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Korean J Gastroenterol  <  Volume 83(3); 2024 <  Articles

Korean J Gastroenterol 2024; 83(3): 123-126  https://doi.org/10.4166/kjg.2024.007
Severe Liver Dysfunction after Donor Lymphocyte Infusion for Relapsed Multiple Myeloma
Tae-Hoon No, Nae-Yun Heo , Seung Ha Park, Joon Hyuk Choi, Junghwan Lee, Sung Nam Lim, Seon Yang Park
Department of Internal Medicine, Inje Univerity Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
Correspondence to: Nae-Yun Heo, Department of Internal Medicine, Inje Univerity Haeundae Paik Hospital, Inje University College of Medicine, 875 Haeun-daero, Haeundae-gu, Busan 48108, Korea. Tel: +82-51-797-2436, Fax: +82-51-797-0941, E-mail: nyheo@hanmail.net, ORCID: https://orcid.org/0000-0001-6571-8935
Received: January 19, 2024; Revised: March 17, 2024; Accepted: March 18, 2024; Published online: March 25, 2024.
© The Korean Journal of Gastroenterology. All rights reserved.

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Donor lymphocyte infusion (DLI) is performed to augment an anti-tumor immune response or ensure donor stem cells remain engrafted following allogeneic stem cell transplantation but may induce graft-versus-host disease (GVHD) involving skin, intestine, and liver. Although hepatic involvement of GVHD can manifest as mild to severe hepatitis, few reports have mentioned acute severe liver dysfunction with encephalopathy. We experienced a case of acute severe liver dysfunction with semicoma after DLI in a patient with relapsed multiple myeloma following allogeneic stem cell transplantation, in whom chronic viral hepatitis B had been suppressed by antiviral treatment. The patient recovered after high-dose glucocorticoid administration based on an assessment of hepatic GVHD. Clinicians should be aware of the possibility of this catastrophic hepatic complication after DLI in hematologic disorders.
Keywords: Graft vs Host Disease; Liver Failure, Acute

Donor lymphocyte infusion (DLI) is a salvage treatment for relapse after allogeneic stem cell transplantation in patients with leukemia, lymphoma, or multiple myeloma.1 Furthermore, a considerable proportion of patients administered DLI present with liver dysfunction, and 30% of patients administered DLI develop hepatic graft-versus-host-disease (GVHD).2 However, it is often difficult to determine the exact cause of liver dysfunction after DLI because several differential diagnoses, including hepatic GVHD and other causes, such as viral hepatitis, drug-induced liver injury, and sepsis-induced cholestasis, must be considered. Herein, we report a rare case of acute severe liver dysfunction occurring after DLI in a patient with multiple myeloma and chronic hepatitis B (CHB), in whom hepatic GVHD may have been the main causative factor rather than hepatitis B virus (HBV) reactivation.


A 63-year-old woman visited our emergency room complaining of acute onset whole body pain of 5 days duration. Seven years previously, the patient received a diagnosis of plasma cell leukemia, IgG kappa type. Autologous stem cell transplantation was performed, and partial remission was accomplished. However, 4 years before this visit, she experienced multiple myeloma relapse that partially responded to salvage chemotherapy. Allogeneic stem cell transplantation was undertaken after a second relapse 3 years ago. Four months before the emergency room visit, a third relapse was detected (serum kappa free light chain 665.4 mg/dL), and salvage chemotherapy, including pomalidomide and dexamethasone, followed by two sessions of DLI were performed. Four days after the 2nd DLI, liver function profiles were within normal limits (AST 22 U/L, ALT 25 U/L), and two weeks after 2nd DLI, she suffered from generalized pain, a febrile sensation, and skin rash and visited our emergency room (hospital day 0).

Initial examination presented an alert mental status, tachycardia (102/min), and a high body temperature (38.9℃). The laboratory evaluation showed thrombocytopenia (92,000/mm3), abnormal liver function profiles (AST 1,081 U/L, ALT 1,417 U/L, ALP 117 U/L, GGT 84 U/L, LDH 1,160 U/L, total bilirubin 1.7 mg/dL, albumin 3.4 g/dL, PT INR 1.54, CRP 11.15 mg/dL, procalcitonin 1.38 ng/mL, PT INR 1.54). Serum kappa-free light chain was 149 mg/dL. Her CHB had been well-suppressed by tenofovir alafenamide for 2 years. Three weeks before emergency room visit, laboratory results revealed AST 25 U/L, ALT 19 U/L, HBeAg (+), anti-HBe (-), and HBV DNA 26.1 IU/mL. Empirical antibiotics were applied, but no pathogen was identified in blood or urine cultures. Abdominal computed tomography (CT) showed no cirrhotic features or definite fever focus (Fig. 1). On suspicion of GVHD liver involvement, methylprednisolone was initially administered at a dosage of 240 mg daily, and this was subsequently reduced to 120 mg daily over the following days.

Figure 1. Initial abdominal CT showed no cirrhotic feature or splenomegaly, suggesting portal hypertension.

On hospital day 1, her mental status became drowsy. Brain CT showed no specific findings, and laboratory tests showed AST 1,113 U/L, ALT 1,606 U/L, albumin 2.7 g/dL, and total bilirubin 2.5 mg/dL. Viral markers were IgM anti-HAV (-), anti- HCV (-), HBsAg (+), HBeAg (+), anti-HBe (+), and HBV DNA 1,260 IU/mL. Autoimmune markers, including antinuclear antibody, anti-smooth muscle antibody, anti-mitochondrial antibody, and anti-LKM, were all negative. On hospital day 3, her mental status was stuporous, and laboratory tests showed AST 630 U/L, ALT 2,133 U/L, albumin 2.7 g/dL, total bilirubin 6.1 mg/dL, serum ammonia 43 μmol/L, and PT INR 1.42.

On hospital day 4, consciousness aggravated to a semi-comatose state, and lactulose and mannitol were administered. The electroencephalogram consisted of symmetrically distributed, diffuse theta and delta activities, suggesting moderate to severe diffuse cerebral dysfunction. Brain MRI showed increased focal high FLAIR signal intensity at the falx and left and right frontoparietal convexity and white matter hyperintensities in bilateral coronal radiata. During high-dose glucocorticoid treatment, serum aminotransferase and total bilirubin levels improved, and her mental status also recovered (Fig. 2). On hospital day 12, she presented alert and intact orientation. Laboratory findings on hospital day 26 presented complete remission of the multiple myeloma (serum kappa free light chain 14.4 mg/L), and she was transferred to a rehabilitation hospital on hospital day 35.

Figure 2. Serum aminotransferase and total bilirubin level changes during acute liver failure. DLI, donor lymphocyte infusion; ER, emergency room; mPD, methyl prednisolone.

At 12 months after episode of acute severe liver dysfunction, the multiple myeloma relapsed for the 4th time, and 10 cycles of salvage chemotherapy (pomalidomide, cyclophosphamide, and dexamethasone) were applied for 18 months. The patient was subsequently lost to follow-up.


DLI is a salvage treatment for recurrent hematologic disorders after stem cell transplantation. Donor lymphocytes are expected to induce an anti-tumor effect in the recipient due to a graft-versus-leukemic effect. However, previous studies have shown that 40–60% of recipients experience GVHD involving skin, intestine, and liver.3 Conventionally, hepatic GVHD has been described as a cholestatic form presenting elevated ALP and bilirubin. However, Fujii et al. reported a case of increased aminotransferase without cholestasis 23 days after allogeneic peripheral blood stem cell transplantation.4 Akpek et al. reported that hepatic GVHD developed in 22 of 73 (30%) cases after DLI, and half of them received a diagnosis of a hepatitic variant.2 According to an analysis of 242 patients who received allogeneic hematopoietic stem cell transplantation (HSCT), acute onset hepatitic GVHD (>10 the upper limits of normal AST or ALT levels) occurred in 23 patients, and this hepatitic variant of GVHD was more frequent administered DLI (26%) than in those with de novo acute GVHD (5%) or chronic GVHD (9%).5 In another report, 11 of 19 patients undergoing DLI for a hematologic malignancy relapse after HSCT had liver involvement with clinical features of the classical cholestatic form in 5 patients and hepatitic form in 6 patients.6 Skert et al. reported a case of acute hepatic failure as the onset of progressive sclerodermatous chronic GVHD after DLI in a patient with acute myeloid leukemia. However, although Skert et al. used the term "acute hepatic failure (ALF)", presumably due to abnormal liver function profiles and ascites, this case could not be classified as "ALF" according to the current definition because there was no episode of acute encephalopathy.7 Although any hepatic GVHD of any type can induce acute severe liver injury, no case of hepatic GVHD associated with ALF has been reported. Therefore, this patients with acute severe liver dysfunction with decreased mental status is the possibility of the first case of ALF based on acute onset of liver dysfunction, coagulopathy, and encephalopathy.8 Even if the brain imaging did not present the definite cerebral edema, its absence does not exclude the diagnosis. Some patients may develop encephalopathy without radiological evidence of cerebral edema, especially in the early stages. Additionally, imaging studies such as CT or MRI may not always capture subtle changes in cerebral edema, especially if performed early in the course of the disease.

It is also possible that HBV reactivation caused the acute liver injury in our case. The patient had maintained partial virological response on an oral nucleotide analog before the ALF episode, and her serum HBV DNA level was slightly elevated (from 26.1 to 1,260 IU/mL). Academic society guidelines define the reactivation of CHB at an HBV DNA level of ≥100-fold the known baseline level.9 Thus, because the increase in HBV DNA was small (<100-fold) in our patient, it is less than likely that the ALF was due to HBV reactivation.

Another possibility of altered mental status in our patient was central nervous system (CNS) involvement by GVHD. Ruggiu et al.10 reported 7 cases of GVHD CNS involvement and reviewed 32 additional cases in the literature. Most of the patients involved experienced a chronic onset after hematopoietic stem cell transplantation, but a few experienced an acute onset like our patient.10 Several studies have reported neurologic deficits and abnormal brain MRI findings in patients with acute or chronic GVHD. However, they did not mention concomitant liver failure.11 Nevertheless, as brain edema was not noted by brain imaging, increased intracranial pressure due to hyperammonemia was not measured, and no brain biopsy was not performed, there is a possibility of coincidental GVHD involving both liver and CNS in our case.

High-dose glucocorticoid has been reported to control hepatic GVHD,2 and our patient also showed improvement in liver function and later consciousness after glucocorticoid injection. Further experience and trials are necessary to determine the optimal approach to such cases.

Experience of this case suggests that clinicians should consider the possibility of ALF in acute severe liver injury after donor lymphocyte infusion as a rare presentation of hepatic GVHD.

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