Clin J Gastroenterol (2009) 2:131–136 DOI 10.1007/s12328-008-0054-8
CASE REPORT
Hereditary hemorrhagic telangiectasia with multiple hepatic and pulmonary nodular lesions Yasuyuki Shimoyama Æ Satoru Kakizaki Æ Akiko Katano Æ Satoshi Takakusaki Æ Masafumi Mizuide Æ Takeshi Ichikawa Æ Ken Sato Æ Hitoshi Takagi Æ Masatomo Mori
Received: 26 October 2008 / Accepted: 28 November 2008 / Published online: 10 January 2009 Ó Springer 2009
Abstract A 50-year-old female visited the hospital for further evaluation of multiple pulmonary and hepatic nodules. First, she visited her primary physician for general fatigue due to anemia. She had recurrent epistaxis, and her mother had suffered from hereditary hemorrhagic telangiectasia (HHT). Telangiectasias were present in the stomach. This patient was diagnosed with HHT. Computed tomography (CT) revealed multiple pulmonary and hepatic nodules. The pulmonary nodules were due to bleeding from arteriovenous malformations of the lung. Abdominal CT and angiography showed a dilated and meandering hepatic artery, arteriovenous shunts and multiple hepatic nodules. Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) showed enhancement in the early dynamic phase and in the liver-specific phase. A liver tumor biopsy of a hepatic nodule showed nodular regenerative hyperplasia (NRH). This report presents a case of HHT with multiple pulmonary and hepatic nodular lesions. Gd-EOBDTPA-enhanced MRI was useful for making a diagnosis of NRH. Keywords Hereditary hemorrhagic telangiectasia Arteriovenous shunt Gd-EOB-DTPA-enhanced magnetic resonance imaging Nodular regenerative hyperplasia
Y. Shimoyama S. Kakizaki (&) A. Katano S. Takakusaki M. Mizuide T. Ichikawa K. Sato H. Takagi M. Mori Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8511, Japan e-mail: [email protected]
Introduction Hereditary hemorrhagic telangiectasia (HHT), or Osler– Rendu–Weber disease, is a predominantly inherited disorder involving structural abnormalities of the small veins in the skin, mucosa and internal organs, causing frequent bleeding episodes [1–3]. It is characterized by epistaxis, muco-cutaneous telangiectasias, visceral involvement and a family history [1–3]. In more than 90% of the patients, epistaxis is the first predominant symptom. Apart from affecting the nose, arteriovenous malformations (AVMs) may also affect the skin, lungs, brain, liver and gastrointestinal tract [1–3]. The two known genes that are implicated in HHT code for endoglin (ENG) and activin receptor-like kinase (ALK1) [4, 5]. Liver involvement in HHT is almost always asymptomatic, while hepatic vascular malformations can induce severe complications, depending on the three types of shunting: arteriovenous (hepatic artery to hepatic vein), arterioportal (hepatic artery to portal vein) and portovenous (portal vein to hepatic vein) [6, 7]. An arteriovenous shunt causes secondary sclerosing cholangitis due to biliary ischemia. The arteriovenous and portovenous shunts cause high-output cardiac failure [6, 7]. The arterioportal shunt causes the portal hypertension [8]. Abnormal liver vascular supply due to arteriovenous and portovenous shunts sometimes causes focal nodular hyperplasia (FNH) or nodular regenerative hyperplasia (NRH) [6–8]. These nodular lesions result from blood shunting that causes perfusion abnormalities in the liver parenchyma that, in turn, lead to hepatocellular regenerative activity, either focal (leading to FNH) or diffuse (leading to NRH). The prevalence of FNH is 2.9% (100-fold greater than in the general population) in the patients with HHT [9]. Although it is a benign liver lesion, its presence can be misleading
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because imaging of a mass would lead to a misdiagnosis of hepatocellular carcinoma [6]. The new liver-specific hepatobiliary contrast agent, gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), offers both the potential of dynamic as well as liver-specific static hepatocyte magnetic resonance imaging (MRI) with accurate delineation and classification as well as characterization of liver tumors [10]. The characterization of FNH provided by Gd-EOBDTPA-enhanced MRI has been reported to be superior to that provided by precontrast MRI alone or spiral computed tomography (CT) [10]. In one case, Gd-EOB-DTPAenhanced MRI showed enhancement in the early dynamic phase after bolus injection, after 20 min in the liverspecific phase enhancement was also seen [10]. Gd-EOBDTPA-enhanced MRI is useful for diagnosis of hepatic nodules to deny hepatocellular carcinoma. Gd-EOBDTPA-enhanced MRI, therefore, enables us to diagnosis the hepatic nodular lesion without the need to perform an invasive liver tumor biopsy. This report presents a case of HHT with multiple pulmonary and hepatic nodular lesions.
Case report A 50-year-old female visited the hospital for further evaluation of pulmonary and hepatic multiple nodules. First, she visited her primary physician for general fatigue due to anemia. At that time, multiple pulmonary and hepatic nodules were detected by CT (Fig. 1), and the patient was referred for further evaluation. On admission, the patient was diagnosed with anemia in the conjunctiva. No abnormal breathing sounds or cardiac murmurs were audible. There were no telangiectasias on the face, mouth, lips and fingers, but upper gastrointestinal endoscopy showed telangiectasias in the stomach. There were no findings of either esophageal varices or portal hypertensive gastropathy based on the findings of upper gastrointestinal endoscopy. She had episodes of recurrent epistaxis and her mother had suffered from HHT. This case was diagnosed to be HHT because of the recurrent epistaxis, family history and visceral telangiectasias. There was no history of alcoholism or intravenous drug use. The laboratory data at admission were as follows: hemoglobin 10.3 g/dl, platelet 226,000/mm3, total protein 7.4 g/dl, serum albumin 4.1 g/dl, blood urea nitrogen 15 mg/dl, creatinine 0.7 mg/dl, total bilirubin 1.1 mg/dl, aspartate aminotransferase 32 IU/l, alanine aminotransferase 20 IU/l, lactate dehydrogenase 156 IU/l, alkaline phosphatase 204 IU/l, gamma-glutamyltranspeptidase 66 IU/l, cholinesterase 6.0 U/l, total cholesterol 162 mg/dl, prothrombin time 90.0%, alpha-fetoprotein 2.2 ng/ml, protein induced by vitamin K absence or antagonist-II 11 AU/ml, brain natriuretic peptide 13.3 pg/ml.
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Hepatitis B and hepatitis C viral markers and antinuclear and antimitochondrial antibodies were negative. There were no findings of cardiomegaly on either the chest X-ray or echocardiography findings. Dynamic CT (Fig. 2a–c) and abdominal angiography (Fig. 2d) showed a dilated and meandering hepatic artery, arteriovenous shunts and multiple hepatic nodules. Multiple hepatic nodules showed a faint enhancement in the early dynamic phase and defect in the portal phase. Abdominal ultrasonography (Fig. 2d) showed the tumor to be an iso-echoic lesion. Contrastenhanced harmonic ultrasonography with Sonazoid (Daiichi Sankyo, Tokyo, Japan), a lipid-stabilized suspension of a perfluorobutane gas microbubble contrast agent, showed faint staining in the early phase and such staining maintained the same levels as that of the surrounding liver in the late phase. There were no abnormal findings observed for the common bile duct and biliary tract according to magnetic resonance cholangiopancreatography. 18F-fluorodeoxyglucose positron emission tomography showed no accumulation in either the pulmonary or hepatic nodules. Gd-EOB-DTPA-enhanced MRI showed enhancement in the early dynamic phase and the liver-specific phase enhancement of the nodules (Fig. 3). A liver tumor biopsy of a hepatic nodule showed a dilatation of the sinusoid and hypercellular hepatocytes without atypical features and was diagnosed as NRH (Fig. 4). Therefore, the hepatic nodules were diagnosed as NRH arising due to the abnormal liver vascular supply due to the arteriovenous shunts characteristic of HHT. A transbronchial lung biopsy (TBLB) was carried out to examine the pulmonary nodules and they showed no atypical features. Follow-up chest CT revealed the disappearance or reduction of nodules. Further, dynamic CT revealed dilated venous flow from the pulmonary nodules into the left atrium. Finally, the pulmonary nodules were diagnosed by dynamic CT findings as bleeding from AVMs of the lung.
Discussion The present patient had episodes of recurrent epistaxis, which were also confirmed in her family’s medical history and telangiectasias in the stomach. This case was diagnosed to be HHT. She had concomitant hepatic nodular changes diagnosed as NRH. Although liver involvement in HHT is usually asymptomatic, hepatic vascular malformations can induce severe complications, depending on the types of shunting [6]. Garcia-Tsao et al. reviewed 83 patients with HHT and liver involvement [11]. They identified three distinct clinical presentations, high-output heart failure, portal hypertension and biliary disease [11]. These three clinical presentations depend on the predominant type and size of the shunts. The arteriovenous and
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Fig. 1 Computed tomography revealed multiple hepatic (a, b) and pulmonary nodules (c, d)
portovenous shunts cause high-output cardiac failure [6, 7]. An arterioportal shunt causes portal hypertension [8]. The arteriovenous shunt cause secondary sclerosing cholangitis due to biliary ischemia [11]. Fortunately, there were no problematic symptoms in our case. However, she had concomitant marked arteriovenous shunts and hepatic nodular changes diagnosed as NRH. Abnormal liver vascular supply due to arteriovenous and portovenous shunts causes nodular hyperplasia of hepatocytes including FNH and NRH. These nodular lesions result from blood shunting leading to perfusion abnormalities in the liver parenchyma that in turn lead to hepatocellular regenerative activity, either diffuse (leading to NRH) or focal (leading to FNH) [6]. The prevalence of nodular lesions in HHT is 2.9% (100fold greater than in the general population) [9], and although this is a benign liver lesion, its presence can be misleading when a mass in a seemingly cirrhotic liver could lead to a misdiagnosis of hepatocellular carcinoma. The new liver-specific hepatobiliary contrast agent GdEOB-DTPA offers both the potential of dynamic as well as liver-specific static hepatocyte MRI with accurate delineation and classification as well as characterization of liver tumors [10]. The characterization of FNH provided by GdEOB-DTPA-enhanced MRI (88.1%) is reported to be superior to that provided by precontrast MRI alone (67.8%, P \ 0.05) or dynamic CT (84.7%, not significant) [10]. In FNH with Gd-EOB-DTPA-enhanced MRI, complete or partial enhancement of the lesions was present in the early dynamic phase (arterial and portovenous dynamic phase) in 94 and 85%, respectively [10]. The pattern of lesion
enhancement in the early dynamic phase was mainly homogenous (78–80%); the median contrast-to-noise ratio was -5.9 in T1-w precontrast images, 14.0 in the arterial phase, 2.4 in the portovenous phase and 2.9 in the equilibrium phase [10]. The enhancement in the hepatocytephase after 10 and 20 min was observed in 88 and 90% of lesions, respectively [10]. Focal nodular hyperplasias show very similar enhancement characteristics to those of other extracellular contrast agents in the early dynamic phase after bolus injection of Gd-EOB-DTPA, after 20 min in the liver-specific phase enhancement is regularly seen. Liver-specific phase enhancement is useful for ruling out hepatocellular carcinoma. Jameson [12] reported a case of primary hepatocellular carcinoma complicated with HHT and reviewed literature. Only two cases including their case were reported at that time. However, another one case was complicated with hepatitis B viral infection [13]. Patients with HHT seem to have risk factors for developing hepatocellular carcinoma, such as post-transfusional hepatitis, hemosiderosis and the administration of estrogen compounds [12]. However, the incidence of HHT complicated with hepatocellular carcinoma is rare [12]. FNH or NRH is more common in the presence of HHT [14]. We diagnosed the hepatic nodules of this case to be NRH. FNH, NRH, nodular lesions associated with idiopathic portal hypertension, non-cirrhotic large regenerative nodules, hepatocellular adenoma-like hyperplastic nodules and partial nodular transformation have been suggested to be related to an abnormal hepatic circulation [15]. In NRH, small multiple nodules of hepatocytes occur diffusely in
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Fig. 2 Dynamic CT (a–c) and abdominal angiography (d) showed a dilated and meandering hepatic artery and arteriovenous shunts. The hepatic nodule showed faint enhancement in the early dynamic phase (a) and defect in the portal phase (c). Abdominal ultrasonography (e) showed the tumor to be an iso-echoic lesion
the liver [15]. Unlike liver cirrhosis, there are no fibrous septa. Typical NRH is a diffuse condition and it is not common for a large nodule to develop, and such nodules must be differentiated from the other nodular lesions [15]. Our case had a relatively large nodule in the liver and it was difficult to distinguish this nodule from other nodular lesions related to an abnormal hepatic circulation. However, unusually large nodules have been recently detected within the liver with macro- and microscopic appearance of NRH [15]. Histologically, abnormal dilated sinusoids, portal tract and hyperplastic hepatocytes tend to be observed without central scar-like tissue and a normal background liver as observed in our case. There were no
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malignant features in hepatocytes. Finally, we diagnosed the hepatic nodules of this case to be NRH. In this case, we performed a liver tumor biopsy to diagnose the hepatic nodule, because the diagnosis of HHT and NRH was concurrently performed. However, once a diagnosis of HHT was made, a liver tumor biopsy may not be needed to make an accurate diagnosis of these nodules, including FNH and NRH [14]. In most cases (more than 70%) of FNH with HHT, appearance on imaging techniques is sufficient to diagnose FNH and a confirmatory biopsy is therefore not required unless the diagnosis is uncertain or the mass increases in size [14]. Further advances in imaging techniques, including the Gd-EOB-DTPA-enhanced MRI,
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Fig. 3 Gadoliniumethoxybenzyldiethylenetriamine pentaacetic acid (Gd-EOB-DTPA)enhanced magnetic resonance imaging showed enhancement in the early dynamic phase and the liver-specific phase enhancement of the nodule (arrow). a T1-weighted image, b T2-weighted image, c early dynamic phase, d liver-specific phase
Fig. 4 Liver tumor biopsy of the hepatic nodule showed dilatation of sinusoid and hypercellular hepatocytes without atypical features, and it was diagnosed to be nodular regenerative hyperplasia [magnification 940 (a) and 9100 (b)]
are expected to enable us to make an accurate diagnosis of these hepatic nodules in HHT patients without performing a liver tumor biopsy. We performed a liver tumor biopsy with a thin needle. However, a liver biopsy with usual needles is not indicated in patients suspected of hepatic involvement in HHT, not only because the procedure may be associated with an increased risk of bleeding, given the presence of widespread vascular malformations, but because the histology is not helpful in making a diagnosis of HHT and it may therefore lead to confusion [14]. In this case, Gd-EOBDTPA-enhanced MRI achieved a clearer image of early enhancement in comparison to dynamic CT or contrastenhanced harmonic ultrasonography with Sonazoid. GdEOB-DTPA-enhanced MRI may offer a higher signal-tonoise ratio and contrast-to-noise ratio than dynamic CT or contrast-enhanced harmonic ultrasonography. Concerning the pulmonary nodules, a TBLB was carried out and showed no atypical features. Interestingly, followup chest CT revealed the disappearance or reduction of
nodules. Furthermore, dynamic CT revealed a dilated vein flow from pulmonary nodules into left atrium. Finally, the pulmonary nodules were diagnosed to be bleeding based on the presence of AVMs due to HHT. Pulmonary vascular manifestations of HHT include pulmonary AVMs (especially in patients with ENG mutations) and, less frequently, pulmonary hypertension (especially in patients with ALK1 mutations) [16]. In 15–33% of the patients with HHT, pulmonary AVMs consist of abnormal communications between pulmonary arteries and pulmonary veins, causing right-to-left shunting and thus, frequently hypoxemia and dyspnea on exertion, although pulmonary AVMs may remain asymptomatic and frequently undiagnosed unless complications occur. Pulmonary AVMs result in severe and frequent complications often at a young age, which may reveal the diagnosis, e.g., transient ischemic attack and cerebral stroke (10–19% of patients), systemic severe infections and abscesses (including cerebral abscess in 5–19% of patients) and rarely massive hemoptysis or
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hemothorax [16]. Pulmonary hypertension is rare in HHT and may be due either to systemic arteriovenous shunting in the liver increasing cardiac output or be clinically and histologically indistinguishable from idiopathic pulmonary arterial hypertension. Concerning the treatment of hepatic involvement of HHT, hepatic arterial coil embolization is employed for hepatic AVM in HHT [17]. Hepatic arterial coil embolization temporarily improves the patient’s cardiac condition, but gradually induces progressive hepatic failure due to intrahepatic cholangitis [17]. Peripheral arterial coil embolization might be temporarily useful for high-output heart failure, but it is harmful to the liver. In the current case, there were no symptoms and no clinical presentations such as high-output heart failure, portal hypertension and biliary disease. Thus, this case will be followed up without treatment for the liver vascular malformations. This report described a case of HHT with multiple hepatic and pulmonary nodular lesions. The hepatic nodular lesions were caused from an abnormal liver vascular supply due to arteriovenous shunts resulting from HHT. Gd-EOB-DTPA-enhanced MRI was useful for the diagnosis of NRH. Further advances in imaging techniques, including Gd-EOB-DTPA-enhanced MRI, are expected to enable us to make an accurate diagnosis of these hepatic nodules in HHT patients without the need to perform an invasive liver tumor biopsy.
References 1. Guttmacher AE, Marchuk DA, White RI Jr. Hereditary hemorrhagic telangiectasia. N Engl J Med. 1995;333:918–24. 2. Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJ, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu–Osler–Weber syndrome). Am J Med Genet. 2000;91:66–7. 3. Sadick H, Sadick M, Go¨tte K, Naim R, Riedel F, Bran G, et al. Hereditary hemorrhagic telangiectasia: an update on clinical manifestations and diagnostic measures. Wien Klin Wochenschr. 2006;118:72–80.
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CASE REPORT
Hereditary hemorrhagic telangiectasia with multiple hepatic and pulmonary nodular lesions Yasuyuki Shimoyama Æ Satoru Kakizaki Æ Akiko Katano Æ Satoshi Takakusaki Æ Masafumi Mizuide Æ Takeshi Ichikawa Æ Ken Sato Æ Hitoshi Takagi Æ Masatomo Mori
Received: 26 October 2008 / Accepted: 28 November 2008 / Published online: 10 January 2009 Ó Springer 2009
Abstract A 50-year-old female visited the hospital for further evaluation of multiple pulmonary and hepatic nodules. First, she visited her primary physician for general fatigue due to anemia. She had recurrent epistaxis, and her mother had suffered from hereditary hemorrhagic telangiectasia (HHT). Telangiectasias were present in the stomach. This patient was diagnosed with HHT. Computed tomography (CT) revealed multiple pulmonary and hepatic nodules. The pulmonary nodules were due to bleeding from arteriovenous malformations of the lung. Abdominal CT and angiography showed a dilated and meandering hepatic artery, arteriovenous shunts and multiple hepatic nodules. Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) showed enhancement in the early dynamic phase and in the liver-specific phase. A liver tumor biopsy of a hepatic nodule showed nodular regenerative hyperplasia (NRH). This report presents a case of HHT with multiple pulmonary and hepatic nodular lesions. Gd-EOBDTPA-enhanced MRI was useful for making a diagnosis of NRH. Keywords Hereditary hemorrhagic telangiectasia Arteriovenous shunt Gd-EOB-DTPA-enhanced magnetic resonance imaging Nodular regenerative hyperplasia
Y. Shimoyama S. Kakizaki (&) A. Katano S. Takakusaki M. Mizuide T. Ichikawa K. Sato H. Takagi M. Mori Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8511, Japan e-mail: [email protected]
Introduction Hereditary hemorrhagic telangiectasia (HHT), or Osler– Rendu–Weber disease, is a predominantly inherited disorder involving structural abnormalities of the small veins in the skin, mucosa and internal organs, causing frequent bleeding episodes [1–3]. It is characterized by epistaxis, muco-cutaneous telangiectasias, visceral involvement and a family history [1–3]. In more than 90% of the patients, epistaxis is the first predominant symptom. Apart from affecting the nose, arteriovenous malformations (AVMs) may also affect the skin, lungs, brain, liver and gastrointestinal tract [1–3]. The two known genes that are implicated in HHT code for endoglin (ENG) and activin receptor-like kinase (ALK1) [4, 5]. Liver involvement in HHT is almost always asymptomatic, while hepatic vascular malformations can induce severe complications, depending on the three types of shunting: arteriovenous (hepatic artery to hepatic vein), arterioportal (hepatic artery to portal vein) and portovenous (portal vein to hepatic vein) [6, 7]. An arteriovenous shunt causes secondary sclerosing cholangitis due to biliary ischemia. The arteriovenous and portovenous shunts cause high-output cardiac failure [6, 7]. The arterioportal shunt causes the portal hypertension [8]. Abnormal liver vascular supply due to arteriovenous and portovenous shunts sometimes causes focal nodular hyperplasia (FNH) or nodular regenerative hyperplasia (NRH) [6–8]. These nodular lesions result from blood shunting that causes perfusion abnormalities in the liver parenchyma that, in turn, lead to hepatocellular regenerative activity, either focal (leading to FNH) or diffuse (leading to NRH). The prevalence of FNH is 2.9% (100-fold greater than in the general population) in the patients with HHT [9]. Although it is a benign liver lesion, its presence can be misleading
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because imaging of a mass would lead to a misdiagnosis of hepatocellular carcinoma [6]. The new liver-specific hepatobiliary contrast agent, gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), offers both the potential of dynamic as well as liver-specific static hepatocyte magnetic resonance imaging (MRI) with accurate delineation and classification as well as characterization of liver tumors [10]. The characterization of FNH provided by Gd-EOBDTPA-enhanced MRI has been reported to be superior to that provided by precontrast MRI alone or spiral computed tomography (CT) [10]. In one case, Gd-EOB-DTPAenhanced MRI showed enhancement in the early dynamic phase after bolus injection, after 20 min in the liverspecific phase enhancement was also seen [10]. Gd-EOBDTPA-enhanced MRI is useful for diagnosis of hepatic nodules to deny hepatocellular carcinoma. Gd-EOBDTPA-enhanced MRI, therefore, enables us to diagnosis the hepatic nodular lesion without the need to perform an invasive liver tumor biopsy. This report presents a case of HHT with multiple pulmonary and hepatic nodular lesions.
Case report A 50-year-old female visited the hospital for further evaluation of pulmonary and hepatic multiple nodules. First, she visited her primary physician for general fatigue due to anemia. At that time, multiple pulmonary and hepatic nodules were detected by CT (Fig. 1), and the patient was referred for further evaluation. On admission, the patient was diagnosed with anemia in the conjunctiva. No abnormal breathing sounds or cardiac murmurs were audible. There were no telangiectasias on the face, mouth, lips and fingers, but upper gastrointestinal endoscopy showed telangiectasias in the stomach. There were no findings of either esophageal varices or portal hypertensive gastropathy based on the findings of upper gastrointestinal endoscopy. She had episodes of recurrent epistaxis and her mother had suffered from HHT. This case was diagnosed to be HHT because of the recurrent epistaxis, family history and visceral telangiectasias. There was no history of alcoholism or intravenous drug use. The laboratory data at admission were as follows: hemoglobin 10.3 g/dl, platelet 226,000/mm3, total protein 7.4 g/dl, serum albumin 4.1 g/dl, blood urea nitrogen 15 mg/dl, creatinine 0.7 mg/dl, total bilirubin 1.1 mg/dl, aspartate aminotransferase 32 IU/l, alanine aminotransferase 20 IU/l, lactate dehydrogenase 156 IU/l, alkaline phosphatase 204 IU/l, gamma-glutamyltranspeptidase 66 IU/l, cholinesterase 6.0 U/l, total cholesterol 162 mg/dl, prothrombin time 90.0%, alpha-fetoprotein 2.2 ng/ml, protein induced by vitamin K absence or antagonist-II 11 AU/ml, brain natriuretic peptide 13.3 pg/ml.
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Hepatitis B and hepatitis C viral markers and antinuclear and antimitochondrial antibodies were negative. There were no findings of cardiomegaly on either the chest X-ray or echocardiography findings. Dynamic CT (Fig. 2a–c) and abdominal angiography (Fig. 2d) showed a dilated and meandering hepatic artery, arteriovenous shunts and multiple hepatic nodules. Multiple hepatic nodules showed a faint enhancement in the early dynamic phase and defect in the portal phase. Abdominal ultrasonography (Fig. 2d) showed the tumor to be an iso-echoic lesion. Contrastenhanced harmonic ultrasonography with Sonazoid (Daiichi Sankyo, Tokyo, Japan), a lipid-stabilized suspension of a perfluorobutane gas microbubble contrast agent, showed faint staining in the early phase and such staining maintained the same levels as that of the surrounding liver in the late phase. There were no abnormal findings observed for the common bile duct and biliary tract according to magnetic resonance cholangiopancreatography. 18F-fluorodeoxyglucose positron emission tomography showed no accumulation in either the pulmonary or hepatic nodules. Gd-EOB-DTPA-enhanced MRI showed enhancement in the early dynamic phase and the liver-specific phase enhancement of the nodules (Fig. 3). A liver tumor biopsy of a hepatic nodule showed a dilatation of the sinusoid and hypercellular hepatocytes without atypical features and was diagnosed as NRH (Fig. 4). Therefore, the hepatic nodules were diagnosed as NRH arising due to the abnormal liver vascular supply due to the arteriovenous shunts characteristic of HHT. A transbronchial lung biopsy (TBLB) was carried out to examine the pulmonary nodules and they showed no atypical features. Follow-up chest CT revealed the disappearance or reduction of nodules. Further, dynamic CT revealed dilated venous flow from the pulmonary nodules into the left atrium. Finally, the pulmonary nodules were diagnosed by dynamic CT findings as bleeding from AVMs of the lung.
Discussion The present patient had episodes of recurrent epistaxis, which were also confirmed in her family’s medical history and telangiectasias in the stomach. This case was diagnosed to be HHT. She had concomitant hepatic nodular changes diagnosed as NRH. Although liver involvement in HHT is usually asymptomatic, hepatic vascular malformations can induce severe complications, depending on the types of shunting [6]. Garcia-Tsao et al. reviewed 83 patients with HHT and liver involvement [11]. They identified three distinct clinical presentations, high-output heart failure, portal hypertension and biliary disease [11]. These three clinical presentations depend on the predominant type and size of the shunts. The arteriovenous and
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Fig. 1 Computed tomography revealed multiple hepatic (a, b) and pulmonary nodules (c, d)
portovenous shunts cause high-output cardiac failure [6, 7]. An arterioportal shunt causes portal hypertension [8]. The arteriovenous shunt cause secondary sclerosing cholangitis due to biliary ischemia [11]. Fortunately, there were no problematic symptoms in our case. However, she had concomitant marked arteriovenous shunts and hepatic nodular changes diagnosed as NRH. Abnormal liver vascular supply due to arteriovenous and portovenous shunts causes nodular hyperplasia of hepatocytes including FNH and NRH. These nodular lesions result from blood shunting leading to perfusion abnormalities in the liver parenchyma that in turn lead to hepatocellular regenerative activity, either diffuse (leading to NRH) or focal (leading to FNH) [6]. The prevalence of nodular lesions in HHT is 2.9% (100fold greater than in the general population) [9], and although this is a benign liver lesion, its presence can be misleading when a mass in a seemingly cirrhotic liver could lead to a misdiagnosis of hepatocellular carcinoma. The new liver-specific hepatobiliary contrast agent GdEOB-DTPA offers both the potential of dynamic as well as liver-specific static hepatocyte MRI with accurate delineation and classification as well as characterization of liver tumors [10]. The characterization of FNH provided by GdEOB-DTPA-enhanced MRI (88.1%) is reported to be superior to that provided by precontrast MRI alone (67.8%, P \ 0.05) or dynamic CT (84.7%, not significant) [10]. In FNH with Gd-EOB-DTPA-enhanced MRI, complete or partial enhancement of the lesions was present in the early dynamic phase (arterial and portovenous dynamic phase) in 94 and 85%, respectively [10]. The pattern of lesion
enhancement in the early dynamic phase was mainly homogenous (78–80%); the median contrast-to-noise ratio was -5.9 in T1-w precontrast images, 14.0 in the arterial phase, 2.4 in the portovenous phase and 2.9 in the equilibrium phase [10]. The enhancement in the hepatocytephase after 10 and 20 min was observed in 88 and 90% of lesions, respectively [10]. Focal nodular hyperplasias show very similar enhancement characteristics to those of other extracellular contrast agents in the early dynamic phase after bolus injection of Gd-EOB-DTPA, after 20 min in the liver-specific phase enhancement is regularly seen. Liver-specific phase enhancement is useful for ruling out hepatocellular carcinoma. Jameson [12] reported a case of primary hepatocellular carcinoma complicated with HHT and reviewed literature. Only two cases including their case were reported at that time. However, another one case was complicated with hepatitis B viral infection [13]. Patients with HHT seem to have risk factors for developing hepatocellular carcinoma, such as post-transfusional hepatitis, hemosiderosis and the administration of estrogen compounds [12]. However, the incidence of HHT complicated with hepatocellular carcinoma is rare [12]. FNH or NRH is more common in the presence of HHT [14]. We diagnosed the hepatic nodules of this case to be NRH. FNH, NRH, nodular lesions associated with idiopathic portal hypertension, non-cirrhotic large regenerative nodules, hepatocellular adenoma-like hyperplastic nodules and partial nodular transformation have been suggested to be related to an abnormal hepatic circulation [15]. In NRH, small multiple nodules of hepatocytes occur diffusely in
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Fig. 2 Dynamic CT (a–c) and abdominal angiography (d) showed a dilated and meandering hepatic artery and arteriovenous shunts. The hepatic nodule showed faint enhancement in the early dynamic phase (a) and defect in the portal phase (c). Abdominal ultrasonography (e) showed the tumor to be an iso-echoic lesion
the liver [15]. Unlike liver cirrhosis, there are no fibrous septa. Typical NRH is a diffuse condition and it is not common for a large nodule to develop, and such nodules must be differentiated from the other nodular lesions [15]. Our case had a relatively large nodule in the liver and it was difficult to distinguish this nodule from other nodular lesions related to an abnormal hepatic circulation. However, unusually large nodules have been recently detected within the liver with macro- and microscopic appearance of NRH [15]. Histologically, abnormal dilated sinusoids, portal tract and hyperplastic hepatocytes tend to be observed without central scar-like tissue and a normal background liver as observed in our case. There were no
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malignant features in hepatocytes. Finally, we diagnosed the hepatic nodules of this case to be NRH. In this case, we performed a liver tumor biopsy to diagnose the hepatic nodule, because the diagnosis of HHT and NRH was concurrently performed. However, once a diagnosis of HHT was made, a liver tumor biopsy may not be needed to make an accurate diagnosis of these nodules, including FNH and NRH [14]. In most cases (more than 70%) of FNH with HHT, appearance on imaging techniques is sufficient to diagnose FNH and a confirmatory biopsy is therefore not required unless the diagnosis is uncertain or the mass increases in size [14]. Further advances in imaging techniques, including the Gd-EOB-DTPA-enhanced MRI,
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Fig. 3 Gadoliniumethoxybenzyldiethylenetriamine pentaacetic acid (Gd-EOB-DTPA)enhanced magnetic resonance imaging showed enhancement in the early dynamic phase and the liver-specific phase enhancement of the nodule (arrow). a T1-weighted image, b T2-weighted image, c early dynamic phase, d liver-specific phase
Fig. 4 Liver tumor biopsy of the hepatic nodule showed dilatation of sinusoid and hypercellular hepatocytes without atypical features, and it was diagnosed to be nodular regenerative hyperplasia [magnification 940 (a) and 9100 (b)]
are expected to enable us to make an accurate diagnosis of these hepatic nodules in HHT patients without performing a liver tumor biopsy. We performed a liver tumor biopsy with a thin needle. However, a liver biopsy with usual needles is not indicated in patients suspected of hepatic involvement in HHT, not only because the procedure may be associated with an increased risk of bleeding, given the presence of widespread vascular malformations, but because the histology is not helpful in making a diagnosis of HHT and it may therefore lead to confusion [14]. In this case, Gd-EOBDTPA-enhanced MRI achieved a clearer image of early enhancement in comparison to dynamic CT or contrastenhanced harmonic ultrasonography with Sonazoid. GdEOB-DTPA-enhanced MRI may offer a higher signal-tonoise ratio and contrast-to-noise ratio than dynamic CT or contrast-enhanced harmonic ultrasonography. Concerning the pulmonary nodules, a TBLB was carried out and showed no atypical features. Interestingly, followup chest CT revealed the disappearance or reduction of
nodules. Furthermore, dynamic CT revealed a dilated vein flow from pulmonary nodules into left atrium. Finally, the pulmonary nodules were diagnosed to be bleeding based on the presence of AVMs due to HHT. Pulmonary vascular manifestations of HHT include pulmonary AVMs (especially in patients with ENG mutations) and, less frequently, pulmonary hypertension (especially in patients with ALK1 mutations) [16]. In 15–33% of the patients with HHT, pulmonary AVMs consist of abnormal communications between pulmonary arteries and pulmonary veins, causing right-to-left shunting and thus, frequently hypoxemia and dyspnea on exertion, although pulmonary AVMs may remain asymptomatic and frequently undiagnosed unless complications occur. Pulmonary AVMs result in severe and frequent complications often at a young age, which may reveal the diagnosis, e.g., transient ischemic attack and cerebral stroke (10–19% of patients), systemic severe infections and abscesses (including cerebral abscess in 5–19% of patients) and rarely massive hemoptysis or
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hemothorax [16]. Pulmonary hypertension is rare in HHT and may be due either to systemic arteriovenous shunting in the liver increasing cardiac output or be clinically and histologically indistinguishable from idiopathic pulmonary arterial hypertension. Concerning the treatment of hepatic involvement of HHT, hepatic arterial coil embolization is employed for hepatic AVM in HHT [17]. Hepatic arterial coil embolization temporarily improves the patient’s cardiac condition, but gradually induces progressive hepatic failure due to intrahepatic cholangitis [17]. Peripheral arterial coil embolization might be temporarily useful for high-output heart failure, but it is harmful to the liver. In the current case, there were no symptoms and no clinical presentations such as high-output heart failure, portal hypertension and biliary disease. Thus, this case will be followed up without treatment for the liver vascular malformations. This report described a case of HHT with multiple hepatic and pulmonary nodular lesions. The hepatic nodular lesions were caused from an abnormal liver vascular supply due to arteriovenous shunts resulting from HHT. Gd-EOB-DTPA-enhanced MRI was useful for the diagnosis of NRH. Further advances in imaging techniques, including Gd-EOB-DTPA-enhanced MRI, are expected to enable us to make an accurate diagnosis of these hepatic nodules in HHT patients without the need to perform an invasive liver tumor biopsy.
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