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Ultrasound in Rare Diffuse Liver Disease Ultraschall seltener diffuser Lebererkrankungen

Authors

A. P. Barreiros1, L. Chiorean2, B. Braden3, C. F. Dietrich4

Affiliations

1

3 4

Medical Department I, University Hospital, University of Regensburg, Regensburg, Germany Department of Ultrasonography, “Octavian Fodor” Institute of Gastroenterology and Hepatology, Cluj-Napoca, Romania Translational Gastroenterology Unit, Oxford University Hospitals, Oxford, U. K. Medical Department II, Caritaskrankenhaus, Bad Mergentheim, Germany

Schlüsselwörter

Zusammenfassung

Abstract

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Die transabdominelle Sonografie ist häufig das erste bildgebende Verfahren zur Evaluierung von Lebererkrankungen. Trotz Fortschritte der Gerätetechnologie ist die sonografische Diagnostik diffuser Lebererkrankungen schwierig. Dies liegt auch an den häufig nicht oder nur unspezifisch nachweisbaren Veränderungen der Leber. Erfassbare Veränderungen beinhalten die Lebergröße, Leberform, Echogenität, Analyse von intrahepatischen Gefäßen sowie die Beurteilung von perihepatischen Strukturen und Lymphknoten. Die häufig nur schwer zu erkennenden Veränderungen des Leberparenchyms wurden bisher kaum beschrieben. Aber auch bei selteneren diffusen Lebererkrankungen können typische sonografische Befunde erhoben werden. Die vorliegende Arbeit ist eine Literaturübersicht zu seltenen diffusen Lebererkrankungen und erläutert charakteristische sonomorphologische Befunde der einzelnen Krankheitsbilder.

Ultrasound is often the first imaging procedure performed in the evaluation of individuals with suspected or known liver disease. Despite technical advances in ultrasound techniques, sonographic detection and evaluation of diffuse liver disease still remains difficult. This is due to the fact that diffuse liver disease does not always cause distortion of the liver parenchymal texture, internal liver architecture, or shape of the liver. On the other hand, the size of the liver, the echo pattern of the hepatic parenchyma, the analysis of intrahepatic vessels and alterations in perihepatic structures and lymph nodes can be helpful sonographic parameters of diffuse liver disease. Until now, the sonographic appearance of some rare diffuse liver diseases is not well known. However, there are some typical sonomorphological signs that, once identified, can facilitate the differentiation between various diseases. The aim of this paper is to highlight some typical ultrasound findings of liver parenchyma and perihepatic lymph node structures in rare diffuse liver diseases based on a review of published data.

Introduction

disease, liver infarcts) are excluded as well. The review focuses on rare adult diffuse liver diseases.

● Leitlinien ● Morbus Wilson ● Schistosomiasis ● PSC ● PBC ● Virushepatitis ● Autoimmunhepatitis " " " " " "

Key words

● guidelines ● Wilson’s disease ● schistosomiasis ● PSC ● PBC ● viral hepatitis ● autoimmune hepatitis " " " " " " "

received accepted

20.5.2014 13.7.2014

Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1384996 Z Gastroenterol 2014; 52: 1247–1256 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0044-2771 Correspondence Prof. Christoph F. Dietrich Med. Klinik 2 Caritaskrankenhaus Bad Mergentheim Uhlandstr. 7 97980 Bad Mergentheim Germany Tel.: ++ 49/0 79 31/58 22 01 Fax: ++ 49/0 79 31/58 22 90 [email protected]

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The value of transcutaneous transabdominal ultrasound in the work-up of diffuse liver diseases mainly focuses on the exclusion of focal liver lesions and dilatation of the bile duct [1, 2]. There are only few sonographic criteria to characterise diffuse liver disease including size [3, 4], shape, border, echogenicity [5, 6], vessels and analysis of perihepatic structures. The value of non-invasive liver fibrosis assessment has been recently published in guidelines [7, 8] and comments to the guidelines [9] and is not topic of this review. Vascular diseases (e. g., portal vein thrombosis, BuddChiari syndrome, veno-occlusive disease, Oslers

What Can We Learn from More Frequent Diffuse Liver Disease? Diffuse liver disease can be classified in acute and chronic liver diseases and/or inflammatory and non-inflammatory. Acute liver diseases are in contrast to chronic liver diseases rare. Depending on geographical focus this is also true for the differentiation between inflammatory and non-inflammatory diseases. In many countries, the prevalence of inflammatory liver diseases such as viral hepatitis [hepatitis B (HBV), hepatitits C (HCV)] or schistosomiasis is high.

Barreiros AP et al. Ultrasound in Rare … Z Gastroenterol 2014; 52: 1247–1256

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In general, criteria for analysing diffuse liver diseases include the evaluation of: (i) liver parenchyma (echo-texture, ultrasound attenuation, vascular architecture, etc.) as well as the liver surface (a high frequency transducer can be helpful to detect details of superficially located structures); (ii) liver hilum structures including perihepatic lymph nodes in the hepatoduodenal ligament, lymph nodes in inflammatory liver disease or neoplastic infiltration; (iii) hepatic vessel flow patterns using colour and pulsed wave Doppler imaging (CDI); (iv) other features like fibrosis assessment (not topic of this paper). This papers aims to analyse and review published data on ultrasound findings in rare diffuse liver diseases. It evaluates sonographic characteristics to differentiate various rare liver diseases.

Evaluation of Perihepatic Lymphadenpathy !

Advances in sonographic technology, techniques [10] and knowledge of well-defined anatomic sites of perihepatic lymph nodes (between the inferior cava and portal vein next to the right renal artery) have led to improved identification of enlarged as well as normal sized lymph nodes in the liver hilum by ultrasound. Normal lymph node size is up to 19 mm in the longitudinal diameter [11 – 15]. Two groups of lymph nodes can normally be detected: one group dorsal in the hepatoduodenal ligament adjacent to the cystic duct (“cystic duct nodes”) and the other ventral in the hepatoduodenal ligament adjacent to the orifice of the foramen epiploicum next to the common hepatic artery. The liver hilum should be examined in a slight left lateral oblique patient position (15 − 30o) with the right arm elevated, thus improving the detection rate from 25 % to 75 % compared with the decubitus position [16]. Whenever the liver is inspected using ultrasound and a diffuse or focal liver disease is suspected, the examination and evaluation of perihepatic lymph nodes is obligatory [17]. Although the lymph node involvement in certain diffuse liver diseases seems to be obvious, only few studies have focussed on this topic. Braden et al. investigated the detection rate in chronic liver diseases [18]. Patients with viral hepatitis, autoimmune hepatitis, primary sclerosing cholangitis or primary biliary cirrhosis showed in 86 − 100 % of the cases enlarged perihepatic lymph nodes. In contrast, perihepatic lymphadenopathy was rare in patients with hemochromatosis, steatosis or cholecystolithiasis. Lymph nodes are detectable within the hepatoduodenal ligament in almost all patients with chronic HCV. The total perihepatic lymph node volume changes according to the antiviral response and shows a progressive normalisation in those with a sustained virological response [12]. A decrease in perihepatic lymph node volume is associated with an improvement in liver histology [14, 19]. Mediastinal lymphadenopathy has also been described in patients with chronic HCV using mediastinal ultrasound [15], whereas other abdominal lymph node locations are not significantly altered in patients with the infection. In contrast-enhanced ultrasound (CEUS) inflammatory perihepatic lymphadenopathy shows homogenous contrast enhancement.

Acute viral hepatitis There are no significant changes in liver echo-texture in acute viral hepatitis. However, enlarged perihepatic lymph nodes are a fairly constant feature, which is also present in chronic hepatitis, conditions such as viral and autoimmune liver diseases but not in toxic hepatitis or haemochromatosis. One study of 40 patients with acute hepatitis found that enlarged perihepatic lymph

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nodes could be identified by transabdominal ultrasound in all patients with adequate visualisation of the liver hilum (a sensitivity of 100 %), which is helpful to differentiate between toxic and viral genesis [18]. Additionally, in the above-mentioned study in patients with chronic liver diseases, perihepatic lymphadenopathy was present in 86 % of the patients with viral hepatitis, in 90 % with AIH, in 100 % with PSC, in 97 % with primary biliary cirrhosis (PBC), but in only 6 % with haemochromatosis, in 1 % with fatty liver disease and in 4 % with cholecystolithiasis [18]. Hepatomegaly and a small amount of perihepatic ascites can sometimes be found in patients with acute hepatitis, but both signs are not pathognomonic. Doppler techniques can be used to exclude complications (e. g., portal vein thrombosis) and reveal an unspecific hyperdynamic state in hepatic vessels with a higher diastolic arterial blood flow when compared with healthy individuals. Portal venous blood flow is increased and, perhaps owing to oedema and narrowing of the hepatic veins, the flow pattern is often monophasic [20]. Gallbladder wall thickening is a short-lived sonographic phenomenon of the early phase of acute hepatitis in approximately 50 % of patients [18, 21]. This finding alone, although non-specific, can sometimes suggest the diagnosis of hepatitis A in the correct clinical situation [22]. This gallbladder wall thickening must not be confused with acute cholecystitis which is associated with circumscript pain on ultrasound palpation. In patients with acute viral hepatitis, especially acute viral hepatitis A, attention should be paid to the presence of this sign and it should be sonographically followed during the course of the disease, since cases with progression to acute acalculous cholecystitis have been reported in the literature [23].

Note 1: Sonographic signs of acute hepatitis:

▶ No characteristic liver parenchyma alterations ▶ Only unspecific signs like: ▶ Hepatomegaly ▶ Inhomogeneity of liver parenchyma ▶ Small amount of perihepatic ascites ▶ Gallbladder wall thickening ▶ But: lymphadenopathy in the liver hilum (lymph node size > 19 mm) in almost all patients [18].

HIV Alterations of the liver parenchyma in patients with human immunodeficiency virus infection are often caused by opportunistic infections, neoplastic infiltration or toxic alterations, e. g., due to antiretroviral therapy [24]. Many causes have to be considered [e. g., bacillary angiomatosis] [25]. In a consecutive series, 82 of 100 patients with acquired immune deficiency syndrome showed enlarged perihepatic lymph nodes (unpublished data by the author). Co-infection with hepatitis B and C virus and mycobacteriosis is common in these patients. There was no significant correlation with HIV viraemia. Hepatobiliary infection as a cause of perihepatic lymphadenopathy should also be considered, e. g., cytomegaly virus infection.

End stage liver disease Enlarged perihepatic lymph nodes have been found in almost all patients with end-stage liver disease and portal hypertension.

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Autoimmune and cholestatic liver diseases !

Primary biliary cirrhosis (PBC): Primary biliary cirrhosis is predominantly found in women and shows a typical serological finding with AMA, M2 positivity. The disease can be classified into stage I − IV depending on the underlying fibrosis. The echo-texture of the liver parenchyma in patients with PBC in stages I and II is often unremarkable. In stage IV typical signs of liver cirrhosis are detectable. The liver parenchyma of patients with stage III PBC shows advanced sonomorphological modifications such as inhomogenous parenchyma, but no indicative signs of liver cirrhosis. The extent of perihepatic lymphadenopathy reflects the progression of the disease with a larger lymph node size in more advanced stages [13]. These results were confirmed by an Italian study which analysed retrospectively the detection rate of abdominal lymph nodes in various chronic liver diseases. Over 1000 patients were included in the study. Lymphadenopathy was detectable more frequently (87.5 %) in patients with PBC " Fig. 1). [27] (●

Note 2: Sonographic signs in PBC:

▶ Initial stage: no pathological alterations of the liver parenchyma

▶ Stage III: unspecific signs: ▶ Irregular liver surface ▶ Inhomogeneity of the parenchyma ▶ Stage IV: lobular-nodular liver cirrhosis ▶ Stage dependent, progressively larger lymphadenopathy Primary sclerosing cholangitis (PSC): Primary sclerosing cholangitis (PSC) is an autoimmune liver disease that leads to a diffuse alteration of the liver texture but predominantly to an alteration of the bile ducts. It can also be found as an overlap-syndrome with AIH or in rare cases as an overlap-syndrome with PBC. It is strongly associated with inflammatory bowel disease (in 70 % of the cases), especially ulcerative colitis [28, 29]. PSC shares also similar demographics with ulcerative colitis as 4th decade males

Fig. 1 Enlarged perihepatic lymph node dorsal in the hepatoduodenal ligament (in between markers).

are most frequently affected. In contrast to other autoimmune liver diseases, PSC patients are at high risk of developing cholangiocellular carcinoma (CCC) (15 % of the cases). Neither clinical symptoms nor the biochemical evidence of cholestasis are specific to PSC and lack sensitivity, particularly in the early course of the disease. Ultrasound is useful in the detection and follow-up of intra- and extrahepatic bile duct lesions, but it should be noted that alterations of the intrahepatic duct system are not displayed under all circumstances. Asymmetric mural thickening is a typical ultrasound finding in advanced PSC but unspecific symmetrical mural thickening as an unspecific sign of cholangitis may oc" Fig. 2). Finally, enlarged hilum lymph nodes are detectable cur (● in almost all patients with PSC [28].

Note 3: Sonographic signs of PSC:

▶ No typical alterations of liver texture ▶ Bile duct alterations are well detectable: thickening of the bile duct walls, strictures

▶ Enlarged hilar lymphadenopathy (lymph nodes > 19 mm) Autoimmune hepatitis (AIH): Autoimmune hepatitis is the most common autoimmune liver disease worldwide. The mean incidence in North Europe and North America is 1 – 2 per 100 000 persons per year [30, 31]. In general, a diffuse, chronic damage of the liver parenchyma can be found but acute hepatitis is also possible. Autoimmune hepatitis might present as sole entity but also as overlap-syndrome with PSC or PBC. AIH develops predominantly in women. On-going disease leads to liver cirrhosis. According to AASLD guidelines, patients with AIH cirrhosis should undergo hepatic ultrasound at 6-month intervals in order to detect HCC (Class IIa, Level C) [31]. Patients with autoimmune hepatitis (AIH) generally show perihepatic lymphadenopathy with lymph nodes over 19 mm in size [18]. Data of our own group underline these findings. Ultrasound findings (grey scale ultrasound, Doppler ultrasound of the hepatic vessels, perihepatic lymph nodes) were investigated in 30 patients with AIH and compared to age-matched healthy controls. The results were correlated with further non-sonographic findings like AIH score, clinical history and blood test results (including autoimmune an-

Fig. 2 Primary sclerosing cholangitis. Asymmetric and irregular thickening of the extrahepatic and sometimes also of the intrahepatic bile duct (GG) wall are typical sonographic signs of PSC. In addition enlarged perihepatic lymph nodes are a highly sensitive but not specific sign [28].

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The largest lymph nodes can be found in PBC, sarcoidosis and tuberculosis [26].

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tibodies). In this analysis no differences were detectable between the two groups despite the significant enlarged size of perihepatic lymph nodes (> 19 mm) in patients with AIH (data not published).

Guideline has been published on diagnosis and treatment of schistosomiasis [36]. Enlarged periportal lymph nodes with increased echogenic hilum and a thin symmetric hypoechoic cortex have been reported in the acute form of the disease [37].

Note 4: Sonographic signs of AIH:

▶ No characteristic liver parenchyma alterations ▶ Only unspecific signs like: ▶ Irregular liver surface ▶ Inhomogeneity of liver parenchyma ▶ But: lymphadenopathy in the hilum region (lymph node size > 19 mm)

Overlap syndromes: All three autoimmune liver diseases may display as overlap syndromes. There are no published data dealing with this topic. The sonographic findings may be the same, respectively a “mixed picture” of the single diseases.

Note 5: Sonographic signs of schistosomiasis:

▶ Early phase: unspecific alterations (enlarged perihilar lymph nodes, hepatosplenomegaly).

▶ Late phase: echorich thickening of the portal vein walls that ▶ ▶ ▶

can reach the liver capsule. Splenomegaly due to portal hypertension originating from fibrosis. Thickening of the gallbladder wall without typical signs of cholecystitis. Lymphadenopathy in the hilum in acute disease.

Infectious diseases with diffuse hepatic alterations in ultrasound

Hemachromatosis and Wilson’s disease

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Hemochromatosis: Hemochromatosis is an iron overload disorder which can be primary or secondary to different diseases. The primary hemochromatosis is an inherited iron storage disease. Clinical symptoms may occur in newborns, children or adults. The underlying mutation is located on the HFE gene. The defect regulation of iron absorption leads to an iron overload in different organs like heart, liver, skin or joints. Patients with hemochromatosis are at a high risk of developing hepatocellular carcinoma (HCC). The chance is about 400-fold higher than in other patients with liver cirrhosis. There are no relevant published papers on sonographic signs in hemochromatosis. Hepatomegaly can be observed in up to 90 % of the cases. A study that investigated 104 patients with HFE mutation analysed the ultrasound findings in these patients at diagnosis and four years after regular venesection [38]. The group described diffuse sonographic alterations in 61 % without characterising these alterations in more detail. The detected pathologies were reversible after therapy in 80 %. In our clinical experience, the liver parenchyma shows a similar echo texture and echo pattern as in steatohepatitis with echo-rich tissue texture and inhomogenous liver parenchyma [39].

Schistosomiasis: Schistosomiasis is worldwide the most common parasitic disease but in Western countries quite rare. The underlying pathology is an infection with Schistosoma mansonii that can be found in more than 200 million people worldwide. There are many publications focussing on this topic, predominantly coming from Africa or Asia; some are highly ranked [32, 33]. A recently published study investigated more than 900 school children in rural Zambia [34]. More than 700 children received an ultrasound scan. 274 school children showed typical sonographic findings for schistosomiasis, namely the presence of periportal, echo-rich, pronounced connective tissue. In another study, ultrasound was compared with magnetic resonance imaging in schistosomiasis [35]. Ultrasound detected periportal fibrosis, visualised as intrahepatic echo-rich patterns and a thickening of the gallbladder " Fig. 3) wall in 54 patients with schistosomiasis (● These findings were compared with MRI results of these patients. The second imaging technique did not add any further significant information. Reviewing all the published data, an AWMF S1-

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Note 6: Sonographic signs of hemochromatosis:

▶ No relevant publications available. ▶ Echorich texture and inhomogenous parenchyma, similar to steatosis hepatis.

Fig. 3 Schistosomiasis. Typically echorich (peri-)portal fibrosis can be visualised without any flow.

Barreiros AP et al. Ultrasound in Rare … Z Gastroenterol 2014; 52: 1247–1256

Wilson’s disease: Wilson’s disease is a rare autosomal-recessive, inherited disorder of copper metabolism, which results in the accumulation of copper in the liver and many other organs. The incidence of the disease is between 1:30 000 and 1:300 000 inhabitants. Typically, the onset of the disease occurs < 40 years. Hepatic dysfunction is the most common manifestation of Wilson’s disease in childhood [40]. The form of liver disease varies from fatty changes to cirrhosis, depending on the severity of the disease at the time of diagnosis. Cirrhotic liver in Wilson’s disease presents with some particular features: a normal caudate lobe and presence of a peri-hepatic fat layer [41, 42]. In 1988 Vogel et al. published the first case series of sonographic findings in patients

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with Wilson’s disease. The authors described the sonographic appearance of an echo-rich liver parenchyma with additional multiple, echo-poor, round lesions [43 – 45]. In the experience of the authors, these detectable echo-poor round lesions may lead to misdiagnosis as hepatocellular carcinoma [www.efsumb.org] [46]. In 8 of 10 consecutive patients these lesions underwent biopsy and the histological examination revealed prominent copper accumulation in comparison with the surrounding liver parenchyma. In two patients additional dysplastic nodules were ob" Fig. 4). served (●

Note 7: Sonographic signs of Wilson’s disease:

▶ Variable hyperechoic liver parenchyma. ▶ Multiple hypoechoic, round lesions of variable size (most < 20 mm).

Storage diseases

Fig. 5 Typical porphyria cutanea tarda lesions which may be mistaken for metastases or focal fatty sparing (focal fatty infiltration).

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Glycogen Storage Disease: Glycogen storage disease refers to a number of syndromes which are characterised by a defect in synthesis, metabolism or storage of glycogen, which can be broadly grouped into myopathic, hepatic and miscellaneous forms depending on the site of predominant organ involvement. The incidence is supposed to be 1:20 000 − 1: 25 000. Regarding the sonographic findings in glycogen storage disease there are few studies and case reports available. In a British study 70 patients were investigated as to whether sonographic alterations of the liver tissue were detectable [47]. 44 % of the patients showed none or mild alterations, (18/70) 26 % had significant changes with inhomogeneity and irregular liver surface, (7/70) 10 % showed hepatic, echo-poor tumours, which could be diagnosed as adenomas. In the published guidelines for management of glycogen storage disease type 1 it is described that unspecific alterations are often detectable like hepatomegaly or alterations of the hepatic tissue [48]. They described also that adenomas are often detectable (single or multiple), especially in the 2nd or 3 rd decade of life. Therefore ultrasound controls should be performed regularly due to the fact of malignant transformation, bleeding complications and mechanical problems [49].

Note 8: Sonographic signs in glycogen storage disease:

▶ Unspecific sonographic findings. ▶ Hepatomegaly. ▶ Diffuse alterations of liver parenchyma. ▶ Additionally: Detection of adenomas.

Recommendation of guidelines [48, 50, 51]:

▶ 0 − 10 years: yearly ultrasound; > 10 years every 6 months ▶ Evaluation: liver size, parenchyma, adenomas, other focal anomalies

Porphyria cutanea tarda (PCT): Porphyria cutanea tarda (PCT) is the most common form of porphyria across the world. It is hereditary or acquired due to exogenous factors such as alcohol intake, iron overload, chronic hepatitis C, estrogen therapy, and cigarette smoking [52]. The prevalence is 1:5000 to 1:70 000. The causes are familiar, sporadic or toxic. The underlying defect is a deficiency of an enzyme involved in the hemsynthesis. Interestingly, there are many publications regarding ultrasound findings in PCT. All of them describe multiple intrahepatic lesions that may be mistaken for metastasis or areas of focal fatty infil" Fig. 5). The lesions are reversible under thertrations [52 – 56] (● apy. Therefore ultrasound is a helpful technique for therapy surveillance in patients with PCT.

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Fig. 4 Wilson’s disease. Hypoechoic round lesions < 10 mm within the liver parenchyma a. Contrast enhanced ultrasound reveals homogenous contrast enhancement b. Shear wave elastography shows no differences compared to the surrounding liver parenchyma c.

Originalarbeit Note 9: Sonographic signs in porphyria cutanea tarda:

▶ Multiple focal intrahepatic lesions, partially with bizarre forms

▶ Well definable echopoor and echorich areas ▶ On the first sight: ▶ Metastasis ▶ Areas of focal fatty infiltrations ▶ Reversible under treatment ▶ Ultrasound suitable for surveillance Gaucher’s disease: Gaucher’s disease is the most common lysosomal storage disease world-wide. A mutation of the β-glucocerebrosidasis gene results in accumulation of glucocerebroside in macrophages of the reticuloendothelial system. The consequences are spleno- and hepatomegaly with secondary hypersplenism. The prevalence is highly variable depending on the geographic region: it ranges from 1: 160 000 in Europe to 1:1000 in Ashkenazi Jews. In a large study from Israel, ultrasound examinations from 500 patients with Gaucher’s disease were analysed and evaluated [57]. In 39/500 patients with Gaucher’s disease, sonographic detectable alterations were revealed. About 8 % of them had hepatosplenomegaly and liver parenchyma changes. 67 % received an enzymatic therapy and 26 % of the patients underwent splenectomy. Out of the 39 patients with sonographic changes 20 patients showed echo-rich hepatic lesions of variable sizes, one patient presented with “target-like” lesions, two patients had echo-poor lesions, 8 patients steatosis hepatitis and two patients liver cysts. No adenomas were detected in this study. All the detectable hepatic lesions were interpreted as accumulation of Gaucher’s cells. The authors summarise that ultrasound is a good tool for therapy control and follow-up.

Note 10: Sonographic signs in Gaucher’s disease.

▶ Splenomegaly ▶ Hepatomegaly ▶ In rare cases further signs like: Mostly echorich hepatic lesions of variable size

Other non-classified rare diffuse liver diseases !

Amyloidosis: Amyloidosis comprises a group of different rare diseases, predominant systemic forms, all leading to a deposition of amyloid fibrils in various tissues and presenting with a variety of symptoms that can occur in patients of all ages. In most countries, AL-amyloidosis is the most common form. In general, every organ can be affected. Hepatic amyloidosis can be primary or secondary and it typically occurs as diffuse infiltration of the liver. The only study on sonographic signs in amyloidosis investigated a group of 30 patients with different forms of amyloidosis [58]. Typical sonographic signs in the liver were spontaneous, initially " Fig. 6) and later in the course of the hemorrhage echo-poor (● echo-rich subcapsular haemorrhage. Correspondingly, the patients suffered severe recurrent pain over weeks before diagnosis. Apart from these hepatic findings, sonographic alterations could also be found concomitantly in other organs, e. g., signs of a cardiac involvement with thickened myocardium, pleural and/or pericardial effusion, echo-rich subendocardial depositions [EFSUMB case of the

Barreiros AP et al. Ultrasound in Rare … Z Gastroenterol 2014; 52: 1247–1256

Fig. 6 Hepatic amyloidosis imaged by panoramic imaging [59]. Subcapsular haemorrhages and unspecific echo-rich spots in the liver [58].

month, www.efusmb.org]. Intestinal involvement was characterized by patchy inhomogeneous deposits.

Note 11: Sonographic signs of amyloidosis

▶ Mostly homogenous parenchyma ▶ Cloddy liver margin ▶ spontaneous subcapsular haemorrhages and unspecific echo-rich spots inthe liver

▶ no detection of enlarged hilar lymph nodes α1-Antitrypsine deficiency: Alpha1-antitrypsine is one of the most important protein inhibitors in serum. Its deficiency is caused by a mutation in the SERPINA1 gene, previously known as Pi gene; the alpha1-antitrypsine deficiency results in an unhindered proteolysis of tissue by proteases. Typically, the lungs are most commonly affected but the liver is also often involved. The incidence is 1:2000 to 1:5000. There is one recently published study that used ultrasound to determine the prevalence and risk factors for liver involvement in alpha1-antitrypsine lung disease [60]. 57 patients with piZZrelated lung disease were sonographically and histologically assessed for the presence of liver involvement. 63 % of the patients had a history or clinical findings suggestive of liver disease. The majority of patients included showed a normal ultrasound finding of the liver (44 %), a hyperechogenic echopattern could be detected in 25 %. Interestingly, concomitant significant chronic liver disease was a common finding in piZZ-related lung disease as in 16 % of the patients liver cirrhosis was sonographically detectable. Compared to liver histology, screening with liver ultrasound provided a sensitivity and negative predictive value for severe fibrosis or cirrhosis of 100 % in this study.

Note 12: Sonographic signs of alpha1-antitrypsine deficiency

▶ in the majority no detectable alterations of liver parenchyma ▶ if alterations are found, they are displayed as hyperechogeneity

▶ ultrasound is an effective screening tool for advanced fibrosis and cirrhosis

Cystic fibrosis: Cystic fibrosis is an inherited, autosomal-recessive genetic disorder, caused by a mutation in the so-called CFTR gene

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Fig. 7 Focal biliary cirrhosis, stage in a child. Nodular texture, irregular liver surface and inhomogenous liver parenchyma are the typical features.

that leads to an abnormal transport of chloride and sodium across epithelial membranes. Subsequently, the disturbed chloride transport results in dehydration of mucus, pancreatic and biliary secretions. Most patients are diagnosed in childhood and the incidence is approximately 1:2000 − 3500 live births. Most patients present with pulmonary symptoms [61], but many have also hepatic, pancreatic or gastrointestinal manifestations [62]. Focal biliary cirrhosis is a typical finding in patients with cystic fibrosis [63], probably due to recurrent blockage of bile ducts by thickened bile. In these patients portal hypertension occurs typi" Fig. 7). cally very soon in the clinical course of the disease (● In the recently published literature none of the cystic fibrosis patients showed enlarged perihepatic lymph nodes (with the exception of patients with CBD stones and cholangitis). The authors found a microgallbladder in 18/72 (25 %) of patients with cystic fibrosis compared to none in the control group [63]. Another study investigated their cohort of 62 paediatric cystic fibrosis patients for the presence of hepatic involvement [64]. The authors found liver disease in 11 %, all with pathological findings in ultrasound. The most common finding was a heterogenous echogenicity followed by hepatomegaly, nodular texture, signs of portal hypertension and an irregular liver surface. The authors highlighted that in a relevant number of patients pathological sonographic findings were detectable when blood tests were still normal and no clinical symptoms detectable [65]. Wiliams et al. evaluated the role of ultrasound in liver disease in cystic fibroses in a study with follow-up over 9-years [66]. 168 patients were analysed in this study via annual ultrasound scans. In this retrospective study, 60 patients could be found with at least one pathological finding in ultrasound. In 39 patients this alterations was persistently detectable, 9 % had splenomegaly and 4 % developed liver cirrhosis. Transient elastography and acoustic radiation force impulse imaging seem to be promising new sonographic tools to detect fibrosis and cirrhosis in patients with cystic fibrosis [8, 9, 65].

Note 13: Sonographic signs of cystic fibrosis

▶ Microgallbladder ▶ Early sonographic alteration: Inhomogenous liver parenchyma

▶ Early detectable nodular tissue pattern ▶ Early signs of portal hypertension

Acute liver failure (ALF): Acute liver failure is a rare disease that is characterised by a sudden liver injury without known underlying liver disease. M. Wilson, acute hepatitis A/B/E, autoimmune hepatitis, vascular disorders like Budd-Chiari syndrome, acute fatty liver of pregnancy/HELLP syndrome or toxic hepatitis (acetaminophen- and non-acetaminophen-related, mushroom poisoning) are only some situations that might lead to ALF [67 – 69]. Also acute severe hepatic infiltration in cases of breast cancer [70, 71], small cell lung cancers [72], lymphoma [73] and melanoma [74] may cause ALF. Mortality of ALF is high and sometimes the pathophysiology of ALF remains unclear. In most cases histology is not useful due to the fact that liver parenchyma is characterised by unspecific necrosis in ALF. Therefore imaging techniques do have an impact in these patients. Romero et al investigated in his retrospective study imaging appearance in 47 patients with ALF [75]. They found that the majority of patients had pathological (but no pathognomonic) imaging findings. Therefore the underlying disease leading to ALF cannot be diagnosed by ultrasound. Ascites was most commonly encountered (65 %), but splenomegaly, collateral vessel formation and hepatofugal flow in the portal vein were also present. Interestingly a nodular liver surface could be detected in 23 % of the patients, especially with duration of the disease of > 7 days. Histologically this finding correlated with massive hepatic necrosis. In patients with acute virus hepatitis A, B, C, and E and ALF perihepatic lymphadenopathy is the predominate feature [18]. In conclusion the diagnosis of an ALF is a combination of analysing clinical features, patient’s history, blood test results and imaging results.

Note 14: Sonographic signs of acute liver failure (ALF)

▶ Ascites ▶ Splenomegaly ▶ Hepatofugal flow in the portal vein ▶ Patients with ALF > 7 days: nodular liver surface

Contrast-enhanced ultrasound (CEUS) in diffuse liver disease !

The described diseases do not have a typical vascularisation pattern on CEUS. They all show a typical homogenous enhancement. On the other hand side typical simultaneous findings like hepatocellular adenoma in patients with Glycogen storage disease can be identified and diagnosed by CEUS [49, 76]. Diffuse growing tumours: Some neoplasia may look like diffuse liver disease at first glance, e. g., hemangioendothelioma [77] or diffuse growing cholangiocellular carcinoma [78]. Contrast-enhanced ultrasound [1, 2, 79] and elastography [7, 8] may be helpful for improved diagnosis Phenomena, prolonged heterogeneous liver enhancement (PHLE): PHLE or long liver enhancement is a rare phenomenon that is similar to the US findings of portal venous gas with “cloudy” or “woollike” appearance of the liver parenchyma using B-mode. It is still not clear why this phenomenon is not reproducible, but it is more likely to occur in patients with high dose (or multiple) injections of UCA. Nevertheless the understanding of its mechanism requires further study. This phenomenon itself should not be misdiagnosed as a pathological finding of the liver during the CEUS examination

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Table 1

Sonographic features of diffuse liver disease.

diffuse liver disease

perihepatic

sonographic characteristics

lymphadenopathy infectious diseases

+

HCV/HBV/HIV

++

acute: hepatomegaly, inhomogenecity of liver parenchyma, small amount of perihepatic ascites, gallbladder wall thickening

schistosomiasis

+

early phase: unspecific, perihilar lymph nodes, hepatosplenomegaly, late phase: echorich thickened portal vein wall, thickened gallbladder wall, splenomegaly, lymphadenopathy

autoimmune diseases AIH

+

unspecific: irregular liver surface, inhomogeneity of liver parenchyma

PBC

++

initial stage: no pathological alterations of the liver parenchyma stage III: unspecific signs: – Irregular liver surface – Inhomogenecity of the parenchyma stage IV: lobular-nodular liver cirrhosis

PSC

+(+)

bile duct alterations, thickening of the bile duct walls, strictures, no alterations of liver texture

metabolic disorders

–

haemochromatosis

–

echo–rich, inhomogenous parenchyma, similar to steatosis

Wilson’s disease

–

hyperechoic liver parenchyma, multiple hypoechoic, round lesions of < 20 mm

porphyria cutanea tarda

–

multiple focal bizarrely shaped intrahepatic lesions, well defined echopoor and echo-rich areas

glycogen storage diseases

–

hepatomegaly, increased adenoma rate

Gaucher’s disease

–

hepatosplenomegaly, echo-rich hepatic lesions of variable size

amyloidosis

–

subcapsular haemorrhage, unspecific echo-rich spots

cystic fibrosis

–

microgallbladder, gall stones, early nodular parenchyma, early signs of cirrhosis and portal hypertension

Α1-antitrypsine deficiency

–

rare sonomorphological alterations, hyperechogenic parenchyma

acute liver failure (ALF)

+

ascites, splenomegaly, hepatofugal flow in the portal vein, eventually nodular liver surface

not helpful for the diagnosis of the majority of diffuse liver diseases. However, there are some rare diffuse liver diseases with typical sonomorphological signs that make it possible to support a suspected diagnosis. It has to be highlighted that not only the liver parenchyma should be assessed but the evaluation of perihepatic lymph nodes is also obligatory. The sonographic assessment of the biliary tract, spleen, hepatic and portal vein flow might add further information. In acute liver failure ultrasound is helpful to evaluate complications like ascites or alterations of portal vein flow. Taking all available data together, detectable enlarged hilar lymph nodes (> 19 mm) in patients with elevated liver enzymes and liver parenchyma alterations may be indicative for underlying infectious or autoimmune liver disease, while hilar lymphadenopathy " Table 1). is uncommon in metabolic or toxic liver disease (● Fig. 8 Prolonged heterogeneous liver enhancement, displayed by B-mode (upper part) and colour Doppler imaging (lower part).

or thereafter. Gastrointestinal diseases with changes of permeability and parameters of gas pressure might be explanatory patho" Fig. 8). physiological features [80] (●

Summary and Conclusions !

There are many liver diseases with specific and unspecific ultrasound changes that are not described here. We have focused on rare, diffuse liver disease. Although certainly technical advances in ultrasound techniques have taken place it still remains difficult to make the diagnosis of a liver disease solely via ultrasound and all findings should be seen in the clinical context. Even CEUS is

Barreiros AP et al. Ultrasound in Rare … Z Gastroenterol 2014; 52: 1247–1256

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