A life-threatening complication of focal nodular hyperplasia

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Letters to the Editor

lysine 125 mg t.i.d was started. The patient usually took this drug joined to a cup of whisky, around ten drinks per day. There was no history of intravenous drug abuse or previous transfusion. He had not taken any other drug during the three previous months. Hematological analyses were normal and biochemical determinations showed increase of aspartate aminotransferase (AST): 333 U/l (N , 37U=l), ALT: 331 U/l (N , 41U=l), alkaline phosphatase (AP):1430 U/l (N , 270 U/l), gamma-glutamil transpeptidase (GGT): 1102 U/l (N , 50 U/l) and bilirubin: 7.9 mg/dl (N , 1 mg/ dl). Anti-HCV, RNA-HCV, HBs-Ag, antiHBC-IgM, antiHAV-IgM, AntiHEV IgM, anti-cytomegalovirus (CMV) IgM, anti-EBV IgM, anti-HSV I and II were negative. Antinuclear antibodies (ANA), antimitochondrial antibodies (AMA), anti smooth muscle antibodies (SMA), anti-liverkidney microsomal antibodies (LKM) and perinuclear anticytoplasm of neutrophils antibodies (p-ANCA) were also negative. Level of albumin and prothrombin was normal. Ultrasound of the liver revealed a diffuse hyperechogenicity without portal hypertension, hepatomegaly or splenomegaly. The biliary tract was not enlarged. A liver biopsy showed a biliary duct damage with cholestasis, eosinophils in the in®ltrate and spotty hepatocellular necrosis with Councilman bodies. No feature of alcoholic hepatitis was seen (Fig. 1). The patient avoided alcohol consumption and fosinopril was discontinued; 4 weeks later the liver function tests were normal. Clonixinate lysine was used again for his lumbar pain without changes in liver function tests. In our patient, liver disease was probably related to fosinopril intake because temporal relationship with appearance of symptoms, resolution of altered biochemical parameters after withdrawal, other causes of acute cholestatic hepatitis were ruled out, and histopathological features with eosinophil in®ltration and centrilobular necrosis [1]. Alcoholic hepatitis was suspected in the ®rst time due to excessive alcohol intake and jaundice. However, ALT levels higher than 8 times the upper normal limit and alkaline phosphatase higher than GGT induced us to keep in mind other possible diagnostics. Viral, metabolic and autoimmune diseases were ruled out by microbiologic and biochemical analysis. In spite of a prescription longer than 5 years, fosinopril has not been associated with hepatotoxicity yet. In two safety studies with 31 145 patients, no patient showed hepatitis during treatment [2,3]. On the other hand, cases of cholestatic hepatitis have occurred after treatment with ACEI as enalapril [4] or captopril [5]. In a review about hepatotoxicity related to ACEI use, a cholestatic pattern

was seen in 8 out of 12 biopsies of ACEI-induced liver injury [6]. Hepatotoxicity generally resolves with cessation of therapy. However, a case of lisinopril-induced fulminant hepatitis has been reported [7]. Chronic alcohol consumption has been associated with enhanced individual susceptibility to toxic liver damage related to drugs as acetaminophen, NSAID and methotrexate. Alcohol intake could induce a profound depletion of mitochondrial glutathion leading to cellular necrosis as a result of the inability to defend against reactive oxygen species. In rat cultured hepatocytes, fosinopril cytotoxicity was enhanced in the absence of suf®cient glutathion or by P450 bioactivation [8]. Thus, situations characterized by cytochrome P450 induction or glutathion depletion could increase the potential risk for fosinopril induced liver disease. Patients treated with fosinopril should avoid alcohol intake. Manuel Romero-GoÂmez 1, Edmundo Juan Miralles 2, Enrique GarcõÂ a DõÂ az 1, Antonio Robles 2, Emilio SuaÂrez 1, Manuel Castro 1 1

Hepatology Unit, Hospital Universitario de Valme, Seville, Spain, Pathology Unit, Hospital Universitario de Valme, Seville, Spain

2

References [1] Benichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol 1990;11:272±276. [2] Berdah J, Guest M, Salvador M. Study of the ef®cacy and safety of fosinopril in general practice in 19435 hypertensive patients. Ann Cardiol Angeiol 1998;47:169±175. [3] Edwards C, Blowers DA, Power GM. Fosinopril national survey: a post-marketing surveillance study of fosinopril in general practice in the UK. Int J Clin Pract 1997;51:394±398. [4] Valle R, Carrascosa M, Cillero L, Perez-Castrillon JL. Enalaprilinduced hepatotoxicity. Ann Pharmacother 1993;27:1405. [5] Nissan A, Spira RM, Seror D, Ackerman Z. Captopril-associated `pseudocholangitis'. A case and review of the literature. Arch Surg 1996;131:670±671. [6] Hagley MT, Hulisz DT, Burns CM. Hepatotoxicity associated with angiotensin converting enzyme inhibitors. Ann Pharmacother 1993;27:228±231. [7] Larrey D, Babany G, Bernhuau J, Andrieux J, Deggott C, Pessayre D, Benhamou JP. Fulminant hepatitis after lisinopril administration. Gastroenterology 1990;99:1832±1833. [8] Jaurima-Romet M, Huang HS. Comparative cytotoxicity of angiotensin-converting enzyme inhibitors in cultured rat hepatotocytes. Biochem Pharmacol 1993;46:2163±2170. PII: S0 168-8278(01 )00 098-8

A life-threatening complication of focal nodular hyperplasia To the Editor: Focal nodular hyperplasia (FNH) is usually an incidental ®nding [1]. This benign hepatic lesion is currently considered as a hyperplastic response of liver parenchyma to a pre-

existing vascular malformation [2].Unlike hepatocellular adenoma which is associated with major complications (hemorrhage and malignant degeneration), FNH has an uncomplicated natural course. Thus it is generally accepted

Letters to the Editor

that no treatment or surveillance is needed after unambiguous diagnosis [1].In this report we describe a case of FNH revealed by spontaneous hemoperitoneum. This life-threatening complication required a selective embolisation and a surgical removal of the FNH to stop bleeding. A 37-year-old woman presented with sudden, rapidly diffusing epigastric pain. Her past medical history was unremarkable and she used oral contraceptives for 20 years. She had completed an uneventful full-term pregnancy 2 years previously. Physical examination revealed tenderness of the right abdomen. Pelvic examination was normal. Hemodynamic status was stable. Following admission laboratory tests were: hemoglobin: 113 g/l; hematocrit: 34%. Liver function tests were normal. Computed tomography showed a spontaneously hyperdense area (a 3 cm in diameter recent intraparenchymal hematoma) around a hypodense mass (4 cm in diameter with low arterial enhancement and a discrete central stellate element) in the right liver associated with a diffuse hemoperitoneum and subcapsular right liver hematoma. Doppler ultrasound detected spectrum pulsative signals characteristic of arterial ¯ow around the tumor. Our presumptive diagnosis was ruptured hepatocellular adenoma. Selective arterial embolization was undertaken. Hepatic angiography showed an enlarged artery supplying the segment VII associated with a pseudoaneurysm near the hypovascularized tumor. Embolization was successful on angiographic control (Fig.1a,b). Eight days later, bleeding recurred (transfusion of 4 units of red cells) associated with increased abdominal pain. Surgical exploration was then undertaken. After removing a 1 l hemoperitoneum, examination revealed that most of the right hepatic lobe was covered by a subcapsular hematoma. A ®brous tumor was palpated in the right posterolateral area. The remaining liver was normal. Right hepatectomy was performed. Postoperative recovery was uneventful and the patient was discharged 12 days later.

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The surgical specimen examination revealed a pale mass (5 cm in diameter) surrounded by localized intraparenchymal hematoma and Glisson's subcapsular hematoma (15 cm in diameter). The tumor was composed mainly of necrotic tissue except for few areas containing normal hepatocytes separated by ®brous tissue septa with proliferating bile ducts and abnormal arterial supply. Hepatic parenchyma was normal. No arteriovenous abnormality was found. The ®nal diagnosis was spontaneous hemorrhagic FNH. This is the ®rst reported case of FNH associated with lifethreatening acute hemoperitoneum requiring two procedures. A previous case involving rupture and hemorrhage was reported but surgical treatment was postponed for 1 month [3]. Infarction and intralesional hemorrhage with or without secondary intraperitoneal bleeding have been reported [4]. The factors that in¯uence the growth and complications of FNH are unclear. Two large studies demonstrated that the risk of growth or life-threatening rupture did not warrant advising women against oral contraceptives [5] or pregnancy [6]. In both studies, tumor size remains unchanged in 80±95%. Experience with long-term observation in non operated patients with FNH is limited [7]. As the natural history of FNH is usually uncomplicated, conservative management is recommended for patients with an established diagnosis of FNH [1,7]. The most common benign hepatic lesion causing spontaneous intraperitoneal bleeding is hepatocellullar adenoma. This diagnosis was proposed prior to treatment in the present case. A well accepted treatment for bleeding hepatocellular adenoma is arterial embolization to reduce the size and the blood supply of the tumor followed by elective surgery [8]. Histologic studies of angioarchitecture and blood circulation in FNH demonstrated abnormally large feeding arteries [2] but no portal blood ¯ow inside the lesion [9]. These ®ndings support the potential effectiveness of symptomatic treatment by ligation or embolization of the hepatic artery [10]. In our case,

Fig. 1. Hepatic angiogram by a enlarged right hepatic artery catheterism (arising from superior mesenteric artery) revealing (a) a pseudoanerysm lesion of the artery supplying the segment VII, without arterio-venous shunting. (b) Successful control after selective embolisation of the artery supplying the segment VII.

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embolization was initially successful, but hemorrhage recurred. Surgical resection was favored to assure hemostasis and removal of the tumor in the same procedure. Becker et al. [3] reported as well a case where FNH was primarily presented with rupture, without any premonitory symptoms. Although outcome in both cases was favorable, these ®ndings suggest that acute hemorrhage is a possible complication of FNH requiring surgical resection. Jean Hardwigsen 1, Julien Pons 1, VeÂronique Veit 2, SteÂphane Garcia 3, Y. Patrice Le Treut 1 1 Department of Surgery and Liver Transplantation, HoÃpital de la Conception, 147 Boulevard Baille, 13005 Marseille, Cedex 5, France, 2Department of Internal Medicine, HoÃpital de la Conception, 147 Boulevard Baille, 13005 Marseille, France, 3 Department of Pathology, HoÃpital Nord, Chemin des Bourelly, 13015 Marseille, France

References [1] Cherqui D, Rahmouni A, Charlotte F, Boulahdour H, Metreau JM, Meignan M, et al. Management of focal nodular hyperplasia and hepatocellular adenoma in young women: a series of 41 patients with clinical, radiological, and pathological correlations. Hepatology 1995;22:1674±1681.

[2] Wanless IR, Mawdsley C, Adams R. On the pathogenesis of focal nodular hyperplasia of the liver. Hepatology 1985;5:1194±1200. [3] Becker YT, Raiford DS, Webb L, Wright JK, Chapman WC, Pinson CW. Rupture and hemorrhage of hepatic focal nodular hyperplasia. Am Surg 1995;61:210±214. [4] Sadowski DC, Lee SS, Wanless IR, Kelly JK, Heathcote EJ. Progressive type of focal nodular hyperplasia characterized by multiple tumors and recurrence. Hepatology 1995;21:970±975. [5] Mathieu D, Kobeiter H, Maison P, Rahmouni A, Cherqui D, Zafrani ES, et al. Oral contraceptive use and focal nodular hyperplasia of the liver. Gastroenterology 2000;118:560±564. [6] Weimann A, Mossinger M, Fronhoff K, Nadalin S, Raab R. Pregnancy in women with observed focal nodular hyperplasia of the liver. Lancet 1998;351:1251±1252. [7] Weimann A, Ringe B, Klempnauer J, Lamesch P, Gratz KF, Prokop M, et al. Benign liver tumors: differential diagnosis and indications for surgery. World J Surg 1997;21:983±990. [8] Leese T, Farges O, Bismuth H. Liver cell adenomas. A 12-year experience from a specialist hepato-biliary unit. Ann Surg 1988;208:558±564. [9] Fukukura Y, Nakashima O, Kusaba A, Kage M, Kojiro M. Angioarchitecture and blood circulation in focal nodular hyperplasia of the liver. J Hepatol 1998;29:470±475. [10] Pain JA, Gimson AE, Williams R, Howard ER. Focal nodular hyperplasia of the liver: results of treatment and options in management. Gut 1991;32:524±527. PII: S0 168-8278(01 )00 096-4

Impact of medical recommendations on alcohol consumption in HCV positive patients To the Editor: Chronic alcohol consumption (AC) worsens the severity of HCV-related chronic hepatitis and is a key factor for the development of liver cirrhosis [1]. The cut-off of `safe drinking' for HCV carriers is still unknown, even if a significant increase in the relative risk of cirrhosis was observed for an AC as low as 25 g/day [2]. Therefore, a majority of hepatologists recommend their HCV positive patients to completely stop drinking or to drink moderately and occasionally [3]. As drinking alcohol is a traditional way of life in several countries, including France, we wonder whether these medical recommendations are implemented by HCV positive patients. One-hundred and twenty-seven randomly selected outpatients in care for HCV-related chronic hepatitis were interviewed, using a currently used local questionnaire, on their alcohol drinking habits before and after diagnosis of HCV infection. They were classi®ed as non-, moderate or excessive drinkers according to the WHO limits (i.e. excessive drinking, .28 units/week for men and .14 units/week for women). All patients had been medically advised that alcohol could worsen their liver disease and asked to reduce their alcohol intake to no more than 1 or 2 drinks occasionally.

The advice was (and still is) regularly repeated while no therapy for alcohol-related problems was undertaken. Such a method is not far from the `brief interventions' by general practitioners towards heavy drinkers [4]. They were 68 men and 59 women, aged 48 ^ 11 years. The median time elapsed between the diagnosis of HCV infection and the present survey was 5 years (1±15 years). According to histopathological data which were available in 104 (81.9%) patients, 68 (53.5%) and 14 (11.0%) had mild and moderate chronic hepatitis, respectively and 22 (17.4%) had liver cirrhosis. Seven ful®lled the questionnaire incompletely and were not available for analysis. Before the diagnosis of HCV infection, AC was nil, moderate or excessive in 14 (11%), 82 (64%) and 25 (18%) patients, respectively. After the diagnosis had been made, 85 (70.2%), 22 excessive and 63 moderate drinkers, immediately modi®ed their AC, but none increased it. Among the 22 excessive drinkers, nine stopped drinking, 11 became moderate drinkers and the latter two reduced their AC but remained in the excessive class; 25 out of the 63 moderate drinkers stopped drinking, while the remaining 38 reduced their alcohol intake. The repartition in drinking classes before and after diagnosis was signi®cantly different (P , 0:05). Among the 36 who did not modify their AC, 14 were non-drinkers, 19 were moderate