LiLi , Yue Dong , Rui-Dong Li , Yi-Feng Tao , Cong-Huan Shen ,Zheng-Xin Wang , ?

a Department of General Surgery, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai 20 0 040, China

b Institute of Organ Transplantation, Fudan University, Shanghai 20 0 040, China

c Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai 20 0 040, China

TotheEditor:

Sinusoidal obstruction syndrome (SOS), also known as venoocclusive disease, is characterized by fibrotic occlusion of small hepatic veins and congestion of sinusoids [1] . This syndrome is mainly observed in hematopoietic stem cell transplantation (HSCT)and its incidence in liver transplantation (LT) ranges from 1.9% to 2.9% [2 , 3] . Although rare, severe SOS following LT can cause liver graft dysfunction with poor prognosis [3] .

Diagnosis of SOS is based primarily on clinical criteria including ascites, hepatomegaly and jaundice [1 , 4] . Liver biopsy is reserved for patients in whom the diagnosis of SOS is unclear and there is a need to exclude other diagnoses including acute rejection, Epstein-Barr virus or cytomegalovirus infection [4] .

In LT, SOS was thought to be mainly triggered by azathioprine and acute rejection (AR) [2] . Despite recent advances in immunosuppressive agents of LT, the incidence of SOS is not reduced [2] . Recently, some studies reported that tacrolimus could cause SOS and its discontinuation may be an effective treatment [3 , 5-7 ]. Herein, we present 5 cases of tacrolimus-related SOS following LT.

All patients underwent donation after cardiac death LT for endstage liver disease. Immunosuppressive treatment with tacrolimus,mycophenolate mofetil and tapering prednisolone was applied.Case 4 experienced AR while others had uneventful postoperative recovery period. The ultrasonography of all patients during course of disease showed normal blood flow in hepatic vein, portal vein, hepatic artery, and inferior vena cava. Besides, no evidence of Epstein-Barr virus nor cytomegalovirus infection was found. All patients achieved clinical remission after withdrawal of tacrolimus and remained asymptomatic until the last follow-up. Characteristics of presented cases are summarized in Table 1 .

Case 1. A 47-year-old man presented jaundice and 10 0 0 mL of ascites demonstrated by ultrasonography about 6 weeks after LT.Analytical values were: total bilirubin (TBil) 45.8 μmol/L, aspartate aminotransferase (AST) 48 IU/L, alanine aminotransferase (ALT)17 IU/L, gamma-glutamyl transpeptidase (GGT) 218 IU/L, alkaline phosphatase (ALP) 423 IU/L. Liver biopsy showed fibroplasia in portal areas and steatosis of hepatocytes ( Fig. 1 A), which confirmed the diagnosis of SOS. Diuretics, albumin infusion, and paracentesis cannot prevent the reappearance of ascites. Ultrasonography at postoperative day (POD) 80 demonstrated more than 10 0 0 mL ascites and enlarged liver. Computed tomography (CT) at POD 94 and 124 ( Fig. 2 A and B) showed massive ascites. This condition was speculated to be tacrolimus-related SOS and tacrolimus was replaced by cyclosporine A (CsA) at POD 203. About 3 months after the adjustment, CT ( Fig. 2 C) and ultrasonography found no ascites and normal liver volume. Serological tests showed normal TBil, AST, ALT, PT-INR and slightly elevated ALP (166 IU/L) and GGT(64 IU/L).

Case 2. A 62-year-old woman presented jaundice and her daily ascites drainage was approximately 600 mL at POD 6. ALP and TBil levels increased continuously after transplantation and peaked at 1453 IU/L and 608.8 μmol/L at POD 13. Liver biopsy on POD 13 showed sinusoidal congestion, dilatation of sinusoid and small branch of the portal vein ( Fig. 1 B). This condition was speculated to be tacrolimus-related SOS and the recipient was then switched from tacrolimus to CsA. Her ALP, TBil levels and ascites decreased immediately and fell to 364 IU/L, 110.8 μmol/L and 50 mL respectively at POD 22 and recovered continuously afterwards.

Case 3. A 25-year-old woman hospitalized at POD 165 for ascites, jaundice and liver dysfunction. Analytical values were: TBil 77 μmol/L, AST 149 IU/L, ALT 42 IU/L, GGT 635 IU/L and ALP 384 IU/L. On ultrasonography, the volume of ascites was 800 mL and oblique diameter of the right liver (ODRL) was 161 mm. This condition was speculated to be tacrolimus-related SOS and immunosuppression treatment was switched to cyclosporine-based regimen.The levels of liver enzymes decreased continuously while TBil level peaked at week 3 after switch and recovered gradually afterwards.Ascites on ultrasonography reduced to below 200 mL and ODRL returned to 134 mm two months after the withdrawal.

Fig 1. The histologic results of liver biopsy (magnification ×400). A: Case 1. Fibroplasia in portal areas and steatosis of hepatocytes. B: Case 2. Sinusoidal congestion,dilatation of sinusoid and small branch of the portal vein. C: Case 4. Acute rejection response. The rejection activity index was 5/9. D: Case 4. Fibrous obliteration and edema in portal area.

Fig. 2. Computed tomography results of Case 1. A: CT images showed massive ascites at POD 94. B: Similar amount of ascites at POD 124. C: The ascites was completely disappeared on the image at POD 278.

Case 4. A 50-year-old woman was diagnosed with AR by liver biopsy at POD 6 ( Fig. 1 C). The rejection activity index was 5/9. We started treatment of augmented immunosuppressive therapy and she recovered well. Her liver enzymes and bilirubin levels returned to nearly normal range within two weeks after operation. However, liver biopsy at POD 46 found fibrous obliteration and edema in portal area instead of AR response ( Fig. 1 D). Six months later,the patient was hospitalized for liver dysfunctions and jaundice.Ultrasonography showed massive ascites and enlarged liver. Analytical values were: TBil 78.1 μmol/L, AST 43 IU/L, ALT 59 IU/L, GGT 115 IU/L and ALP 148 IU/L. This condition was speculated to be tacrolimus-related SOS. Then tacrolimus was replaced by CsA. In the following week, daily volume of ascites drainage was decreased from 1200 mL to 150 mL, and remission of jaundice and liver functions were observed. The withdrawal of tacrolimus led to a rapid clinical improvement.

Table 1 Characteristics of presented cases.

Case 5. A 54-year-old woman presented 1550 mL daily volume of ascites drainage at POD 6 and it peaked at 2300 mL at POD 10 with the exacerbation of jaundice. TBil level reached 236.2 μmol/L at POD 10 while the levels of AST, ALT and ALP remained nearly normal. Treatment with a diuretic was ineffective and the ODRL reached 156 mm. This condition was speculated to be tacrolimusrelated SOS. Thus, CsA was initiated to replace the tacrolimus at POD 29. One month after the replacement, her liver returned to normal size and TBil level fell to 25 μmol/L. Meanwhile, daily volume of ascites drainage remained over 1500 mL for over a month and then decrease to 400 mL at POD 76.

SOS is characterized by injury to sinusoidal endothelial cell.Many toxic agents containing pyrrolizidine alkaloids, preconditioning regimens, and chemotherapeutic drugs are relevant to it [1] .AR and azathioprine, an immunosuppressant widely used in last century, were the major pathogenic factors of SOS post-LT [7] .Although AR rate decreased significantly due to advances in immunosuppression regimens, the prevalence of SOS in LT is nearly constant [2] . Recently, some tacrolimus-related cases following LT were reported [5-8] . Herein we describe 5 patients transplanted for end-stage liver disease, among which only one experienced AR.The symptoms of all patients were relieved within three months after discontinuation of tacrolimus, indicating that tacrolimus may be the major pathogeny.

Diagnosis of SOS in solid organ transplantation was based on clinical symptoms consisting of ascites, hepatomegaly and jaundice [1 , 7] . Although pathology is the gold standard, most patients do not tolerate liver biopsy due to its significant risks [4 , 5] . Some authors claimed the detection of reversed blood flow in the segmental branch of portal vein in SOS patients [1] . But none of our patients showed abnormal flow on ultrasonography.

There is a significant lack of evidence-based therapy for SOS following LT. Although approved for the treatment of HSCT patients with severe SOS, defibrotide was not efficient for LT patients. Only one out of five previously reported cases using defibrotide for SOS after LT proved efficient [7 , 9 , 10] . It seems that discontinuation of tacrolimus is the only effective treatment for now.

In conclusion, we present five SOS patients after LT. The diagnosis was based on clinical symptoms such as jaundice, enlarged liver and refractory ascites. Liver biopsy was done to confirm the diagnosis in 3 cases. Tacrolimus, but not AR, may be the major cause of SOS in LT. Organ transplantation physicians should raise the suspicion of tacrolimus-related SOS. Further fundamental researches are required to clarify the underlying mechanism.

CRediT authorship contribution statement

Li Li:Data curation, Investigation, Writing - original draft.Yue Dong:Data curation, Investigation, Writing - original draft.Rui-Dong Li:Data curation, Investigation.Yi-Feng Tao:Writing -review & editing.Cong-Huan Shen:Writing - review & editing.Zheng-Xin Wang:Conceptualization, Funding acquisition, Investigation, Writing - review & editing.

Funding

This research was supported by grants from the National Natural Science Foundation of China ( 81873874 ) and two subprojects ( 2017ZX10203205-0 02-0 04 and 2017ZX10203205-0 03-003 ) under the National Science and Technology Major Project( 2017ZX10203205 ).

Ethical approval

The consent for publication was obtained from the reported patients.

Competing interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.