Acute Cellular Rejection Presenting With Sinusoidal Obstruction Syndrome and Refractory Ascites Postliver Transplantation : ACG Case Reports Journal

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Acute Cellular Rejection Presenting With Sinusoidal Obstruction Syndrome and Refractory Ascites Postliver Transplantation

Harris, Elizabeth MD1; Hanish, Steven MD2; Vagefi, Parsia MD3; Mufti, Arjmand MD4

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ACG Case Reports Journal 10(1):p e00919, January 2023. | DOI: 10.14309/crj.0000000000000919
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Sinusoidal obstruction syndrome (SOS) is a rare cause of ascites postliver transplantation. There are numerous etiologies of SOS in the general population, with antineoplastic agents being the most frequently identified culprits. Among liver transplant recipients who develop SOS, some cases have been attributed to immunosuppressive agents, namely, azathioprine, tacrolimus, and mycophenolate mofetil. However, acute cellular rejection (ACR) itself seems to cause SOS in rare cases. The limited studies on patients with SOS as a sequela of ACR suggest that the development of SOS portends a poorer outcome. We report a case of ACR complicated by SOS in a patient with glycogen storage disease type 1a (GSD 1a) who underwent liver transplantation.


A 21-year-old woman with GSD 1a with multiple enlarging hepatic adenomas and imaging findings concerning for malignant transformation was hospitalized for liver transplantation. She underwent exploratory laparotomy and concurrent cholecystectomy with orthotopic liver transplantation using a cadaveric liver allograft with standard arterial anatomy. Inferior vena cava anastomosis was performed in a piggyback fashion. The explanted liver was later determined to have hepatocellular carcinoma with numerous foci arising from hepatic adenomatosis, with the largest tumor measuring 10.5 cm in diameter, and microvascular invasion. She tolerated surgery well and was discharged home on postoperative day 3. She was discharged with an immunosuppressive regimen of tacrolimus 4 mg twice daily, mycophenolate mofetil 750 mg twice daily, and prednisone 20 mg daily. For Pneumocystis jirovecii prophylaxis, she was placed on trimethoprim-sulfamethoxazole. As the donor was cytomegalovirus-positive and the recipient was cytomegalovirus-negative, she was also started on prophylactic valganciclovir.

She returned 7 days later with a chief concern of shortness of breath and weakness. New ascites was present on physical examination. Abdominal and pelvic computed tomography done on presentation showed findings of hepatic congestion and significant periportal edema with mild splenomegaly and moderate amount of ascites (Figure 1). An ultrasound of the transplanted liver with Doppler showed new stagnant/slow hepatofugal flow in the left portal vein with no definite echogenic filling defect to suggest thrombus. The right portal vein and the remaining hepatic arterial and venous vasculature were patent with appropriate directional flow. She subsequently underwent paracentesis, transjugular liver biopsy, and hepatic venography. The ascitic fluid had an albumin content of 1.8 g/dL with a serum ascites albumin gradient of less than 1.1 g/dL. However, the average hepatic venous pressure gradient was 12 mm Hg, compatible with portal hypertension. The hepatic venography demonstrated patent hepatic veins, with minimal stenosis of the upper donor inferior vena cava segment. The liver biopsy showed moderate to severe mixed portal inflammation including eosinophils and endothelialitis as well as bile duct damage (Figure 2). The lobules showed sinusoidal dilatation with scattered congestion (Figures 3 and 4). Mild cholestasis was noted. Taken together, these findings were consistent with severe ACR (Rejection Activity Index = 8) and SOS.

Figure 1.:
Abdominal and pelvic computed tomography showing hepatic congestion and significant periportal edema with mild splenomegaly and moderate ascites.
Figure 2.:
Liver biopsy tissue showing mixed portal inflammation and bile duct inflammation with damage consistent with acute cellular rejection.
Figure 3.:
Liver biopsy tissue showing dilatation and congestion of sinusoids consistent with sinusoidal obstruction syndrome.
Figure 4.:
Liver biopsy tissue showing congestion of sinusoid terminal hepatic venule intimal edema consistent with sinusoidal obstruction syndrome.

For ACR, she received pulse dose steroids for 3 days. She was discharged on a new immunosuppressive regimen of tacrolimus 5 mg twice daily, mycophenolate mofetil 1,000 mg twice daily, and a high-dose prednisone taper. She was also placed on furosemide for volume overload. Her Pneumocystis jirovecii prophylaxis was changed from trimethoprim-sulfamethoxazole to atovaquone. For the next few months, she followed up weekly in clinic and had rapid complete resolution of ascites. The furosemide was stopped, and she was able to successfully wean off high-dose prednisone. She has been doing clinically well since then.


This case describes both an unusual reason for liver transplantation, namely, GSD 1a, and a rare complication postliver transplantation—SOS in the setting of ACR. To date, there have been only slightly over 100 instances of liver transplantation for GSD 1a since the first case in 19821. To our knowledge, this is the only reported case of ACR complicated by SOS in patient status postliver transplantation for GSD 1a.

GSD is an autosomal recessive genetic disorder that occurs in roughly 1 in 100,000 live births. Type 1a accounts for 80% of those with the disease and is caused by mutations in the G6PC gene that result in a deficiency in the glucose-6-phosphatase enzyme that leads to impaired glucose release and excessive accumulation of glycogen and fat in the liver, kidneys, and intestinal mucosa.1 The disorder has variable clinical severity but primarily affects the liver and kidneys, with hepatomegaly, hypoglycemia, lactic acidosis, hyperlipidemia, and hyperuricemia as frequent clinical manifestations.1 Patients with GSD type 1a are prone to develop numerous hepatocellular adenomas that in some cases transform into hepatocellular carcinoma.2 Regular screening with abdominal ultrasound and alpha fetal protein as well as carcinoembryonic antigen every 3 months is the current guideline recommendation for GSD type 1a patients with hepatic adenomas.2 The incidence with which these adenomas transform into carcinomas is unknown, but liver transplantation is the ultimate treatment and is considered for patients with multifocal, growing lesions.1,3 In fact, our patient was found on explant to have had hepatocellular carcinoma with numerous foci arising from hepatic adenomatosis. In addition to removing cancer or tissue prone to transformation into cancer, liver transplantation also corrects the metabolic derangements that characterize GSD 1a.1,3 The 1-, 5-, and 10-year survival for adults and children with GSD 1a in North America who have undergone liver transplantation is 82%, 76%, and 64%, respectively.1

SOS, previously known as veno-occlusive disease, is clinically characterized by hepatomegaly, ascites, and jaundice and can arise in a variety of clinical conditions, usually due to exposure to a toxic agent.4 The syndrome is histologically characterized by diffuse damage in the centrilobular zone of the liver with marked sinusoidal fibrosis, necrosis of pericentral hepatocytes, and narrowing and eventual fibrosis of central veins.4 Studies suggest that the primary site of toxic injury is the sinusoidal endothelial cell.4–6 The damage to the small sinusoidal hepatic vessels can eventually lead to partial or complete occlusion of small hepatic veins.5

SOS has rarely been observed in liver transplant recipients, and a number of different etiologies have been implicated for its presence in this subset of patients. One study, with the aim of determining the prevalence of this syndrome after liver transplantation, identified SOS in 19 of 1,023 patients transplanted in a 9-year period.7 They found that the syndrome occurred at a median of 30 days posttransplantation and that 17 of 19 patients had an episode of acute rejection before or at the time of onset of SOS.7 Another study examined the histologic features of patients who developed ascites in the setting of ACR postliver transplantation and compared them with control patients who had ACR without ascites.6 Of the 5 patients with ACR who had ascites, all had histologic evidence of SOS, while the 10 patients with ACR without ascites did not.6 This study also found that all 5 of the patients with SOS either died or required retransplantation, having a much poorer prognosis than the 10 control patients.6 In liver transplant recipients who develop SOS in the absence of ACR, immunosuppressive agents themselves—namely, azathioprine, tacrolimus, or mycophenolate mofetil—are identified as the most likely culprits.7-9 Withdrawal of the agent usually results in resolution of the syndrome in these cases.

The occurrence of ascites in the setting of ACR (without evidence of large vessel occlusion) is rare and has poorly understood pathophysiology. SOS, when noted on histology, is likely to be the main mediator of this phenomenon, and the limited studies on this entity suggest a poor prognosis for ACR with SOS than ACR without SOS. However, we describe a case of SOS in the setting of ACR postliver transplantation for GSD type 1a that resolved completely with treatment of ACR.


Author contributions: E. Harris wrote the manuscript. S. Hanish and P. Vagefi edited the manuscript. A. Mufti cared for patient, developed idea to submit the manuscript, edited the manuscript, and is the article guarantor.

Financial disclosure: None to report.

Previous presentation: This case report was presented as an oral presentation at the Texas Transplantation Society meeting; July 16, 2022; Frisco, TX.

Informed consent was obtained for this case report.


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8. Poli E, Kounis I, Guettier C, et al. Post-liver transplantation sinusoidal obstruction syndrome with refractory ascites induced by mycophenolate mofetil. Hepatology. 2020;71(4):1508–10.
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liver transplantation; sinusoidal obstruction syndrome; glycogen storage disease

© 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.