months of follow-up at 3½ years post-transplant. Analysis of patients with IHC having HCV-CLD as primary pathology revealed that patients with high baseline HCV-RNA levels pretransplant and who had deranged liver function test (LFT) post-transplant along with biopsy showing IHC, even without fibrosis or ballooning HCV RNA, should be performed as an initial investigation. In our group of patients, RNA levels during follow-up were significantly high to favor diagnosis of FCH [Table 3] and [Table 4].
|Table 3: Distribution of cases of intrahepatic cholestasis with follow-up|
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|Table 4: Cases of intrahepatic cholestasis in hepatitis C virus chronic liver disease cases|
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There were 6 patients with biliary cholangiopathy. The native liver diseases in this group included HCV-CLD in all 6 patients. All patients responded to ERCP and stenting. Biopsy showed prominent perivenular cholestasis, feathery degeneration, and bile ductular reaction. There was no duct loss or ductopenia. Timing of biliary complication seen post-transplant was 5–9 months. Age of the patients ranged from 38 to 54 years.
Hepatitis C virus recurrence
There were 5 cases of HCV recurrence. Age of the patients ranged from 51 to 58 years. Timing of biopsy was from 1 to 10 months post-transplant. Histology showed ballooning degeneration of hepatocytes, focal apoptosis, and portal inflammatory infiltrate comprising of mainly lymphocytes. One case showed lymphoid aggregate [Figure 2]. One case did not reveal HCV-RNA whereas biopsy showed features of recurrence. The patient was treated with antiviral therapy and responded well. There was one case of FCH showing prominent ballooning degeneration, with apoptosis with aggregates of Kupffer cells. Masson's Trichrome stain showed perisinusoidal fibrosis [Figure 3].
|Figure 2: (a) Showing portal lymphoid aggregate, (b) showing Kupffer cells (yellow arrow), (c and d) showing ballooning degeneration with apoptosis|
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|Figure 3: (a and b) Showing prominent ballooning with focal apoptosis (blue arrowhead) (H and E, ×10), (c) showing bile ductular reaction (yellow arrowhead), (d) showing pericellular fibrosis (white arrowhead)|
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Plasma cell hepatitis
There were 2 cases of plasma cell hepatitis (PCH). Both patients had native liver disease as HCV-CLD. Biopsy tissue showed dense plasma cell infiltrate with interface activity. Patients were treated with pulse with steroids. PCH being considered as a variant of rejection by few authors. Both patients were male and the age was 29 and 54 years, respectively. PCH cases were treated with longer duration of steroids. Antinuclear antibody (ANA) was performed which was positive in one patient. Biopsy tissue showed prominent portal tract plasma cell infiltrate with interface activity. There were occasional foci of lobular inflammation and apoptosis [Figure 4].
|Figure 4: (a and b) Showing dense plasma cell (yellow arrow) infiltrate (H and E, ×40), with interface activity (H and E, ×20)|
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Isolated central perivenulitis
There were 2 cases of ICP: a 39-year-old male and a 51-year-old female. Cases were seen at 6 and 8 months post-transplant. Possibility of late ACR was kept in both cases and patients were treated with pulse therapy. Both patients responded. Biopsy tissue in these cases showed only changes of central perivenulitis seen as perivenular hepatocyte dropout without associated portal tract changes [Figure 5].
Chronic hepatitis was seen >2 years of transplant. The native liver disease in one patient was HCV-CLD and other was alcoholic CLD. The patient presented 2 and 3 years post-transplant. The degree of necroinflammatory activity was moderate in both cases. One case also had abundant liver glycogen bodies. Due to necroinflammation and deranged LFTs, addition of oral steroids was done which helped in both patients.
| Discussion|| |
Analysis of post-transplant liver biopsies forms a critical part of management of transplant recipient. We analyzed 45 cases of post-transplant liver biopsies from 39 patients admitted to our institute from May 2015 to May 2016.
Most common cause of transplant in this group of patients was found to be HCV-CLD seen in 66.6% cases. Similar findings have also been reported by da Silva and Hora Rios.
Liver biopsy assessment has been reported to be gold standard in diagnosing problems about transplant pathology.,,
ACR was the most common pathology seen in our group of patients in 33.3% cases. The results were comparable to other groups from China where ACR is reported as the most common pathology in 35.6% of cases. The authors from Iran reported ACR as common post-transplant pathology in 47% of cases. Grading of ACR was performed using Banff RAI.,
Isolated central perivenulitis has been analyzed in great details by Demetris et al. who postulated ICP as a bridge between late acute rejection and chronic rejection. They also postulated a grading system for same.
HCV recurrence is a major complication of a liver transplant. Distinction of HCV recurrence from rejection is of great importance as management of two differs and wrong diagnosis has severe impact on graft survival. The subtle differences between the two are beautifully illustrated by Neil and Hübscher. HCV recurrence showed hepatocellular injury seen as ballooning degeneration, apoptosis, lobular inflammation, and portal mononuclear lymphoid aggregate as compared to rejection which shows mainly portal-based changes comprising of mixed inflammatory infiltrate. These features help in establishing the correct diagnosis in all cases examined.
Chronic hepatitis is seen >2 years of transplant. The patient presented with mild transaminesemia during routine follow-up and addition of oral steroids helped in both patients examined.
Assessment of cases with IHC has not been examined in greater details previously. We tried to evaluate cases with IHC with their follow-up and tried to categorize these cases. Our analysis showed that cases of who underwent transplant for HCV related chronic liver disease and have high baseline HCV RNA levels show early and severe reoccurrence in form rising bilirubin and intrahepatic cholestasis on post transplant biopsies. Thus emphasising that in such cases, possibility of HCV recurrence should be kept as first differential over others of biliary/sepsis even in absence of other classical features of HCV recurrence. The other cause of ICH in our group was found to be sepsis, resistant rejection, biliary stricture, and recurrence of primary disease as isolated cases.
Ben-Ari et al. have reviewed IHC in post-transplant liver biopsies and categorized them as early and late cholestasis depending on whether they are occurring before or after 6 months post-transplant.
| Conclusions|| |
This study has evaluated the types, incidence, and timing of major complications occurring after liver transplant with special emphasis on cases of IHC. The findings of IHC in early FCH, though found significant in our patients, need to be evaluated further in a larger cohort of patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4]