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Multiple intrahepatic vascular shunts causing hyperammoniaemic encephalopathy in a patient without liver cirrhosis
Digestive and Liver Disease 38 (2006) 347–351
Brief Clinical Observation
Multiple intrahepatic vascular shunts causing hyperammoniaemic encephalopathy in a patient without liver cirrhosis E. Caturelli a,∗ , G. Ghittoni a , G.A. Niro b , R. Clemente b , L. Accadia b , M. Nardella c , A. Andriulli b , M. Anti a a
c
Gastrointestinal Unit, “Belcolle” Hospital, Strada Sammartinese, 01100 Viterbo, Italy b Gastrointestinal Unit, “Casa Sollievo della Sofferenza” IRCCS, viale Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy Diagnostic Imaging Department, “Casa Sollievo della Sofferenza” Hospital IRCCS, viale Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy Received 25 April 2005; accepted 14 June 2005 Available online 1 August 2005
Abstract The very rare case of a non-cirrhotic patient with multiple intrahepatic portosystemic and arteriosystemic vascular shunts, presenting with hyperammoniaemic type B encephalopathy and hypoalbuminaemia due to proteinuria, is reported. The correct diagnosis, suspected by abdominal ultrasound and colour-Doppler imaging, was confirmed by hepatic and superior mesenteric angiography. A comparison with the few similar cases existing in the literature is offered. © 2005 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Doppler ultrasound; Hepatic angiography; Hyperammoniaemia; Intrahepatic vascular shunts
1. Introduction
2. Case report
Portosystemic venous collaterals are usually extrahepatic and are found in patients with portal hypertension following liver cirrhosis. Intrahepatic vascular shunts are very rare and their cause is controversial. We report a very singular case of a non-cirrhotic patient with multiple intrahepatic portosystemic and arteriosystemic vascular shunts, presenting with hyperammoniaemic encephalopathy and hypoalbuminaemia due to proteinuria. The correct diagnosis, suspected by abdominal ultrasound and colour-Doppler imaging, was confirmed by hepatic and superior mesenteric angiography.
A 68-year-old Caucasian man with recurrent episodes of encephalopathy was admitted to the Gastroenterology Unit of Ospedale “Casa Sollievo della Sofferenza”. He denied family history of disease or alcohol intake. Arterial hypertension and episodes of mental confusion and abnormal behaviour occurred since the last 3 years. Eighteen months before, during the first diagnostic workup in another hospital, elevated serum ammonia level was found (68 g/dl; normal range 15–45 g/dl), while all other routine laboratory tests were normal (including blood cell count, bilirubin, alanine aminotransferase, albumin and creatinine serum levels). Proteinuria was absent. HbsAg was positive with negativity of other HBV and HCV markers. Congenital abnormality in the urea metabolic cycle was excluded by quantitative chromatography of amino acids (plasmatic and urinary). A diagnosis of vascular leucoencephalopathy was obtained by means of cranial CT scan and MR imag-
∗
Corresponding author. Tel.: +39 0761 339495; fax: +39 0761 339471. E-mail address: [email protected] (E. Caturelli).
1590-8658/$30 © 2005 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2005.06.005
348
E. Caturelli et al. / Digestive and Liver Disease 38 (2006) 347–351
Fig. 1. (A) Selective angiography of the common hepatic artery, early phase. Evidence of multiple peripheral arteriosystemic shunts with early filling of the hepatic veins. (B) Selective angiography of the common hepatic artery, delayed phase. Multiple arteriosystemic shunts are more evident and intense enhancement of hepatic veins anticipates the parenchymographic effect of the contrast media.
ing. Low-protein intake diet, lactulose and neomycin were administered and he recovered from encephalopathy. Four months before the present admission, the patient had been studied in another hospital for a new episode of encephalopathy. Hyperammoniaemia was still present (90 g/dl) and increased levels of immunoglobulins (IgA 607 mg/dl; normal range 70–400 mg/dl) were observed, as well as proteinuria (150 mg/dl) and hypoalbuminaemia (2.8 g/dl); other liver function tests resulted normal. On admission to our hospital, the patient appeared to be lethargic and disorientated for time and place, with occasionally inappropriate behaviour (grade 2 encephalopathy according to West Haven scale) [1]. At physical examination, no non-cognitive abnormality (such as extrapyramidal alterations) was detectable, but lower limbs oedema was present. During the months before the admission he followed a free diet. Albumin serum level was 1.9 g/dl, total proteins serum level was 4.2 g/dl and IgA level persisted high (588 mg/dl), as well as serum ammonia level (58 g/dl). Total bilirubin, alanine and aspartate aminotransferases, gamma-glutamyl transferase, alkaline phosphatase and creatinine serum levels were all into the normal range, as well as serum electrolytes, blood urea nitrogen and creatinine clearance. Oesophagogastroduodenoscopy was performed, but no signs of portal hypertension were found. An ultrasound scan of the upper abdomen revealed a normal liver (smooth surface, regular edges, normal size of the caudate lobe, homogeneous echo texture); the main portal vein had a normal diameter (12 mm) and no signs of thrombosis. Colour-Doppler evaluation of the portal circulation showed a very high hepatopetal velocity flow (mean 34 cm/s; normal range 12–18 cm/s); however, the Doppler examination was not useful to disclose any other
abnormality. Other upper abdominal organs, including the spleen, were normal. Due to persistent mixed proteinuria (mean 8850 mg/24 h), complement levels (C3 and C4) were investigated, and low C3 and C4 fractions were found. A renal biopsy was performed, and the ultrastructural evaluation showed a thickened basal membrane with subepithelial deposits suggesting a membranous glomerulonephritis (I–II stages). Liver biopsy was consistent with an inactive chronic hepatitis (grading 0, staging 1 according to Scheuer’s classification [2]), probably related to chronic HBV infection. Hepatic arteriography was performed in order to explain the increased blood velocity flow in the main portal vein; just after the injection of the iodinised contrast media into the hepatic artery, multiple arteriosystemic shunts became evident with early filling of the hepatic veins (Fig. 1A); during the delayed phase, the filling became more intense (Fig. 1B). Moreover, multiple small portosystemic shunts were visible in the liver parenchyma during the portal phase of superior mesenteric arteriography with early filling of the hepatic veins (Fig. 2). A diagnosis of multiple arteriosystemic and portosystemic intrahepatic vascular shunts was performed, thanks to these angiographic findings, which could explain the finding of elevated serum ammonia level. Accordingly, with the Vienna 1998 Consensus Statement [3], this was classified as a type B of encephalopathy (associated with portal–systemic bypass and no intrinsic hepatocellular disease). The normalisation of ammonia level, with a rapid improvement of encephalopathy symptoms, was obtained within 5 days from the starting of a therapy based upon a strict dietary control (with low-protein intake) and administration of lactulose and rifaximin.
E. Caturelli et al. / Digestive and Liver Disease 38 (2006) 347–351
Fig. 2. Selective angiography of the superior mesenteric artery, portal phase (arterial portography). Multiple small peripheral portosystemic shunts are visible in the liver parenchyma with early filling of the hepatic veins.
3. Discussion Abnormal intrahepatic communication between portal veins, hepatic arteries, or hepatic veins has been described in relatively few reports, although an optimal evaluation of the liver during arterial and portal venous phases of contrast enhancement can be obtained with increasing frequency thanks to the advances in cross-sectional imaging (multiphase helical CT and multiphase dynamic MR). Among the three types of intrahepatic shunts, the portosystemic venous ones are commonly present in cirrhotic liver as a consequence of portal hypertension [4]. Less frequently, intrahepatic portosystemic shunts are not associated to liver cirrhosis and portal hypertension, and their origin is still unknown. Hepatic encephalopathy, caused by elevated serum ammonia level, represents the common clinical manifestation of these shunts. Arterioportal shunts are typically associated with hepatocellular carcinoma due to the almost exclusively arterial feeding of this neoplasm, and their prevalence has been reported up to 63% of the cases [5]. In cirrhotic patients, arterioportal shunts not related to hepatocellular carcinoma may simulate hypervascular neoplastic lesions both at CT imaging [6] and at angiography [7]; however, a correct differential diagnosis can be performed by accurate two-phase spiral CT findings [8]. Uncommon causes of arterioportal shunting have been described, as penetrating (also iatrogenic) liver trauma, congenital vascular malformations, hereditary haemorrhagic teleangectasia [9] and hepatic haemangiomas [10]. Among intrahepatic vascular shunts, arteriosystemic are the less frequent ones, and they may be associated with benign and malignant neoplasms as haemangioma [10] and hepatocellular carcinoma [11], or more rarely, with hereditary haemorrhagic teleangectasia [9].
349
Intrahepatic vascular shunts produce clinical manifestations when they are large enough to divert great amounts of blood from the normal hepatic to the systemic circulation, as in the case of portosystemic shunting due to portal hypertension, causing type C hepatic encephalopathy [3]. Another possible cause of clinical manifestation of these shunts is the progressive liver failure subsequent to nodular transformation, in the case of extensive arteriovenous and arterioportal shunting in hereditary haemorrhagic teleangectasia [12]. To our knowledge, 20 cases of intrahepatic portosystemic shunts have been previously described (Table 1), and only four out of them presented as multiple communications between peripheral portal and hepatic veins involving both liver lobes, as in the present case. Usually, portohepatic venous shunts develop in cirrhotic patients; they are represented by a single channel or an aneurismatic structure connecting the right portal vein to the inferior vena cava, or single or multiple peripheral connections between portal branches and hepatic veins in a single liver segment or diffusely in both lobes [4] (Table 1). In our case, the diversion of the blood flow from the hepatic to the systemic circulation was caused by the intrahepatic portosystemic shunts (via the portal vein) and it was increased by the arteriosystemic shunts (via the hepatic artery). Because of this haemodynamic pattern, a substantial amount of blood skipped the liver filter, causing the chronic hyperammoniaemia observed in this patient (type B hepatic encephalopathy according to Ferenci et al. [3]). In the hereditary haemorrhagic teleangectasia (or Weber–Rendu–Osler disease), it is possible to find an extensive diffuse intrahepatic shunting; in our patient, no main diagnostic criterion besides visceral lesions (multiple intrahepatic shunts) was present. At least three out of four criteria (the other three are epistaxis, teleangectasias and appropriate family history) are necessary to diagnose hereditary haemorrhagic teleangectasia [13]. Moreover, the hereditary haemorrhagic teleangectasia is characterised by arteriovenous and arteriosystemic intrahepatic shunts, and not by portosystemic shunts. At the beginning, the presence of hyperammoniaemic encephalopathy and extended oedemas due to hypoalbuminaemia suggested the diagnosis of decompensated liver cirrhosis, but the evidence of a normal liver at ultrasound and the finding of hyperafflux in the main portal vein at colourDoppler ultrasound permitted to exclude portal hypertension and suggested the presence of intrahepatic portosystemic shunts. The connections between either portal branches and hepatic venous vessels, or arterial and hepatic venous vessels were below the threshold of visualisation of ultrasound and Doppler imaging [14], and for this reason angiography was necessary to perform the diagnosis [15]. The cause of diffuse intrahepatic shunting is still unknown, and either a congenital origin [16,17] or an acquired abnormality [18] has been suggested. Only three out of four published cases in which the intrahepatic shunting consisted of multiple small communications
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Table 1 Intrahepatic portosystemic shunts Authors
Type of shunt (according to Park et al. [4])
Presence of cirrhosis
Reported cerebral manifestations
Doehner et al. [20] Raskin et al. [16] Kozuka et al. [18]
Type 2 Type 4 Type 1
Not available No Yes
Okuda et al. [21] Yamashita et al. [22] Ohnishi et al. [23] Charnsangavej et al. [24]
Type 2 Type 4 Type 1 Type 2
No Not reported Yes No
Not available Personality changes Difficulty in walking, changes in personality, mental dullness, slurred speech, antisocial behaviour, ataxic gait, tremors Not reported Not reported Mental confusion, headache, nausea Not reported
Taguchi et al. [25] (two cases: a and b)
Type 2 (a) Type 2 (b)
Yes Yes
(a) None (b) None
Takayasu et al. [26] Wittich et al. [27] Kadoya et al. [28]
Type 3 Not reported Type 1
Yes Not reported Not reported
None Not reported Not reported
Chagnon et al. [17] (two cases: c and d)
Type 2 (c) Type 3 (d)
No No
(c) Bilateral cerebellar and pyramidal signs, asterixis (d) None
Ohtomo et al. [19]
Type 4
No
Consciousness disturbances, tremors, scanning speech, ataxia, spastic tetraplegia
Mori et al. [15] (four cases: e–h)
Type 1 (e) Type 1 (f) Type 1 (g) Type 4 (h)
Yes Yes Yes No
(e) Abnormal behaviour, disorientation, headache (f) Abnormal behaviour, loss of consciousness, flapping tremor (g) Mental confusion (h) Abnormal behaviour, disorientation
Park et al. [4] Present case
Type 1 Type 4
Yes No
Altered mental status Lethargy, disorientation, inappropriate behaviour
Review of the literature. Type 1: single large tube of constant diameter connecting the right portal vein to the inferior vena cava. Type 2: localised peripheral shunt with single or multiple communications between peripheral branches of portal and hepatic veins in one hepatic segment. Type 3: peripheral portal and hepatic veins connected through an aneurysm. Type 4: multiple communications between peripheral portal and hepatic veins diffusely in both lobes.
in the peripheral liver parenchyma are well documented [16,15,19]; all of these cases, including ours also, revealed a normal histological pattern at liver biopsy and none of them showed portal hypertension. For this reason, Raskin [16], who described this condition for the first time, supposed that it had a congenital origin and suggested that the late clinical manifestation was caused by a decreasing in hepatic tolerance to toxic metabolites with increasing age. In our opinion, the long time elapsed before the appearance of cerebral symptoms, an element present in our patient (68 year old), as well as in the other three cases – respectively, 56 [16], 42 [19] and 66 year old [15] – is an important element opposing to the congenital origin of these abnormalities. Nevertheless, it is well known that ageing causes the reduction of mechanisms permitting adequate mental function despite brain ammonia intoxication. The appearance of neurological symptoms, however, might be favoured by the presence of vascular leucoencephalopathy, whilst a pathogenetic mechanism involving a decreased renal function or an electrolyte imbalance could be excluded by means of haematochemical findings. Proteinuria could have had a relevant role in the appearance of neurological symptoms, since it might aggravate hypoalbuminaemia, so increasing the levels of protein-bound neurotoxic substances. Our patient developed the symptoms of hyperammoniaemic encephalopathy simultaneously with proteinuria due to
a renal damage, and this coincidence induces to hypothesise a common pathogenesis for the two diseases. A connection between the status of HbsAg carrier (whose duration in time unfortunately was not known) and the development of an immunomediated damage involving both the hepatic microcirculation and the renal glomeruli can be only supposed. The patients described by Ohtomo [19] and Mori [15] presented hypoproteinaemia too, but the possible causes have not been reported. A congenital origin of portosystemic shunting, instead, is easier to be supposed for types of connection represented by a single channel or structure, since the abundance of embryonic venous anastomoses connecting the portal to the systemic intrahepatic circulation, such as the vitelline veins and the ductus venosus. All these embryonic vascular remnants may develop as intrahepatic collateral pathways in the presence of portal hypertension due to liver cirrhosis. In conclusion, in the reported case the correct use of colour-Doppler ultrasound, guided by the complete knowledge of the clinical situation of the patient, led to recognise the diagnostic key point (high velocity flow in the main portal vein) and to indicate the imaging technique (angiography with arterial portography) allowing the correct diagnosis of a very rare disease. Intrahepatic vascular shunts must be considered in the differential diagnosis of hyperammoniaemic encephalopathy, above all in the absence of liver cirrhosis, in
E. Caturelli et al. / Digestive and Liver Disease 38 (2006) 347–351
order to prevent misdiagnosis as psychiatric or neurological disorders. Conflict of interest statement None declared.
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[13] Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJ, et al. Diagnostic criteria for hereditary hemorrhagic teleangectasia (Rendu–Osler–Weber syndrome). Am J Med Genet 2000;91:66–7. [14] Itai Y, Sekiyama K, Ahmadi T, Obuchi M, Yoshiba M. Fulminant hepatic failure: observation with serial CT. Radiology 1997;202:379–82. [15] Mori H, Hayashi K, Fukuda T, Matsunaga N, Futagawa S, Nagasaki M, et al. Intrahepatic portosystemic venous shunt: occurrence in patients with and without liver cirrhosis. Am J Roentgenol 1987;149:711–4. [16] Raskin NH, Price JB, Fishman RA. Portal systemic encephalopathy due to congenital intrahepatic shunts. N Engl J Med 1964;270:225–9. [17] Chagnon SF, Vallee CA, Barge J, Chevalier LJ, Gal JL, Blery MV. Aneurismal portohepatic venous fistula: report of two cases. Radiology 1986;159:693–5. [18] Kozuka S, Sassa R, Kakumu S. An enormous intrahepatic shunt between portal vein and hepatic one. Angiology 1975;26:365–71. [19] Ohtomo K, Furui S, Saito M, Kokubo T, Itai Y, Iio M. Enormous intrahepatic communication between the portal vein and the hepatic vein. Clin Radiol 1986;37:513–4. [20] Doehner GA, Ruzicka Jr FF, Rousselot LM, Hoffmann G. The portal venous system: on its pathological roentgen anatomy. Radiology 1956;66:206–17. [21] Okuda K, Kanda Y, Fukuyama Y, Musha H, Sumikoshi T. Hepatic vascular anomalies in non parasitic cysts of the liver. Acta Hepatogastroenterol 1976;23:110–3. [22] Yamashita S, Nakata K, Muro T, Furukawa R, Kusumoto Y, Munehisa T, et al. A case of hepatic encephalopathy due to diffuse intrahepatic porto-systemic shunts. Nippon Naika Gakkai Zasshi 1982;71:844–50. [23] Ohnishi K, Hatano H, Nakayama T, Kohno K, Okuda K. An unusual portal–systemic shunt, most likely through a patent ductus venosus. A case report. Gastroenterology 1983;85:962–5. [24] Charnsangavej C, Soo CS, Bernardino NE, Chuang VP. Portal–hepatic venous malformation: ultrasound, computed tomographic, and angiographic findings. Cardiovasc Intervent Radiol 1983;6:109–11. [25] Taguchi H, Horiguchi Y, Kitano T. Two cases of intrahepatic portosystemic shunt. Jpn J Med Ultrasonics 1983;43:71–2. [26] Takayasu K, Moriyama N, Shima Y, Muramatsu Y, Goto H, Yamada T, et al. Spontaneous portal–hepatic venous shunt via an intrahepatic portal vein aneurysm. Gastroenterology 1984;86:945–8. [27] Wittich G, Jantsch H, Tscholakoff D. Congenital portosystemic shunt diagnosed by combined real-time and Doppler sonography. J Ultrasound Med 1985;4:315–8. [28] Kadoya M, Takashima T, Matsui O, Kitagawa K, Chohtoh S. Unusual portosystemic collateral penetrating the liver parenchyma. Gastrointest Radiol 1985;10:115–8.
Brief Clinical Observation
Multiple intrahepatic vascular shunts causing hyperammoniaemic encephalopathy in a patient without liver cirrhosis E. Caturelli a,∗ , G. Ghittoni a , G.A. Niro b , R. Clemente b , L. Accadia b , M. Nardella c , A. Andriulli b , M. Anti a a
c
Gastrointestinal Unit, “Belcolle” Hospital, Strada Sammartinese, 01100 Viterbo, Italy b Gastrointestinal Unit, “Casa Sollievo della Sofferenza” IRCCS, viale Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy Diagnostic Imaging Department, “Casa Sollievo della Sofferenza” Hospital IRCCS, viale Cappuccini, 71013 San Giovanni Rotondo, Foggia, Italy Received 25 April 2005; accepted 14 June 2005 Available online 1 August 2005
Abstract The very rare case of a non-cirrhotic patient with multiple intrahepatic portosystemic and arteriosystemic vascular shunts, presenting with hyperammoniaemic type B encephalopathy and hypoalbuminaemia due to proteinuria, is reported. The correct diagnosis, suspected by abdominal ultrasound and colour-Doppler imaging, was confirmed by hepatic and superior mesenteric angiography. A comparison with the few similar cases existing in the literature is offered. © 2005 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Doppler ultrasound; Hepatic angiography; Hyperammoniaemia; Intrahepatic vascular shunts
1. Introduction
2. Case report
Portosystemic venous collaterals are usually extrahepatic and are found in patients with portal hypertension following liver cirrhosis. Intrahepatic vascular shunts are very rare and their cause is controversial. We report a very singular case of a non-cirrhotic patient with multiple intrahepatic portosystemic and arteriosystemic vascular shunts, presenting with hyperammoniaemic encephalopathy and hypoalbuminaemia due to proteinuria. The correct diagnosis, suspected by abdominal ultrasound and colour-Doppler imaging, was confirmed by hepatic and superior mesenteric angiography.
A 68-year-old Caucasian man with recurrent episodes of encephalopathy was admitted to the Gastroenterology Unit of Ospedale “Casa Sollievo della Sofferenza”. He denied family history of disease or alcohol intake. Arterial hypertension and episodes of mental confusion and abnormal behaviour occurred since the last 3 years. Eighteen months before, during the first diagnostic workup in another hospital, elevated serum ammonia level was found (68 g/dl; normal range 15–45 g/dl), while all other routine laboratory tests were normal (including blood cell count, bilirubin, alanine aminotransferase, albumin and creatinine serum levels). Proteinuria was absent. HbsAg was positive with negativity of other HBV and HCV markers. Congenital abnormality in the urea metabolic cycle was excluded by quantitative chromatography of amino acids (plasmatic and urinary). A diagnosis of vascular leucoencephalopathy was obtained by means of cranial CT scan and MR imag-
∗
Corresponding author. Tel.: +39 0761 339495; fax: +39 0761 339471. E-mail address: [email protected] (E. Caturelli).
1590-8658/$30 © 2005 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2005.06.005
348
E. Caturelli et al. / Digestive and Liver Disease 38 (2006) 347–351
Fig. 1. (A) Selective angiography of the common hepatic artery, early phase. Evidence of multiple peripheral arteriosystemic shunts with early filling of the hepatic veins. (B) Selective angiography of the common hepatic artery, delayed phase. Multiple arteriosystemic shunts are more evident and intense enhancement of hepatic veins anticipates the parenchymographic effect of the contrast media.
ing. Low-protein intake diet, lactulose and neomycin were administered and he recovered from encephalopathy. Four months before the present admission, the patient had been studied in another hospital for a new episode of encephalopathy. Hyperammoniaemia was still present (90 g/dl) and increased levels of immunoglobulins (IgA 607 mg/dl; normal range 70–400 mg/dl) were observed, as well as proteinuria (150 mg/dl) and hypoalbuminaemia (2.8 g/dl); other liver function tests resulted normal. On admission to our hospital, the patient appeared to be lethargic and disorientated for time and place, with occasionally inappropriate behaviour (grade 2 encephalopathy according to West Haven scale) [1]. At physical examination, no non-cognitive abnormality (such as extrapyramidal alterations) was detectable, but lower limbs oedema was present. During the months before the admission he followed a free diet. Albumin serum level was 1.9 g/dl, total proteins serum level was 4.2 g/dl and IgA level persisted high (588 mg/dl), as well as serum ammonia level (58 g/dl). Total bilirubin, alanine and aspartate aminotransferases, gamma-glutamyl transferase, alkaline phosphatase and creatinine serum levels were all into the normal range, as well as serum electrolytes, blood urea nitrogen and creatinine clearance. Oesophagogastroduodenoscopy was performed, but no signs of portal hypertension were found. An ultrasound scan of the upper abdomen revealed a normal liver (smooth surface, regular edges, normal size of the caudate lobe, homogeneous echo texture); the main portal vein had a normal diameter (12 mm) and no signs of thrombosis. Colour-Doppler evaluation of the portal circulation showed a very high hepatopetal velocity flow (mean 34 cm/s; normal range 12–18 cm/s); however, the Doppler examination was not useful to disclose any other
abnormality. Other upper abdominal organs, including the spleen, were normal. Due to persistent mixed proteinuria (mean 8850 mg/24 h), complement levels (C3 and C4) were investigated, and low C3 and C4 fractions were found. A renal biopsy was performed, and the ultrastructural evaluation showed a thickened basal membrane with subepithelial deposits suggesting a membranous glomerulonephritis (I–II stages). Liver biopsy was consistent with an inactive chronic hepatitis (grading 0, staging 1 according to Scheuer’s classification [2]), probably related to chronic HBV infection. Hepatic arteriography was performed in order to explain the increased blood velocity flow in the main portal vein; just after the injection of the iodinised contrast media into the hepatic artery, multiple arteriosystemic shunts became evident with early filling of the hepatic veins (Fig. 1A); during the delayed phase, the filling became more intense (Fig. 1B). Moreover, multiple small portosystemic shunts were visible in the liver parenchyma during the portal phase of superior mesenteric arteriography with early filling of the hepatic veins (Fig. 2). A diagnosis of multiple arteriosystemic and portosystemic intrahepatic vascular shunts was performed, thanks to these angiographic findings, which could explain the finding of elevated serum ammonia level. Accordingly, with the Vienna 1998 Consensus Statement [3], this was classified as a type B of encephalopathy (associated with portal–systemic bypass and no intrinsic hepatocellular disease). The normalisation of ammonia level, with a rapid improvement of encephalopathy symptoms, was obtained within 5 days from the starting of a therapy based upon a strict dietary control (with low-protein intake) and administration of lactulose and rifaximin.
E. Caturelli et al. / Digestive and Liver Disease 38 (2006) 347–351
Fig. 2. Selective angiography of the superior mesenteric artery, portal phase (arterial portography). Multiple small peripheral portosystemic shunts are visible in the liver parenchyma with early filling of the hepatic veins.
3. Discussion Abnormal intrahepatic communication between portal veins, hepatic arteries, or hepatic veins has been described in relatively few reports, although an optimal evaluation of the liver during arterial and portal venous phases of contrast enhancement can be obtained with increasing frequency thanks to the advances in cross-sectional imaging (multiphase helical CT and multiphase dynamic MR). Among the three types of intrahepatic shunts, the portosystemic venous ones are commonly present in cirrhotic liver as a consequence of portal hypertension [4]. Less frequently, intrahepatic portosystemic shunts are not associated to liver cirrhosis and portal hypertension, and their origin is still unknown. Hepatic encephalopathy, caused by elevated serum ammonia level, represents the common clinical manifestation of these shunts. Arterioportal shunts are typically associated with hepatocellular carcinoma due to the almost exclusively arterial feeding of this neoplasm, and their prevalence has been reported up to 63% of the cases [5]. In cirrhotic patients, arterioportal shunts not related to hepatocellular carcinoma may simulate hypervascular neoplastic lesions both at CT imaging [6] and at angiography [7]; however, a correct differential diagnosis can be performed by accurate two-phase spiral CT findings [8]. Uncommon causes of arterioportal shunting have been described, as penetrating (also iatrogenic) liver trauma, congenital vascular malformations, hereditary haemorrhagic teleangectasia [9] and hepatic haemangiomas [10]. Among intrahepatic vascular shunts, arteriosystemic are the less frequent ones, and they may be associated with benign and malignant neoplasms as haemangioma [10] and hepatocellular carcinoma [11], or more rarely, with hereditary haemorrhagic teleangectasia [9].
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Intrahepatic vascular shunts produce clinical manifestations when they are large enough to divert great amounts of blood from the normal hepatic to the systemic circulation, as in the case of portosystemic shunting due to portal hypertension, causing type C hepatic encephalopathy [3]. Another possible cause of clinical manifestation of these shunts is the progressive liver failure subsequent to nodular transformation, in the case of extensive arteriovenous and arterioportal shunting in hereditary haemorrhagic teleangectasia [12]. To our knowledge, 20 cases of intrahepatic portosystemic shunts have been previously described (Table 1), and only four out of them presented as multiple communications between peripheral portal and hepatic veins involving both liver lobes, as in the present case. Usually, portohepatic venous shunts develop in cirrhotic patients; they are represented by a single channel or an aneurismatic structure connecting the right portal vein to the inferior vena cava, or single or multiple peripheral connections between portal branches and hepatic veins in a single liver segment or diffusely in both lobes [4] (Table 1). In our case, the diversion of the blood flow from the hepatic to the systemic circulation was caused by the intrahepatic portosystemic shunts (via the portal vein) and it was increased by the arteriosystemic shunts (via the hepatic artery). Because of this haemodynamic pattern, a substantial amount of blood skipped the liver filter, causing the chronic hyperammoniaemia observed in this patient (type B hepatic encephalopathy according to Ferenci et al. [3]). In the hereditary haemorrhagic teleangectasia (or Weber–Rendu–Osler disease), it is possible to find an extensive diffuse intrahepatic shunting; in our patient, no main diagnostic criterion besides visceral lesions (multiple intrahepatic shunts) was present. At least three out of four criteria (the other three are epistaxis, teleangectasias and appropriate family history) are necessary to diagnose hereditary haemorrhagic teleangectasia [13]. Moreover, the hereditary haemorrhagic teleangectasia is characterised by arteriovenous and arteriosystemic intrahepatic shunts, and not by portosystemic shunts. At the beginning, the presence of hyperammoniaemic encephalopathy and extended oedemas due to hypoalbuminaemia suggested the diagnosis of decompensated liver cirrhosis, but the evidence of a normal liver at ultrasound and the finding of hyperafflux in the main portal vein at colourDoppler ultrasound permitted to exclude portal hypertension and suggested the presence of intrahepatic portosystemic shunts. The connections between either portal branches and hepatic venous vessels, or arterial and hepatic venous vessels were below the threshold of visualisation of ultrasound and Doppler imaging [14], and for this reason angiography was necessary to perform the diagnosis [15]. The cause of diffuse intrahepatic shunting is still unknown, and either a congenital origin [16,17] or an acquired abnormality [18] has been suggested. Only three out of four published cases in which the intrahepatic shunting consisted of multiple small communications
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Table 1 Intrahepatic portosystemic shunts Authors
Type of shunt (according to Park et al. [4])
Presence of cirrhosis
Reported cerebral manifestations
Doehner et al. [20] Raskin et al. [16] Kozuka et al. [18]
Type 2 Type 4 Type 1
Not available No Yes
Okuda et al. [21] Yamashita et al. [22] Ohnishi et al. [23] Charnsangavej et al. [24]
Type 2 Type 4 Type 1 Type 2
No Not reported Yes No
Not available Personality changes Difficulty in walking, changes in personality, mental dullness, slurred speech, antisocial behaviour, ataxic gait, tremors Not reported Not reported Mental confusion, headache, nausea Not reported
Taguchi et al. [25] (two cases: a and b)
Type 2 (a) Type 2 (b)
Yes Yes
(a) None (b) None
Takayasu et al. [26] Wittich et al. [27] Kadoya et al. [28]
Type 3 Not reported Type 1
Yes Not reported Not reported
None Not reported Not reported
Chagnon et al. [17] (two cases: c and d)
Type 2 (c) Type 3 (d)
No No
(c) Bilateral cerebellar and pyramidal signs, asterixis (d) None
Ohtomo et al. [19]
Type 4
No
Consciousness disturbances, tremors, scanning speech, ataxia, spastic tetraplegia
Mori et al. [15] (four cases: e–h)
Type 1 (e) Type 1 (f) Type 1 (g) Type 4 (h)
Yes Yes Yes No
(e) Abnormal behaviour, disorientation, headache (f) Abnormal behaviour, loss of consciousness, flapping tremor (g) Mental confusion (h) Abnormal behaviour, disorientation
Park et al. [4] Present case
Type 1 Type 4
Yes No
Altered mental status Lethargy, disorientation, inappropriate behaviour
Review of the literature. Type 1: single large tube of constant diameter connecting the right portal vein to the inferior vena cava. Type 2: localised peripheral shunt with single or multiple communications between peripheral branches of portal and hepatic veins in one hepatic segment. Type 3: peripheral portal and hepatic veins connected through an aneurysm. Type 4: multiple communications between peripheral portal and hepatic veins diffusely in both lobes.
in the peripheral liver parenchyma are well documented [16,15,19]; all of these cases, including ours also, revealed a normal histological pattern at liver biopsy and none of them showed portal hypertension. For this reason, Raskin [16], who described this condition for the first time, supposed that it had a congenital origin and suggested that the late clinical manifestation was caused by a decreasing in hepatic tolerance to toxic metabolites with increasing age. In our opinion, the long time elapsed before the appearance of cerebral symptoms, an element present in our patient (68 year old), as well as in the other three cases – respectively, 56 [16], 42 [19] and 66 year old [15] – is an important element opposing to the congenital origin of these abnormalities. Nevertheless, it is well known that ageing causes the reduction of mechanisms permitting adequate mental function despite brain ammonia intoxication. The appearance of neurological symptoms, however, might be favoured by the presence of vascular leucoencephalopathy, whilst a pathogenetic mechanism involving a decreased renal function or an electrolyte imbalance could be excluded by means of haematochemical findings. Proteinuria could have had a relevant role in the appearance of neurological symptoms, since it might aggravate hypoalbuminaemia, so increasing the levels of protein-bound neurotoxic substances. Our patient developed the symptoms of hyperammoniaemic encephalopathy simultaneously with proteinuria due to
a renal damage, and this coincidence induces to hypothesise a common pathogenesis for the two diseases. A connection between the status of HbsAg carrier (whose duration in time unfortunately was not known) and the development of an immunomediated damage involving both the hepatic microcirculation and the renal glomeruli can be only supposed. The patients described by Ohtomo [19] and Mori [15] presented hypoproteinaemia too, but the possible causes have not been reported. A congenital origin of portosystemic shunting, instead, is easier to be supposed for types of connection represented by a single channel or structure, since the abundance of embryonic venous anastomoses connecting the portal to the systemic intrahepatic circulation, such as the vitelline veins and the ductus venosus. All these embryonic vascular remnants may develop as intrahepatic collateral pathways in the presence of portal hypertension due to liver cirrhosis. In conclusion, in the reported case the correct use of colour-Doppler ultrasound, guided by the complete knowledge of the clinical situation of the patient, led to recognise the diagnostic key point (high velocity flow in the main portal vein) and to indicate the imaging technique (angiography with arterial portography) allowing the correct diagnosis of a very rare disease. Intrahepatic vascular shunts must be considered in the differential diagnosis of hyperammoniaemic encephalopathy, above all in the absence of liver cirrhosis, in
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order to prevent misdiagnosis as psychiatric or neurological disorders. Conflict of interest statement None declared.
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