Abstract
Acute liver failure following COVID-19 infection and/or vaccination is very rare and can be secondary to hemophagocytic lymphohistiocytosis (HLH). Liver injury in such cases appears to be extrinsic and thus treatment hinges on prompt diagnosis and reversal of the primary disease. We describe a patient who developed acute liver failure secondary to HLH after receiving a second dose of the Pfizer COVID-19 vaccine. Persistently elevated liver function tests, fevers, and cytopenia following COVID-19 vaccination should prompt clinicians to calculate an H-score to evaluate for the presence of HLH.
Keywords: Acute liver failure, COVID-19, hemophagocytic lymphohistiocytosis, vaccination
Acute liver failure (ALF) has multiple etiologies, but one-third of cases remain idiopathic.1 HLH can be classified into primary and secondary types and is a rare cause of liver failure.2 The literature has reported a handful of cases of secondary HLH following COVID-19 viral illness and vaccination.3–5
CASE PRESENTATION
In September 2021, a 33-year-old healthy man with a past medical history of hyperlipidemia and seasonal allergies presented to the emergency department with fever, rash, malaise, elevated liver enzymes, and leukopenia. He received his second dose of the Pfizer COVID vaccine on August 25, 2021, and 3 days later developed fever (102°F), chills, and headaches. He was sent home for outpatient follow-up and eventually saw a hematologist for persistent cytopenia, believed to be a likely sequela of a viral infection. He tested negative for COVID-19, although serology was positive for COVID-19 antibodies due to vaccination. Moreover, the patient continued to have intermittent fevers, body aches, and a 15-lb weight loss, eventually culminating in his first hospitalization on October 22, 2021, for fever of unknown origin and acute liver injury.
During this hospitalization, the patient had pancytopenia and elevated liver function tests (LFTs). Abdominal ultrasound revealed splenomegaly, and a bone marrow biopsy was unremarkable. Viral, fungal, protozoal, helminthic, and bacterial etiologies were ruled out. A liver biopsy revealed significant hepatic inflammation without any confirmatory etiology. At this point, rheumatology started the patient on prednisolone for adult-onset Stills disease (AOSD), with fever, myalgias/arthralgias, rash, splenomegaly, and elevated ferritin. The patient improved and was discharged home on prednisone 20 mg twice a day with gastroenterology follow-up, as LFTs did not return to normal.
On November 23, 2021, the patient followed up with a hepatologist; LFTs had improved remarkably. Rheumatology tapered his steroids to 40 mg and started to work on procurement of canakinumab. However, soon after steroid tapering, the patient developed arthralgias, rash, jaundice, and fever, again resulting in hospitalization on December 14, 2021, for management of AOSD flare-up. His LFTs and inflammatory markers continued to worsen despite being on methylprednisolone, anakinra, and intravenous immunoglobulin. Since he was no longer meeting the Cush and Fautrel criteria, the rheumatologists were not convinced he had AOSD.
Due to lack of response to therapy, there was concern that he had secondary HLH. The H-score was 274, showing a >99% probability of HLH. Therefore, he was started on the HLH 2004 protocol (etoposide and dexamethasone). Repeat bone marrow biopsy on January 10, 2022, showed marrow consistent with HLH. He continued to worsen clinically. Due to severe liver dysfunction, etoposide was discontinued on January 13, 2022. His inflammatory markers, LFTs, and cytopenia continued to worsen, and ultimately he was in multiorgan failure, after which he was transitioned to comfort care.
DISCUSSION
HLH is a rare but lethal diagnosis for ALF. It is characterized by an exaggerated immune response causing multiorgan dysfunction and thus carries a high mortality rate of 40% to 75%.6,7 It is rare to acquire HLH after COVID-19 viral infection and even rarer after COVID-19 vaccination.5 The HLH frequency is <5% in COVID-19.8 Studies have shown that ∼85% of secondary HLH patients can have elevated aspartate aminotransferase and alanine aminotransferase levels and up to 50% have hyperbilirubinemia.9 Liver histopathology is usually nonspecific, showing hepatocellular necrosis and steatosis.10 The pathophysiology is unknown, but it is postulated that invasion of hemophagocytic histiocytes or overproduction of inflammatory cytokines triggers liver damage.11 Liver involvement in HLH portends a poor prognosis when there’s cholestasis and/or a high aspartate aminotransferase level.7,12 In our case, liver involvement developed early (Table 1).
Table 1.
Clinical and laboratory values
| Clinical features | Result |
|---|---|
| Duration of symptoms (months) | 3 |
| Fever | + |
| Rash | + |
| Jaundice | + |
| Encephalopathy | + |
| Diagnostic criteria: H-score (points) | >274 |
| Lymphadenopathy | – |
| Splenomegaly | + |
| Pancytopenia | + |
| Alkaline phosphatase (U/L) | 214 |
| Aspartate aminotransferase (U/L) | 148 |
| Alanine aminotransferase (U/L) | 279 |
| Total bilirubin (mg/dL) | 1.7 |
| Albumin (g/dL) | 3.1 |
| Prothrombin time/international normalized ratio | 1.4 |
| Hemoglobin (g/dL) | 12.6 |
| Total lymphocyte count (/mm3) | 1.59 |
| Platelets (/mm3) | 22 |
| Ferritin (ng/mL) | >26,000 |
| Triglycerides (mg/dL) | 738 |
| Fibrinogen (ng/mL) | 81 |
| Hemophagocytosis on bone marrow biopsy | + |
| IL-2 receptor (pg/mL) (ref. range 175.3–858.2) | 49,421.8 |
| IL-6 (pg/mL) (ref. range ≤1.8) | 25.9 |
| IL-18 (pg/mL) | 22,134 |
| CXCL9 (pg/mL) (ref. range ≤647) | 91,804 |
Early diagnosis and timely treatment with the HLH 2004 protocol has been shown to improve survival in HLH patients.7 Even though etoposide is a potential hepatotoxic drug, it is an integral component of the regimen; hence, recognizing HLH before development of ALF is crucial.7
Liver transplant in secondary HLH patients carries poor outcomes.13,14 In one center, three patients with HLH-related ALF were evaluated for urgent liver transplantation but died during the hospitalization.15 In contrast, one transplant center reported nine pediatric patients who underwent liver transplant due to ALF secondary to reversible HLH, and six of the nine patients survived a median of 24 months, with one requiring repeat liver transplant.16 In summary, liver transplantation is not recommended when ALF is due to an end-stage and irreversible HLH.13
Gastroenterologists receiving referrals for post-COVID-19 infections or vaccinations with deranged LFTs, cytopenia, and fever should promptly determine an H-score for initial evaluation of HLH. Time is of the essence; early diagnosis not only ensures the patient’s candidacy for appropriate treatment options but also increases the chances of treatment success.
References
- 1.Zhao P, Wang C, Liu W, et al. Causes and outcomes of acute liver failure in China. PLoS One. 2013;8(11):e80991. doi: 10.1371/journal.pone.0080991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Jagtap N, Sharma M, Rajesh G, et al. Hemophagocytic lymphohistiocytosis masquerading as acute liver failure: a single center experience. J Clin Exp Hepatol. 2017;7(3):184–189. doi: 10.1016/j.jceh.2017.01.119. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Kayaaslan BU, Asilturk D, Eser F, et al. A case of hemophagocytic lymphohistiocytosis induced by COVID-19, and review of all cases reported in the literature. J Infect Dev Ctries. 2021;15(11):1607–1614. doi: 10.3855/jidc.14829. [DOI] [PubMed] [Google Scholar]
- 4.Zellweger NM, Huber J, Tsakiris DA, Tzankov A, Gebhard CE, Siegemund M.. Haemophagocytic lymphohistiocytosis and liver failure-induced massive hyperferritinaemia in a male COVID-19 patient. Swiss Med Wkly. 2021;151:w20420. doi: 10.4414/smw.2021.20420. [DOI] [PubMed] [Google Scholar]
- 5.Tang LV, Hu Y.. Hemophagocytic lymphohistiocytosis after COVID-19 vaccination. J Hematol Oncol. 2021;14(1):1–5. doi: 10.1186/s13045-021-01100-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Parikh SA, Kapoor P, Letendre L, Kumar S, Wolanskyj AP.. Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis. Mayo Clin Proc. 2014;89(4):484–492. doi: 10.1016/j.mayocp.2013.12.012. [DOI] [PubMed] [Google Scholar]
- 7.Arca M, Fardet L, Galicier L, et al. Prognostic factors of early death in a cohort of 162 adult haemophagocytic syndrome: impact of triggering disease and early treatment with etoposide. Br J Haematol. 2015;168(1):63–68. doi: 10.1111/bjh.13102. [DOI] [PubMed] [Google Scholar]
- 8.Retamozo S, Brito-Zerón P, Sisó-Almirall A, Flores-Chávez A, Soto-Cárdenas M-J, Ramos-Casals M.. Haemophagocytic syndrome and COVID-19. Clin Rheumatol. 2021;40(4):1233–1244. doi: 10.1007/s10067-020-05569-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Li J, Wang Q, Zheng W, et al. Hemophagocytic lymphohistiocytosis: clinical analysis of 103 adult patients. Medicine (Baltimore). 2014;93(2):100–105. doi: 10.1097/MD.0000000000000022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Tsui W, Wong K, Tse C.. Liver changes in reactive haemophagocytic syndrome. Liver. 1992;12(6):363–367. doi: 10.1111/j.1600-0676.1992.tb00590.x. [DOI] [PubMed] [Google Scholar]
- 11.Chen J-H, Fleming MD, Pinkus GS, et al. Pathology of the liver in familial hemophagocytic lymphohistiocytosis. Am J Surg Pathol. 2010;34(6):852–867. doi: 10.1097/PAS.0b013e3181dbbb17. [DOI] [PubMed] [Google Scholar]
- 12.De Kerguenec C, Hillaire S, Molinié V, et al. Hepatic manifestations of hemophagocytic syndrome: a study of 30 cases. Am J Gastroenterol. 2001;96(3):852–857. doi: 10.1111/j.1572-0241.2001.03632.x. [DOI] [PubMed] [Google Scholar]
- 13.Cappell MS, Hader I, Amin M.. Acute liver failure secondary to severe systemic disease from fatal hemophagocytic lymphohistiocytosis: case report and systematic literature review. WJH. 2018;10(9):629–636. doi: 10.4254/wjh.v10.i9.629. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Wright G, Wilmore S, Makanyanga J, et al. Liver transplant for adult hemophagocytic lymphohistiocytosis: case report and literature review. Exp Clin Transplant. 2012;10(5):508–512. doi: 10.6002/ect.2011.0204. [DOI] [PubMed] [Google Scholar]
- 15.Schneier A, Stueck AE, Petersen B, Thung SN, Perumalswami P.. An unusual cause of acute liver failure: three cases of hemophagocytic lymphohistiocytosis presenting at a transplant center. Semin Liver Dis. 2016;36(1):99–105. doi: 10.1055/s-0036-1571299. [DOI] [PubMed] [Google Scholar]
- 16.Amir AZ, Ling SC, Naqvi A, et al. Liver transplantation for children with acute liver failure associated with secondary hemophagocytic lymphohistiocytosis. Liver Transpl. 2016;22(9):1245–1253. doi: 10.1002/lt.24485. [DOI] [PubMed] [Google Scholar]