Liver cirrhosis in ptients newly dignosed with neurologicl phenotype of Wilson s disese Adm Przybyłkowski, MD, PhD Grżyn Gromdzk MD, PhD,b Grzegorz Chbik, MD b Agt Wierzchowsk, MD b Tomsz Litwin, MD, PhD b Ann Członkowsk, MD, PhD,b Deprtment of Experimentl nd Clinicl Phrmcology, Medicl University of Wrsw, Wrsw, Polnd b Second Deprtment of Neurology, Institute of Psychitry nd Neurology, Wrsw, Polnd Correspondence to: Adm Przybyłkowski E-mil: przybylkowski@wum.edu.pl Summry Wilson's disese (WD) cn mnifest itself in different clinicl forms, the neurologicl nd heptic ones being the most common. It is suggested tht neurologicl signs nd psychitric symptoms develop secondry to liver involvement. The im of this study ws to chrcterize the liver disese in ptients newly dignosed with the neurologicl form of WD. Tretment-nive ptients dignosed with WD were clssified into three phenotypic groups: heptic, neurologicl nd pre-symptomtic. Liver involvement ws scertined through surrogte mrkers: bdominl ultrsound nd lbortory prmeters. In ddition, study prticipnts were screened for esophgel vrices. Of 53 consecutively dignosed WD ptients, 23 individuls (43.4%) hd predominntly neurologicl presenttion. In this group, cirrhosis ws dignosed in 11 (47.8%) subjects. Esophgel vrices were present in ll of them. In every ptient with neurologicl WD, there ws t lest one sign of heptic disese on ultrsound exmintion, indicting universl presence of liver involvement. The prevlence of surrogte signs of cirrhosis ws similr in ptients with the neurologicl nd in those with the heptic phenotype. KEY WORDS: esophgel vrices, liver cirrhosis, Wilson s disese Introduction Wilson s disese (WD) is n utosoml recessive inborn error of metbolism which results in defective copper homeostsis nd systemic copper toxicosis. The metbolic defect is due to impired copper trnsport resulting from muttions in the ATP7B gene encoding P-type denosine triphosphtse (Tnzi et l., 1993). ATP7B is involved in excretion of copper from heptocytes into the bile. The billelic ATP7B muttion in WD ptients is responsible for copper ccumultion within the liver nd other orgns. This copper overlod leds to orgn dmge nd the clinicl mnifesttions of WD (Al et l., 2007). Three brod ctegories re recognized on the bsis of the signs nd symptoms: heptic, neurologicl nd pre-symptomtic (symtopmtic). Furthermore, there is wide clinicl spectrum even within ech of these phenotypic ctegories. For exmple, liver disese in ptients clssified s heptic WD rnges from symptomtic elevtion of liver enzymes to cute heptitis, occult cirrhosis nd fulminnt heptic filure. Similrly, neurogicl WD ptients show wide clinicl spectrum of neurologicl mnifesttions, which rnge from behviorl symptoms to incpcitting movement disorder (Al et l., 2007). The nturl history of WD is still not fully understood. It is not cler whether neurologicl signs nd symptoms occur erly in the course of the disese when liver involvement is mild (i.e., pre-cirrhotic) or whether they pper fter the development of liver dmge nd cirrhosis. It hs been suggested tht neuropsychitric symptoms in WD develop secondry to liver involvement (Hrris et l., 2007). However, there is pucity of informtion on the true prevlence nd stging of liver disese mong ptients with neurologicl symptomtology. Correct stging of liver disese, especilly the detection of dvnced liver fibrosis or cirrhosis in ptients with WD, is of therpeutic nd prognostic importnce. For exmple, the presence of cirrhosis lters the mngement of ptients s regrds monitoring for esophgel nd gstric vrices nd heptocellulr crcinom (D'Amico nd Luc, 1997; Schuppn nd Afdhl, 2008; Wlshe et l., 2003). Histologicl exmintion of percutneous biopsy specimens is the gold stndrd for ssessment of fibrosis nd cirrhosis; however, liver biopsy is n invsive procedure. Serum mrkers nd ultrsonogrphic chrcteristics of liver prenchym my be used s surrogte mrkers of cirrhosis (Schuppn nd Afdhl, 2008). Ultrsonogrphy (USG) is non-invsive nd inexpensive procedure for the dignosis of prenchyml diseses of the liver. The sensitivity nd specificity of USG in the detection of cirrhosis vry between uthors, showing tht this method Functionl Neurology 2014; 29(1): 23-29 23
A. Przybylkowski et l. is highly dependent on the exminer s experience. Nevertheless it is believed tht USG cn show liver cirrhosis with cceptble dignostic ccurcy (Aube et l., 2004). In this prospective study, we imed to determine the extent of liver disese through surrogte lbortory mrkers nd bdominl ultrsound in consecutive series of newly dignosed WD ptients with the neurologicl phenotype, compring the findings with those recorded in ptients showing predominntly heptic presenttion. In ddition, we present the results of endoscopic screening for portl hypertension signs. Mterils nd methods Ptients A consecutive series of 53 dult ptients dignosed with WD t the Second Deprtment of Neurology, Institute of Psychitry nd Neurology, Wrsw, Polnd, nd t the Deprtment of Gstroenterology, Sint Ann s Hospitl, Wrsw, Polnd, were included in this study. Blood smples were obtined on dmission to hospitl. USG nd endoscopy were performed during initil evlution for WD. The study ws pproved by the locl ethics committee nd informed consent ws obtined from ll the ptients. The study protocol conforms to the ethicl guidelines of the 1975 Declrtion of Helsinki s reflected in priori pprovl by the institution's humn reserch committee. All ptients met the WD dignostic criteri of the 8 th Interntionl Meeting on Wilson disese nd Menkes disese (Ferenci et l., 2003). No ptient enrolled in the study hd received ny tretment for WD. The extent of the disese ws scertined on the bsis of the presence of heptic, neurologicl or psychitric signs nd symptoms. The comprehensive evlution llowed the ptients to be clssified into three phenotypic ctegories ccording to criteri proposed by Ferenci et l. (2003): - ptients with symptomtic liver disese without neurologicl nd psychitric symptoms were clssified s hving heptic presenttion; - ptients in whom neurologicl nd/or psychitric symptoms were present t dignosis were clssified s neurologicl WD; - ptients without heptic nd neuropsychitric symptoms (siblings of ffected WD ptients dignosed through fmily screening) were clssified s presymptomtic WD. Liver function tests nd non-invsive mrkers of liver fibrosis/cirrhosis For the ssessment of liver involvement, bttery of blood tests ws performed in ll the ptients. Detoxifiction nd excretory functions of the liver were ssessed determining the ctivity of: lnine minotrnsferse (ALT), sprgine minotrnsferse (AST) nd gmm-glutmyl trnspeptidse (GGTP). In ddition, bilirubin concentrtion ws mesured. Biosynthetic function of the liver ws scertined by mesuring serum lbumin concentrtion nd interntionl normlized rtio (INR). Thrombocytopeni resulting from sequestrtion of pltelets in congested spleen is frequently present in ptients with chronic liver disese; therefore, pltelet count ws mesured in ll the ptients. All tests were performed using stndrd lbortory methods. The following non-invsive mrkers of liver fibrosis were clculted: i) AST/ALT rtio (AAR); ii) AST to pltelet rtio index (APRI). The APRI is routine biochemicl nd hemtologicl test creted by Wi et l. (2003) to evlute the presence of liver cirrhosis. An AAR cutoff vlue of 1.0 ws set for predicting dvnced fibrosis (Mnning nd Afdhl, 2008), while the APRI threshold vlue for severe fibrosis ws set t 1.0. Abdominl ultrsound exmintion Ultrsound exmintion of the liver ws performed ccording to uniform protocol using Philips HD11XE (Philips Helthcre, Best, The Netherlnds), equipped with 2-5 MHz brodbnd curved rry trnsducer. The following seven vribles for dvnced liver fibrosis/cirrhosis were ssessed: nodulr liver surfce, inhomogeneity of liver prenchym, presence of collterl circultion, splenomegly, scites, portl vein dimeter nd men velocity of the flow in the portl vein (Aube et l., 1999). The surfce nodulrity vrible ws considered positive if, insted of stright nd regulr hyperechoic line, the liver surfce ppered s dotted or irregulr line. If the liver prenchym ws not homogeneous but showed res with different echogenicity, prenchyml inhomogeneity ws deemed to be present. Collterl circultion ws defined s umbilicl vein dimeter >3 mm or left gstric vein >5 mm or ny bnorml vein such s spleno-renl shunt. Spleen size ws ssessed by the longitudinl section nd the spleen ws considered enlrged when this ws >13 cm (Frnk et l., 1986). Ascites ws recorded when present. Portl vein dimeter ws considered bnorml when it ws >13 mm (Goyl et l., 2009). For portl vein ssessment, men flow velocity cut-off vlue of 15 cm/s ws used (Goyl et l., 2009). For the dignosis of cirrhosis, the following ultrsonogrphic criteri were rbitrrily estblished: presence of nodulr surfce ccompnied by t lest two other signs of liver fibrosis. Endoscopy Upper gstrointestinl trct endoscopy ws performed by two experienced endoscopists. The ptients were screened for the presence of esophgel vrices, portl-hypertensive gstropthy nd gstric vrices. Esophgel vrix stge ws defined ccording to the Itlin Liver Cirrhosis Project (ILCP) criteri (Merkel et l., 2000). ILCP group stging of vricel size is function of the percentge of the esophgel lumen occupied by the lrgest vrix: grde 1 vrix occupies <25% of the esophgel lumen, grde 2 vrix occupies 25-50% of the esophgel lumen, nd grde 3 vrix occupies > 50% of the esophgel lumen. 24 Functionl Neurology 2014; 29(1): 23-29
Liver involvement in neurologicl form of Wilson s disese Sttisticl nlysis The dt were nlyzed using STATISTICA 10.0 (SttSoft, Crcow, Polnd). The normlity of nlyzed vribles ws determined using the Kolmogorov- Smirnov nd Lilliefors tests. Normlly distributed vribles were presented s men nd stndrd devition. Vribles tht were not normlly distributed in the nlyzed popultion were presented s medin nd interqurtile rnge. Student s t-test nd the Mnn- Whitney U test were used for further nlysis of normlly/not-normlly distributed vribles, respectively. Ctegoricl vribles were compred between groups by Fisher s exct test. Reltionships between vribles were exmined using the Spermn rnk correltion coefficient. The significnce level ws set t 0.05. Results Ptient chrcteristics Fifty-three consecutively dignosed ptients were phenotyped s heptic or neurologicl WD. The bseline chrcteristics of the ptients re presented in tble I. The symptoms nd signs suggestive of WD were neuropsychitric in 23 cses (43.4%) nd heptic in 19 cses (35.8%); the other 11 individuls were evluted for WD fter dignosis of the disese in sibling (20.7%). The study group comprised 25 (47.2%) women nd 28 (52.8%) men (Tble I). The men ge t dignosis of WD ws significntly lter in the neurologicl phenotype group compred with the heptic group: 35.3 yers (rnge 18-50) vs 26.3 yers (rnge 18-57; p<0.02). The men ge t dignosis of symptomtic ptients dignosed through fmily screening ws 27.8 yers (rnge 20-44). The men symptom durtion before dignosis did not differ between the groups. On physicl exmintion, heptic signs were present in 43.5% of the neurologicl group ptients, with peripherl edem being the most common sign (Tble I). Jundice ws present in three neurologicl ptients, while one subject presented fulminnt liver filure (Tble I). Tremor ws the most frequent neurologicl bnormlity, while 11 ptients complined of psychitric symptoms. Kyser-Fleischer (KF) ring ws detected in ll 23 ptients in the neurologicl group compred with 11 ptients in the heptic phenotype group (57.9%; p<0.0003). Four pre-symptomtic indi- Tble I - Bseline nd clinicl chrcteristics of the Wilson s disese ptients prticipting in the study. (n = 23) (n = 19) (n = 11) Age t dignosis (yers), men ± SD 35.3 ± 11.2 26 ± 6.7 27.8±8.0 Sex, n (%) - femle 10 (43.5) 8 (42.1) 7 (63.6) - mle 13 (56.5) 11 (57.9) 4 (36.4) Durtion of symptoms in yers, 1.0 (2.0) 1.0 (1.0) 0 medin (IQR) Heptic signs, n (%): 10 (43.5) 19 (100.0) - - heptomegly, n (%) 6 (26.1) 8 (42.1) - - jundice, n (%) 3 (13.0) 4 (21.1) - - scites, n (%) 2 (8.7) 3 (15.8) - - peripherl edem, n (%) 9 (39.1) 10 (52.6) - Neurologicl signs: - tremor, n (%) 15 (65.2) - - - rigidity, n (%) 5 (21.7) - - - dystoni, n (%) 5 (21.7) - - - txi, n (%) 5 (21.7) - - Psychitric symptoms, n (%) 11 (47.8) - - Kyser-Fleischer ring; n (%) 23 (100.0) 11 (57.9) 4 (36.4) Serum ceruloplsmin in mg/dl 15.1 (28.5) 16.7 (37.5) 17.9 (24.4) (norml: 25-45); medin (IQR) Serum copper in µg/dl 42.7 (39.2) 46.0 (38.9) 63.9 (28.9) (norml: 70-140); medin (IQR) Copper excretion in urine within 24 h in 141.0 (297.0) 219.5 (141.0) 83.0 (306.0) µg/24 h (norml: 0-50); medin (IQR) Abbrevitions: SD=stndrd devition; IQR=interqurtile rnge. p<0.05 for the comprison with the heptic group. Student s t-test or Mnn-Whitney U test for normlly/not normlly distributed vribles, respectively. Ctegoricl vribles were compred between groups by Fisher s exct test. Functionl Neurology 2014; 29(1): 23-29 25
A. Przybylkowski et l. viduls (16.4%) dignosed through fmily screening lso hd KF rings, finding tht underscores the insidiously progressive nture of WD. Tble II shows the results of muttion nlysis of the ATP7B gene. The H1069Q muttion ws the most common. Non-invsive mrkers of liver fibrosis/cirrhosis A significntly lower prevlence of bnorml liver function tests ws found mong the ptients exhibiting the neurologicl phenotype compred with the heptic phenotype; ALT nd AST were elevted in 30.4% of the neurologicl WD ptients compred with 63.2% of the heptic ptients (p<0.03); GGTP ws elevted in 17.4% vs 73.7%, respectively (p<0.0003). Moreover, the groups differed in bsolute vlues of lbortory tests (Tble III). Serum bilirubin, lbumin, INR nd pltelet count vlues did not differ significntly between the heptic phenotype group nd the neurologicl group. An AAR>1, positive for fibrosis, ws found in 16 (69.6%) neurologicl WD ptients nd in 10 (52.6%) ptients with the heptic phenotype. Six symptomtic subjects were lso positive for AAR. APRI>1 ws present in eight (34.8%) neurologicl ptients nd nine (47.4%) heptic ptients, but none from the fmily screening group. Abdominl ultrsound exmintion Irregulr liver surfce nd prenchyml inhomogeneity were present more frequently in the neurologicl WD ptients thn in the heptic WD ptients (Tble IV). Irregulr surfce ws not observed in ny ptient from the fmily screening group, but prenchyml inhomogeneity ws observed in three (27.3%) of them. Collterl circultion indicting underlying portl hypertension ws present in minority of WD ptients Tble II - Distribution of muttions of the ATP7B gene. (two ptients with the neurologicl nd two with the heptic phenotype). Splenomegly ws detected in seven (30.4%) neurologicl WD ptients nd in seven (36.8%) heptic WD ptients. Interestingly, sple - nomegly ws present in one symptomtic ptient dignosed through fmily screening. Free fluid in the peritonel cvity ws present in three (13.0%) neurologicl WD ptients compred with five (26.3%) ptients exhibiting the heptic phenotype. The frequency of portl vein dilttion nd the prevlence of decresed portl flow were similr in ptients with neurologicl nd heptic presenttion, but these signs were rre in siblings nd reltives of index cses. Ultrsonogrphic criteri for liver cirrhosis were fulfilled by 11 (47.8%) neurologicl ptients nd by seven (36.8%) heptic ptients. One ptient dignosed symptomticlly through fmily screening lso exhibited ultrsonogrphic signs of dvnced liver disese. In every ptient with neurologicl WD, there ws t lest one ultrsonogrphic sign, indicting universl presence of liver involvement. The number of ultrsonogrphic signs correlted significntly with APRI (ρ=0.5; p<0.05) nd with presence of esophgel vrices (ρ=0.3; p<0.05). No significnt correltion ws found between the AAR nd the number of ultrsonogrphic signs. Endoscopy None of the studied WD ptients suffered from vricel bleeding. However, grde 1-2 esophgel vrices were present in 47.8% of ptients with the neurologicl phenotype (Tble V). In heptic WD, grde 1-3 esophgel vrices were detected in 36.9% of ptients. Esophgel vrices were present in one symptomtic ptient dignosed through fmily screening (Tble V). Neither portlhypertensive gstropthy nor gstric vrices were detect- Muttion Exon Nucleotide chnge n of llelles Frequency (%) p.h1069q 14 c.3207c>a 69 65.1 p.q1351x 20 c.4051c>t 5 4.7 p.a1135fs 15 c.3402delc 3 2.8 p.g1341d 20 c.4022g>a 2 1.9 p.p1273l 18 c.3818c>t 2 1.9 p.v1217_l1218del 17 c.3649_3654del6 2 1.9 p.ivs16-2a>g 17 c.3557-2a>g 2 1.9 p.g1186c 16 c.3556g>t 2 1.9 p.g1158fs 16 c.3472_3482del 2 1.9 p.w1353s 20 c.4058g>c 1 0.9 p.i1148t 16 c.3443t>c 1 0.9 p.r969fs 13 c.2905delc 1 0.9 p.q544x 4 c.1630c>t 1 0.9 p.a1135t 15 c.3403g>a 1 0.9 The dt do not totl 100% s pthogenic muttions were not lwys identified in both lleles in ll 53 ptients. 26 Functionl Neurology 2014; 29(1): 23-29
Liver involvement in neurologicl form of Wilson s disese Tble III - Liver function tests nd indirect mrkers of liver fibrosis in ptients with Wilson s disese. (n = 23) (n = 19) (n = 11) ALT, IU/L (norml: 0-38), medin (IQR) 23.0 (19.0) 53.0 (51.0) 29.4 (29.0) Ptients with elevted ALT, n (%) 7 (30.4) 12 (63.2) 3 (27.3) AST, IU/L (norml: 0-40), medin (IQR) 27.0 (23.4) 46.0 (24.0) 30.0 (15.0) Ptients with elevted AST, n (%) 7 (30.4) 12 (63.2) 1 (9.1) GGTP (norml: 8.0-54.0), medin (IQR) 35.9 (22.2) 106.0 (86.4) 42.0 (48.2) Ptients with elevted GGTP, n (%) 4 (17.4) 14 (73.7) 3 (27.3) Bilirubin in mg/dl (norml: 0.2-1.2), medin (IQR) 1.1 (0.3) 1.3 (1.0) 1.1 (0.2) Ptients with elevted bilirubin, n (%) 8 (34.8) 10 (52.6) 0 Serum lbumin in g/dl (norml: 3.5-5.3), men ± SD 3.7 ± 1.0 3.8 ± 1.7 3.9 ± 0.8 Ptients with decresed serum lbumin, n (%) 9 (39.1) 8 (42.1) 1 (9.1) INR rtio (norml 0.8-1.2), men ± SD 1.2 ± 0.2 1.3 ± 0.6 1.3 ± 0.2 Ptients with elevted INR, n (%) 15 (65.2) 9 (47.4) 0 Pltelet count x10 9 /L (norml: 140-440), medin (IQR) 125.0 (97.0) 120.0 (128.0) 231.0 (84.0),b Ptients with decresed pltelet count, n (%) 12 (52.2) 12 (63.2) 0 AAR >1, n (%) 16 (69.6) 10 (52.6) 6 (54.5) APRI > 1, n (%) 8 (34.8) 9 (47.4) 0 Abbrevitions: SD=stndrd devition; IQR=interqurtile rnge; AST= sprgine minotrnsferse; ALT=lnine minotrnsferse; GGTP=gmmglutmyl trnspeptidse; INR=interntionl normlized rtio; AAR=sprgine minotrnsferse/lnine minotrnsferse rtio; APRI= AST to pltelet rtio index. p<0.05 for the comprison with the heptic group; b p<0.05 for the comprison with the neurologicl group. Student s t-test or Mnn-Whitney U test for normlly/not normlly distributed vribles, respectively. Ctegoricl vribles were compred between groups by Fisher s exct test. Tble IV - Prevlence of ultrsonogrphic signs of liver cirrhosis in ptients with Wilson s disese. (n=23) (n=19) (n=11) Irregulr surfce, n (%) 15 (65.2) 7 (36.8) 0 Prenchyml inhomogeneity, n (%) 21(91.3) 10 (52.6) 3 (27.3) Collterl circultion, n (%) 2 (8.7) 2 (10.5) 0 Free peritonel fluid, n (%) 3 (13.0) 5 (26.3) 1 (9.1) Enlrgement of the spleen, n (%) 7 (30.4) 7 (36.8) 1 (9.1) Dilted portl vein, n (%) 11 (47.8) 11 (57.9) 1 (9.1) Decresed portl vein flow, n (%) 8 (34.8) 9 (47.4) 2 (18.2) p<0.05 for the comprison with the heptic group; ctegoricl vribles were compred between the heptic nd the neurologicl group by Fisher s exct test. Tble V - Prevlence of esophgel vrices. (n=23) (n=19) (n=11) Vrices grde 1; n (%) 8 (34.8) 4 (21.1) 1 (9.1) Vrices grde 2; n (%) 3 (13.0) 2 (10.5) 0 Vrices grde 3; n (%) 0 1 (5.3) 0 Itlin Liver Cirrhosis Project (ILCP) criteri were pplied to stge esophgel vrices. Functionl Neurology 2014; 29(1): 23-29 27
A. Przybylkowski et l. ed in ny ptient. Presence of esophgel vrices correlted significntly with number of ultrsonogrphic signs (s bove). Correltions with single ultrsonogrphic signs were significnt for liver homogeneity: ρ=0.4, p<0.05, collterl circultion: ρ=0.4, p<0.05, nodulr surfce: ρ=0.3, p<0.05, nd dilted portl vein: ρ=0.3, p<0.05. A significnt correltion ws lso found between esophgel vrices nd APRI 1.0: ρ=0.4, p<0.05. Discussion Although WD is single gene disorder, it is highly heterogeneous in its mnifesttions. The bsis of this phenotypic vrition is uncler s of yet. Thus when ptient is clssified s hving neurologicl WD with no clinicl evidence of liver disese, it is not known whether the ptient hrbors miniml liver involvement or, t the other extreme, dvnced liver disese tht is not reveled by stndrd criteri (i.e., liver function tests, liver synthetic function or clinicl signs of portl hypertension). In this series of consecutively evluted WD ptients, high prevlence of surrogte signs of dvnced liver disese ws found mong ll the ptients with symptomtic disese. It is importnt to note tht ptients with neurologicl WD nd no overt clinicl signs of liver disese hd high prevlence of surrogte mrkers of cirrhosis. It is suggested tht neurologicl symptoms in Wilsonin ptients typiclly develop secondry to liver involvement (Hrris et l., 2007). However, the true prevlence nd stging of liver disese mong ptients with neurologicl symptomtology re not yet clerly defined. In one utopsy study, heptitis nd micro-/mcronodulr cirrhosis were observed in ll ptients with neurologicl presenttion of the disese (Meenkshi-Sundrm et l., 2008). In nother cohort of 30 ptients, cirrhosis ws lso dignosed in ll the ptients presenting neurologicl symptoms; however, this group comprised only three subjects (Gow et l., 2000). Detection of cirrhosis is crucil for tretment plnning (qulifiction for liver trnsplnttion) nd from the perspective of surveillnce for cirrhosis complictions such s portl hypertension. Anlysis of deths in WD reveled tht liver filure nd vricel bleeding re common cuses (Wlshe, 2007; Czlonkowsk et l., 2005). USG-bsed dignosis of liver cirrhosis cn be bsed on heptic nd extr-heptic signs, nd the ccurcy of USG vries cross different studies lso becuse of the different prmeters exmined (Aube et l., 1999). There is no pproved score for ultrsonogrphic dignosis of cirrhosis, thus in common prctice the dignosis is mde t the exmining physicin s discretion (Bonekmp et l., 2009). In the present study, it ws decided on the bsis of the uthors experience tht the presence of t lest three ultrsonogrphic signs (one of which must be nodulr surfce of the liver) is relible for liver cirrhosis dignosis. Applying this criterion, liver cirrhosis ws observed in 11 of the 23 (47.8%) neurologicl ptients. All of them hd bnorml liver function tests nd in ll of them esophgel vrices were detected. Interestingly, mong 11 reltives who hd never sought medicl dvice for heptic or neurologicl problems, subtle liver involvement signs (nd even esophgel vrices in one cse) were present. This observtion strongly supports the ide tht the fmily members of newly dignosed WD ptients should be screened s soon s possible nd immeditely strted on nticopper therpy if the dignosis of WD is confirmed in them. At present, liver biopsy is still the reference stndrd for the ssessment nd stging of liver disese. Therefore, n obvious limittion of the present study is the lck of verifiction of the exmined surrogte mrkers of liver cirrhosis with histologicl ssessment of the liver prenchym. In this study, liver biopsy ws not performed routinely in ll the WD ptients. However biopsy confirmtion of cirrhosis is not mndtory if cler signs of cirrhosis (scites, cogulopthy, shrunken nodulr-ppering liver on imging studies) re present (Schuppn nd Afdhl, 2008). Therefore, in some WD cses, conventionl ultrsound exmintion in combintion with endoscopy nd lbortory test results my be sufficient to dignose liver cirrhosis. In conclusion, using lbortory mrkers, ultrsonogrphic signs or endoscopy, cirrhosis ws dignosed in 47.8% of newly dignosed ptients with the neurologicl form of WD. Some of them hd liver dysfunction signs in their medicl history, but hd not been further evluted. In every ptient with neurologicl WD, there ws t lest one ultrsonogrphic sign of dvnced liver disese. These results indicte the need for detiled ssessment of the liver in ll newly dignosed ptients with neurologicl presenttion of WD even if they do not show obvious heptic signs nd symptoms. 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