We report a rare case of marked elevation of α-fetoprotein in the absence of hepatocellular carcinoma caused by a relapse of hepatitis C virus (HCV) infection. A 58-year-old man underwent liver transplantation to treat hepatocellular carcinoma caused by HCV-related liver cirrhosis. The HCV was of genotype 2a, and the ribonucleic acid titer was >8.0 log IU/mL. Direct-acting antiviral drugs were prescribed for 12 weeks; however, the HCV infection relapsed after treatment had ended, and α-fetoprotein levels increased to 8,981 ng/mL. Imaging did not reveal any malignancies. The patient initiated interferon therapy, at which time AFP levels decreased, and the HCV was successfully cleared.
Hepatitis C virus (HCV) infection frequently recurs in liver transplant (LT) recipients with hepatocellular carcinomas (HCCs) caused by HCV-related liver cirrhosis.1 HCV re-infection triggers inflammation of the host liver.2 The level of α-fetoprotein (AFP) is a diagnostic marker of HCC, although the proportion of lesitine (L3) is more specific. AFP levels also increase during viral hepatitis.2 The recurrence-free survival rate has been reported to be 83% after LT in patients who had undergone LT due to HCC.3
A 58-year-old Asian man underwent LT to treat HCC caused by HCV-related liver cirrhosis. He had no history of treatment for HCV prior to transplant. One HCC (5.0 cm in diameter) was located in S5 and was moderately differentiated and of the simple nodular type; another HCC (1.5 cm in diameter) was located in S8/4 and was of the green hepatoma type (ie, associated with mutations in the hepatocyte nuclear factor 1A gene). No portal invasion was apparent. The patient’s AFP level was 153 ng/mL.
Figure 1. The α-fetoprotein level was notably elevated in the absence of hepatocellular carcinoma at 9 months post-liver transplant, and the level normalized after interferon therapy. PSL, methylprednisolone/prednisolone; MMF, mycophenolate mofetil; TAC, tacrolimus; SNMC, stronger neo-minophagen C; EVR, everolimus; LT, liver transplantation; SOF, sofosbuvir; RBV, ribavirin; PET, positron emission tomography; CT, computed tomography; PEG-IFN, pegylated-interferon; AST, aspartate aminotransferase; T-BIL, total bilirubin; HCV, hepatitis C virus; AFP, α-fetoprotein; DCP, des-gamma-carboxy prothrombin; HCC, hepatocellular carcinoma.
After LT, HCV of genotype 2a re-infected the grafted liver. The HCV ribonucleic acid (RNA) level was >8.0 log IU/mL. We started the patient on an immunosuppressant cocktail of tacrolimus, mycophenolate mofetil, and a steroid (methylprednisolone/prednisolone) (Figure 1). Transaminase and total bilirubin levels increased 2 months after LT, and fibrosing cholestatic hepatitis was suspected. Therefore, direct-acting antiviral drugs (ie, sofosbuvir+ribavirin 400 mg once daily) were given for 12 weeks. The HCV RNA level fell during treatment but increased again 1 month later, in association with marked elevation of liver enzymes. The steroid and mycophenolate mofetil were discontinued, and a daily injection of glycyrrhizin (SNMC; 80 mL stronger neo-minophagen C containing 40 mg glycyrrhizin in 20 mL) was commenced. At 6 months post-trasnplant, although the transaminase levels had improved, AFP levels were elevated to 167 ng/mL. Blood testing revealed aspartate aminotransferase 134 U/L, alanine aminotransferase 147 U/L, HCV RNA 7.6 log IU/mL, and des-gamma-carboxy prothrombin (DCP) 47 mAU/mL. Although we searched for HCC via whole-body imaging (including the brain, lungs, abdomen, and pelvic cavity), all results were negative, and an ascites aspirate assay revealed no malignant cells. Fluorodeoxyglucose-position emission tomography and computed tomography scans from head to pelvis/prostate were performed at 8 months post-transplant (Figure 2). No HCC or AFP-producing tumor was detected. AFP levels increased to 8,981 ng/mL (L3 proportion, 7.5%) at 9 months; DCP levels were 74 mAU/mL at this time. A once-weekly pegylated interferon (IFN)-α-2a treatment was commenced to prevent HCC development. Fever and pancytopenia developed, and treatment was stopped 6 weeks later. The condition improved on discontinuation of IFN. In addition, HCV RNA levels fell, and a sustained virological response was obtained. AFP levels gradually decreased to undetectable levels by 17 months post-transplant.
Figure 2. Post-liver transplant images: (A) Abdominal computed tomography. (B) Fluorodeoxyglucose-PET (FDG-PET) and CT scans of the liver. (C) FDG-PET and CT scan of the whole body 8 months after transplant. No malignancy was apparent.
AFP is a glycoprotein secreted by fetal cells during embryogenesis and is a well-known diagnostic marker of HCC.2 However, the sensitivity and specificity of AFP in terms of HCC detection are only 41–65% and 80–90%, respectively.4,5 AFP is also elevated in various extrahepatic tumors, including gastrointestinal tract tumors and pancreatic, gallbladder, lung, and bladder cancers.6 AFP levels >1,000 ng/mL are highly indicative of HCC. AFP-L3 exhibits the highest lectin affinity and is commonly seen in patients with HCCs. Some reports have described AFP elevation in the absence of HCC; however, in these cases the AFP levels were only around 2,000 ng/mL.7-10 Viral infections activate multiple proinflammatory mediators such as tumor necrosis factor α, malondialdehyde, and nitric oxide, which recruit immune cells to the liver to generate an antiviral response.11 It is believed that AFP elevation is attributable to hepatic inflammation and viral replication. Elevated levels of AFP as high as 5,480 ng/mL that resulted from chronic viral hepatitis have been described, as well as a reduction in levels with both IFN and direct-acting antiviral drug therapy; in addition, the measurement of the L3 proportion is important to diagnose HCC.12,13
In our patient, his AFP levels increased to 8,981 ng/mL without an increase in the proportion of L3. DCP, which perhaps is best known as the protein induced by vitamin K deficiency or antagonist II (PIVKA-II) and as an abnormal form of prothrombin, is another biomarker of HCC, and it was not significantly increased in this case.14 We found no evidence of HCC or an AFP-producing tumor, and we doubt that an occult cancer was present. Direct-acting antiviral drugs often exhibit high efficacy and tolerability in patients after LT, but they cannot be administered to patients with HCCs.15 Thus, we selected IFN therapy because of its association with reduced HCCs.16,17 AFP levels decreased after the eradication ofHCV. There is some risk of AFP increase associated with chronic hepatitis, and elevated AFP serum levels, elevated aspartate aminotransferase, prolonged international normalized ratio (international normalized ratio), hepatic steatosis, and HCV load are significantly associated with fibrosis.18 In our case, we speculate that acute HCV overgrowth due to immunosuppression in this LT recipient may contribute to a strong host-immune response and accelerated liver inflammation, leading to a sharp increase in AFP. Although the HCV RNA viral load was high, the AFP elevation occurred at 9 months post-transplant despite the decreased aspartate aminotransferase level after treatment with SNMC, which has been shown to have an anti-inflammatory effect and is approved in Japan for the treatment of chronic hepatic diseases.19 In patients who do not tolerate anti-viral therapy for HCV, ursodeoxycholic acid and/or glycyrrhizin is selected to reduce the transaminase level. In addition, it may be assumed that the rise in AFP levels was due to liver regeneration; however, the underlying mechanism is unknown.
We present a rare case with AFP elevation above 8,000 ng/mL attributable to acute hepatitis exacerbation in the absence of HCC under immunosuppressive conditions. The condition normalized following anti-viral therapy. In cases exhibiting AFP elevation, malignancy should first be ruled out, and thereafter viral inflammation should be considered as a potential cause.
Author contributions: T. Kogiso wrote the manuscript, T. Sagawa collected the data, Y. Kotera performed the liver transplant, H. Egawa provided advice regarding this case report, and M. Yamamoto and K. Tokushige supervised this case study. K. Tokushige is article guarantor.
Financial disclosure: K. Tokushige received research funding from Sumitomo Dainippon Pharma Co., Ltd.; Astellas Pharma, Inc.; Eisai Co., Ltd.; TAIHO Pharmaceutical Co., Ltd.; Chugai Pharmaceutical Co., Ltd.; Daiichi Sankyo Pharmaceutical Co., Ltd.; AbbVie GK; Takeda Pharmaceutical Co., Ltd.; Asahi Kasei Corporation; AJINOMOTO CO., Inc.; and Otsuka Pharmaceutical Co., Ltd.
Informed consent was obtained for this case report.
Correspondence: Dr. Tomomi Kogiso, 8-1, Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan (firstname.lastname@example.org).
Received June 13, 2018; Accepted November 07, 2018
- Berenguer M, Schuppan D. Progression of liver fibrosis in post-transplant hepatitis C: Mechanisms, assessment and treatment. J Hepatol. 2013;58(5):1028–41.Article | PubMed
- Tai WC, Hu TH, Wang JH, et al. Clinical implications of alpha-fetoprotein in chronic hepatitis C. J Formos Med Assoc. 2009;108(3):210–18.Article | PubMed
- Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693–9.Article | PubMed
- European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908–43.Article | PubMed
- Soresi M, Magliarisi C, Campagna P, et al. Usefulness of alpha-fetoprotein in the diagnosis of hepatocellular carcinoma. Anticancer Res. 2003;23(2C):1747–53.PubMed
- Su JS, Chen YT, Wang RC, Wu CY, Lee SW, Lee TY. Clinicopathological characteristics in the differential diagnosis of hepatoid adenocarcinoma: A literature review. World J Gastroenterol. 2013;19(3):321–7.Article | PubMed
- Yoon YM, Kang DY, Kim DY, Seo JW, Lim HJ, Lee HJ, Park SG. Extremely elevated alpha-fetoprotein due to acute exacerbation of chronic hepatitis B without malignancy: A case report. J Med Case Rep. 2016;10(1):140.Article | PubMed
- Sugimoto M, Itsukaichi T, Ishii K, Sumino Y, Sugano S, Abei T, Imamura Y. Marked increase in serum alpha-fetoprotein level in cirrhosis: a case report. Am J Gastroenterol. 1987;82(1):69–71.PubMed
- van der Veek PP, de Vos Tot Nederveen Cappel WH, Langers AM, van Hoek B. Two patients with extremely elevated tumor markers: Where is the malignancy?Gastroenterol Res Pract. 2011;2011:123743.Article | PubMed
- Patil M, Sheth KA, Adarsh CK. Elevated alpha fetoprotein, no hepatocellular carcinoma. J Clin Exp Hepatol. 2013;3(2):162–4.Article | PubMed
- Tawadrous GA, Aziz AA, Amin DG, et al. RANTES, TNF-α, oxidative stress, and hematological abnormalities in hepatitis C virus infection. J Investig Med. 2012;60(6):878–2.Article | PubMed
- Chen TM, Huang PT, Tsai MH, et al. Predictors of alpha-fetoprotein elevation in patients with chronic hepatitis C, but not hepatocellular carcinoma, and its normalization after pegylated interferon alfa 2a-ribavirin combination therapy. J Gastroenterol Hepatol. 2007;22(5):669–75.Article | PubMed
- Bae JS, Park SJ, Park KB, et al. Acute exacerbation of hepatitis in liver cirrhosis with very high levels of alpha-fetoprotein but no occurrence of hepatocellular carcinoma. Korean J Intern Med. 2005;20(1):80–5.Article | PubMed
- Carr BI, Kanke F, Wise M, Satomura S. Clinical evaluation of lens culinaris agglutinin-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin in histologically proven hepatocellular carcinoma in the United States. Dig Dis Sci. 2007;52(3):776–82. Article | PubMed
- Saxena V, Khungar V, Verna EC, et.al . Safety and efficacy of current direct-acting antiviral regimens in kidney and liver transplant recipients with hepatitis C: Results from the HCV-TARGET study. Hepatology. 2017;66(4):1090–101.Article | PubMed
- Imai Y, Tamura S, Tanaka H, et al. Reduced risk of hepatocellular carcinoma after interferon therapy in aged patients with chronic hepatitis C is limited to sustained virological responders. J Viral Hepat. 2010;17(3):185–91.Article | PubMed
- Yoshida H, Shiratori Y, Moriyama M, et al. Interferon therapy reduces the risk for hepatocellular carcinoma: National surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT study group. Inhibition of hepatocarcinogenesis by interferon therapy. Ann Intern Med. 1999;131(3):174–81.Article | PubMed
- Hu KQ, Kyulo NL, Lim N, et al. Clinical significance of elevated alpha-fetoprotein (AFP) in patients with chronic hepatitis C, but not hepatocellular carcinoma. Am J Gastroenterol. 2004;99(5):860–5.Article | PubMed
- Iino S, Tango T, Matsushima T, et al. Therapeutic effects of stronger neo-minophagen C at different doses on chronic hepatitis and liver cirrhosis. Hepatol Res. 2001;19(1):31–40.Article | PubMed
Copyright: © 2018 Kogiso et al. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0.