Osler disease is caused by mutations in one of two genes. Accordingly, it is subclassification into type 1 and 2. Both genes encode transmembrane proteins involved in the transforming growth factor (TGF)-β signaling pathway and are expressed predominantly on the vascular endothelium . In type 1, the mutation is located on chromosome 9 in the gene that encodes endoglin (ENG), a type III TGF-β receptor . In type 2, the mutation is located on chromosome 12, in the gene that encodes activin receptor-like kinase type I (ALK-1 or ACVRL1), a type I TGF-β receptor . Although the genotypic–phenotypic correlations are not yet fully defined, it appears that liver involvement is more prevalent in type 2 . The patient in this report had a history of recurrent epistaxis and dilatation of the peripheral blood vessels on his skin. Hence, he was diagnosed with Osler disease based on the Curacao criteria; however, the type was unknown, because the patient did not receive a genetic test.
Liver involvement is observed in 67–84% of Osler disease patients . The pathophysiology, which mediates the development liver involvement, is due to an imbalance between hepatic artery and portal venous blood flow and ultimately leads to increased hepatic arterial inflow [10,11,12]. The flow imbalance in the liver parenchyma facilitates the development of hepatocellular over-regenerative activity, and nodular regenerative hyperplasia (NRH) or focal nodular hyperplasia (FNH) often develop in the liver of patients with Osler disease [13, 14]. Among these patients, the prevalence of FNH is 2.9% (100-fold greater than in the general population) . Although FNH is a benign liver lesion, it is sometimes difficult to distinguish from hepatocellular carcinoma (HCC), and its presence can lead to diagnostic confusion in Osler disease patients, because typical findings of HCC on dynamic CT scan can be masked by widespread arteria–venous shunts in the liver .
There is no established opinion regarding the development of HCC in Osler disease patients. On one hand, it is assumed that the imbalance between the hepatic artery and portal vein induces an increase in the level of hepatic growth factors, and the sequential reactions may facilitate the development of HCC [11, 12]. On the other hand, it was reported that Osler disease patients with no other risk factors rarely develop HCC , or develop HCC less frequently in comparison with the general population . A search of the relevant literature using the PubMed database (key words: Osler disease and hepatocellular carcinoma) yielded only five reports on HCC in Osler disease, and 3 of these 5 cases had other risk factors for the development of HCC (e.g., hepatitis) [19,20,21,22,23].
For liver lesions, percutaneous liver biopsy is usually selected when the tumor size increases and malignancy cannot be ruled out. Although a past case series reported that 6 Osler disease patients underwent percutaneous biopsy without any complications , percutaneous liver biopsy is generally avoided for the diagnosis and treatment as the procedure is associated with a high risk of bleeding. In our case, malignancy was suspected, because the size increased during 8 years, and total biopsy was performed surgically. In the past reports, only three cases underwent hepatectomy and postoperative complications occurred in two cases. One patient had ascites, and the other had hepatic vein thrombosis. In both cases, the complications improved with medication [22, 25]. In the present case, we determined our approach after giving the patient a detailed explanation of the surgical risks. As a result, the perioperative period was uneventful and the pathological findings of the resected specimen showed no malignancy and the diagnosis was FNH.
Postoperative hemorrhage often occurs within 24 h after surgery. Two months after surgery is considered to be the late stage of the wound healing process, and postoperative hemorrhage at this timepoint is considered rare. Delayed postoperative hemorrhage (DPH) is defined as hemorrhage observed more the 24 h postoperatively. A past report suggested that the incidence rate of DPH in hepatobiliary and pancreatic surgery was 1.5% . Most cases occurred in association with infection. In our case, the patient did not show an increased inflammatory response, there was no accumulation of fluid on the resected liver surface, and there were no complications, such as bile leakage. However, at 2 months after the surgery, hemorrhage from an artery on the resected surface of the liver occurred. Therefore, we assumed that the etiology of DPH might be related to Osler disease.
CT at the time of bleeding showed poor liver regeneration, and the site of vascular resection was exposed on the surface of the liver. Telangiectasia were scattered in whole liver same as preoperatively, and we could not reveal that there was shunt formation in the bleeding site. The comparison of CT scans before and after postoperative bleeding revealed that the periphery of the right hepatic vein ran around the area, where the extravasation of the contrast medium is observed. Thus, we hypothesized that the mechanism of DPH was as follows. First, the vein running on the surface of the liver fused with a hepatic peripheral artery belonging to the A6 branch. Subsequently, shunt formation gradually increased the venous pressure, and sealing of the vein by the sealing device might not have been tolerated. Besides, the blood vessels of patients with this disease are in extremely fragile. Eventually, the vein on the liver surface—which also showed hepatic artery shunt—ruptured. Additional suturing was considered during surgery when hemostasis was difficult under common surgical procedure of hepatectomy, nevertheless, it was not necessary and we felt relieved at the time of finish surgery. However, we experienced this case in which DPH occurred, and we regret that we might have to ligate all vessels.
Although the exact cause of this episode was unknown, this case represents a valuable example that demonstrates the risk of hemorrhage in patients with Osler disease after hepatectomy, even if there are no complications during the perioperative period.