Introduction
Histopathological, regenerative nodules are hyperplastic proliferations of hepatocytes in response to necrosis, altered circulations, or other stimuli.1 They usually occur in patients with hepatitis or alcoholic cirrhosis, vascular liver diseases such as Budd-Chiari syndrome,2 or cholangiopathic disorders such as biliary atresia3 or Alagille syndrome.4,5 Regenerative nodules are classified by size as micronodules (<3 mm) or macronodules (≥3 mm).1,6 Large regenerative nodules are usually 5 to 15 mm in diameter, but they can be 5 cm or larger.1,6 Giant nodules as larger as 5 cm have been reported in patients with liver cirrhosis,7 Budd-Chiari syndrome,8 biliary atresia,3 or Alagille syndrome.4,5 Giant nodules of 10 cm in diameter or more have only been reported in patients with biliary atresia3 or Alagille syndrome.4,5 We report a rare and unique case who presented with a giant hepatic regenerative nodule more than 10 cm in size and associated with hepatitis B virus (HBV)-related cirrhosis.
Case report
A 50 year-old man was found to have a hepatic mass suspected to be liver cancer by ultrasonography. He denied any clinical symptoms. Physical examination revealed an enlarged non-tender liver with a firm and uneven surface. The lower edge of the liver extended to the right iliac crest. The spleen was not palpable. A routine blood workup found a white blood cell count of 5.3×109/L, a red blood cell count of 4.5×1012/L, a hemoglobin level of 141 g/L, and a platelet count of 80×109/L. Liver function tests showed increased levels of alanine aminotransferase (ALT) 107.8 IU/L (reference range, 0–40 IU/L), aspartate aminotransferase (AST) 69.4 IU/L (reference range, 0–38 IU/L), alkaline phosphatase 171.3 IU/L (reference range, 30–150 IU/L), and gamma-glutamyl transferase 452.4 IU/L (reference range, 0–47 IU/L), normal serum total bilirubin, albumin, plasma prothrombin time, international normalized ratio, and ammonia. Hepatitis virus tests were positive for hepatitis B surface antigen (HBsAg), HB e antigen, HB e antibody, and HB core antibody, and negative for HB surface antibody, hepatitis C virus antibody, and hepatitis C antigen. Alpha-fetoprotein and carcinoembryonic antigen assays were negative.
A CT scan showed pronounced nodular irregularity of the liver surface, enlargement of the interlobar fissure, hypertrophy of the left lobe, and dilatation of the portal vein, with a diameter of 21.0 mm (Fig. 1). Diffuse multiple nodules of <1 cm diameter in the liver parenchyma showed slight hyperdensity on precontrast CT images and became isodense in post-contrast phases (Fig. 1). Precontrast CT showed a well-circumscribed 11.3×9.4×11.2 cm oval hypodense mass in segment VI of the liver, including a focal hypodense area extending downward to the right iliac fossa (Fig. 2A, A′). Contrast-enhanced CT showed isoenhancement in the arterial phase (Fig. 2B, B′) with slight hyperenhancement, a portal vein branch crossing through the lesion in the portal phase (Fig. 2C, C′), and slight hypoenhancement in the delayed phase (Fig. 2D, D′). The focal hypodense area within the lesion was not enhanced from the arterial phase to the delayed phase.
A follow-up contrast-enhanced MRI with gadoxetic acid at 6 months found no significant differences in the size, shape, margin, internal characteristics, and three-phase contrast-enhancement patterns compared with the original CT images, except for slight hyperenhancement in the delayed 20 and 30 m hepatobiliary phases (Fig. 3). At 10.5 months after the first hospital admission, a CT-guided percutaneous biopsy resulted in pathological confirmation of a hepatic regenerative nodule (Fig. 4).
Discussion
When assessing a patient with a liver mass, noninvasive diagnosis of HBV-related cirrhosis and the imaging characteristics of hepatic regenerative nodules are important. Non-invasive diagnosis of HBV-related cirrhosis depends on calculation of the AST-to-platelet ratio index (APRI) and the fibrosis-4 score (FIB-4) using indirect markers of fibrosis such as ALT, AST and platelet count.9 APRI = [(AST/ASTULN)/platelet count] × 100 and the Fib-4 score = (age in years × AST)/(platelet count × √ALT). In clinical practice, liver biopsy has been replaced by noninvasive methods as APRI and FIB-4 scores and imaging.9 An APRI score >2 is recommended as the preferred noninvasive threshold to determine the presence of cirrhosis in resource-limited settings by the World Health Organization HBV guidelines. A FIB-4 >3.25 has a 97% specificity and a 65% positive predictive value for advanced fibrosis.9 Conventional ultrasound, CT, and MRI can detect morphologic changes in the liver related to advanced fibrosis, but the methods have a limited ability to identify early-stage fibrosis.10,11 Our patient was positive for HBV, with an APRI of 2.283 and a FIB-4 of 4.18. CT scan showed morphological changes in the liver and the dilation of portal veins. We diagnosed HBV-related cirrhosis based on the findings.
During imaging evaluation, predominant portal perfusion was visible in dynamic contrast-enhanced imaging, including CT, MRI, and ultrasound. The vascular supply of regenerative nodules is similar to the surrounding hepatic parenchyma,3-5,7,12 unlike hepatocellular carcinoma (HCC), which usually shows arterial wash-in and late washout, regenerative nodules are usually isointense during the arterial and portal venous phases and become more isointense or hypointense during the equilibrium and delayed phases.7,12 In the hepatobiliary phase of gadoxetic acid-enhanced MRI, regenerative nodules commonly appear as isointense or mildly hyperintense signals, and not hypointense, relative to the surrounding liver parenchyma because of the preserved hepatocellular function.13 In addition to the contrast-enhancement pattern, the image of the portal vein crossing through the mass is reported to be characteristic of giant hepatic regenerative nodules in the portal phase images3–5 because the nodules have normal portal tracts at the center.1–5,7,12 Therefore, hepatic regenerative nodules of various sizes should be categorized as Liver Imaging and Reporting Data System category 2, as they did not have the major and ancillary imaging features of HCC and other malignancies.14,15
Current international guidelines recommend that all HBsAg-positive patients with cirrhosis should be routinely monitoring for disease activity and progression to HCC.9 Recent clinical practice guidelines include gadoxetic acid-enhanced liver MRI as the first-line diagnostic and monitoring tool for hepatic nodules instead of biopsy. A single dynamic CT or MRI study rather than two dynamic imaging modalities is recommended for the diagnosis of HCC lesions of < 2 cm.13 Huge lesions should be considered as focal malignant transformations if major and/or ancillary imaging features of Liver Imaging and Reporting Data System category to assess HCC or other malignancies have developed.16 Percutaneous needle biopsies may be difficult to obtain in cases of focal malignant transformation. During the initial stage of tumor initiation, HCC may retain hepatocellular function and isointense or mildly hyperintense signals similar to regenerative nodules.17 For early HCC in cirrhotic livers, patients should be evaluated with multiparametric imaging, including T1 hypointensity, T2 hyperintensity, diffusion-weighted imaging hyperintensity, arterial enhancement, late washout, and hepatobiliary hypointensity at a size threshold of ≥1.5 cm on gadoxetic acid-enhanced MRI. The findings should be interpreted with care.18–20 Finally, if imaging features and laboratory results still cannot support a definitive diagnosis, a multidisciplinary team may discuss the atypical features to help to develop an appropriate approach for the patient.19 In conclusion, giant hepatic regenerative nodules in the background of liver cirrhosis have characteristic imaging features that can help guide clinical management and avoid unnecessary medical interventions.
Abbreviations
- ALT:
alanine aminotransferase
- APRI:
aspartate aminotransferase-to-platelet ratio index
- AST:
aspartate aminotransferase
- CT:
computed tomography
- FIB-4:
fibrosis-4 score
- HBsAg:
hepatitis B surface antigen
- HBV:
hepatitis B virus
- HCC:
hepatocellular carcinoma
- HU:
Hounsfield units
- IU:
international unit
- MRI:
magnetic resonance imaging
Declarations
Patient consent
The patient provided written informed consent and gave permission for publication of this case report and any accompanying images.
Funding
None to declare.
Conflict of interest
The authors have no conflict of interests related to this publication.
Authors’ contributions
Both authors, LL and FJ, contributed to the design and implementation of the study and to the analysis of the results and to the writing of the manuscript.