Hepatectomy in a case of hepatocellular carcinoma with constitutional indocyanine green excretory defect

Highlights • Constitutional indocyanine green excretory defect is extremely rare.• The ICGR15 is important for estimating hepatic functional reserve and selection of the appropriate surgical procedure.• Because of the rarity of constitutional ICG excretory defect, its clinical features are not well understood.• At present, the indications for surgery for this condition should be comprehensively considered.• Findings of liver function tests, such as a general liver function test and GSA liver scintigraphy, are important for treating this disorder.


Introduction
Constitutional indocyanine green (ICG) excretory defect is extremely rare. Only five reports of hepatectomy in patients with a constitutional ICG excretory defect have been published in the English language literature until 2017 (Table 1) [1][2][3][4][5]. Loss of active ICG transport across the hepatic membrane is thought to be the cause of this disorder [6,7]. Because of advances in preoperative assessment of liver function, liver resection is a relatively safe procedure. The indocyanine green retention rate at 15 min (ICGR15) is Abbreviations: ICG, indocyanine green; ICGR15, indocyanine green retention rate at 15 min; GSA, 99m Tc-galactosyl human serum albumin; CT, computed tomography; S, segment; (PET)-CT, positron emission tomography; HCC, hepatocellular carcinoma; CP, Child-Pugh; LHL15, liver scintigraphy; HH15, heart uptake ratio; GSA-Rmax, maximal removal rate of 99m Tc-GSA; GSA-RL, GSA-Rmax in the predicted residual liver.
* important for estimating hepatic functional reserve and selection of the appropriate surgical procedure before hepatectomy is performed. Because of the rarity of constitutional ICG excretory defect, its clinical features are not well understood. We report here evaluation and treatment of a patient with such a disorder. This work has been reported in line with the SCARE criteria [8].

Case presentation
An 83-year-old man was admitted to our hospital for evaluation and management of a symptomatic liver mass. His medical history included diffuse large B-cell lymphoma, which was treated with rituximab + pirarubicin + cyclophosphamide + vincristine + prednisone therapy at 81 years old, and had bladder cancer (resected at 67 years) on follow-up. After resection of the bladder cancer, no recurrence was detected for 16 years. Liver dynamic computed tomography (CT) showed a low-density mass in the segment (S) 4 area, measured 40 mm in diameter. The density of the tumor was well enhanced in the arterial phase and washed-out in the portal phase. (Fig. 1a-d). The hepatobiliary phase of Gd-EOB-DTPA-MRI shows tumor nodules in the liver with low intensity (Fig. 1e)   of the liver was 3.2 (Fig. 1f). MRI and PET-CT confirmed a single liver tumor that was 40 mm in diameter and located in the S4 region. Liver metastasis of malignant lymphoma was suspected because of the patient's medical history. Therefore, we performed a liver biopsy preoperatively. The patient was diagnosed with hepatocellular carcinoma (HCC) based on the biopsy results and imaging findings. Upon presentation, the patient was afebrile, had no history of weight loss, and his appetite was good. His height was 166 cm, body weight 72 kg, and BMI 26.12. He has no drinking history. In a preoperative indocyanine green (ICG) test, the ICGR15 was 76.2%. The total bilirubin level was 1.1 mg/dL and the direct bilirubin level was 0.2 mg/dL. The serum albumin level was 4.7 g/dL and prothrombin activity was 96.3%. The Child-Pugh (CP) score was 5 points, which indicated a grade of A. The degree of liver damage was equivalent to A in accordance with the scoring system of the Liver Cancer Study Group of Japan. Table 2 shows the patient's laboratory data on admission. The hepatic uptake ratio of 99m Tc-galactosyl human serum albumin (GSA) by liver scintigraphy (LHL15) was 0.931 and the heart uptake ratio (HH15) was 0.482. The maximal removal rate of 99m Tc-GSA (GSA-Rmax) was 0.874 mg/min. GSA-Rmax in the predicted residual liver (GSA-RL) was greater than 0.765 mg/min, which was within the range considered safe for surgical procedures. Despite this finding, Child-Pugh classification and 99m Tc-GSA liver scintigraphy did not show any abnormal findings, and there was no background disease. Antibody against hepatitis C virus and hepatitis B virus surface antigen were negative. The serum antimitochondrial antibody and anti-nuclear antibody were negative. The serum tumor markers alpha-fetoprotein, carcinoembryonic antigen, and cancer antigen 19-9 were within the and normal range, but the protein level induced by vitamin K absence-II levels was increased (92 mg/dL). Therefore, we diagnosed constitutional ICG excretory defect with HCC and decided to perform radical surgery. Therefore, the patient underwent partial hepatectomy (S4). Pathologically, the tumor was diagnosed as moderately differentiated HCC (Fig. 2a). There was expansion and bleeding of perisinusoidal cells and an atrophic hepatic cord in the background of liver tissue. Because of previous chemotherapy, the diagnosis of sinusoidal obstruction syndrome (SOS) of the liver was established (Fig. 2b). After partial hepatectomy (S4), the postoperative course was uneventful and the patient was discharged on the 8th postoperative day. The patient remains in good general condition.

Discussion
Hepatectomy in cases of constitutional ICG excretory defect is exceedingly rare. Only five reports of hepatectomy with this defect have been reported. Among these cases, only three patients had HCC [2,4,5]. Two other cases showed cavernous hemangioma and biliary cystadenocarcinoma [1,3]. All of the patients were Japanese. The postoperative course in these patients was uneventful, except for only one patient with liver cirrhosis who also suffered from hyperbilirubinemia [5].
To the best of our knowledge, constitutional ICG excretory defect has only been reported in Japan. The ICG test is not usually performed in countries other than Japan and this disorder does not show any clinical symptoms. Therefore, unless the ICG test is frequently carried out on a regular basis, this disorder will likely not be observed. In Japan, the ICG test is considered one of the most important preoperative factors for estimation of hepatic functional reserve [9][10][11]. For assessment of patient hepatic functional reserve, the ICGR15 is an important factor, but it was outside the normal range in our case. Because variability in ICG values depends on hepatic blood flow, parenchymal cellular function, and biliary excretion, ICGR15 values are not reliable in the case of jaundice, the presence of a port-systemic shunt, or an ICG excretory defect [12]. Therefore, there is a problem of determining what the next step should be for evaluating patients.
GSA liver scintigraphy has been hypothesized to be the best modality with which to evaluate hepatic functional reserve [4]. Because this agent binds to hepatocytes for a long period, the distribution of the functioning hepatocyte mass can be assessed by performing single-photon emission computed tomography with 99m Tc-GSA [13]. Significant correlations have been observed between ICGR15 and both LHL15 (a receptor index) and HH15 (an index of blood clearance) (12). GSA-Rmax, which is calculated by using a radiopharmacokinetic model, is also correlated with the severity of liver disease. There is a significant difference in GSA-Rmax between patients with chronic hepatitis and normal liver function [14]. GSA-Rmax is useful for selecting candidates for hepatectomy. Extended hepatectomies are high-risk surgical procedures in the case of low GSA-Rmax scores (<0.35) [14]. GSA-RL should be maintained at greater than 0.15 to avoid postoperative hyperbilirubinemia or hepatic failure [15]. Aoki et al. reported that patients with Dubin-Johnson syndrome and an ICG excretory defect should be analyzed by GSA scintigraphy for safe and successful hepatectomy procedures [5]. GSA scintigraphy showed a more accurate hepatic functional reserve in our case, which is why we used it to evaluate the predictive score.
In our case, liver injury included histological changes as SOS may be correlated to administration of cyclophosphamide as side effect [16]. A correlation between ICGR15 values and SOS has been described [17,18]. The cut-off point of the ICGR15 test that corre- lated with diagnosis of SOS was 8% [19]. Although the background of liver tissue was mild SOS pathologically, the ICG R15 value was extremely high. Furthermore, GSA-Rmax was within the normal range. We finally concluded that the high value of the ICGR15 was affected by constitutional ICG excretory defect rather than SOS.

Conclusion
In conclusion, constitutional ICG excretory defect is an extremely rare disorder. At present, the indications for surgery for this condition should be comprehensively considered. Findings of liver function tests, such as a general liver function test and GSA liver scintigraphy, are important for treating this disorder.