Case Study Pitfalls of Diagnosis in the Early Stages of Wilson's Disease FR ANK E. CR UMLEY, M .D . Abstract. Diagnosis of Wilson' s Disease in the early stages may be elusive in patients presenting without neurological symptoms. A case history is presented which demonstra tes the pitfalls in makin g the diagnosis. Presenting psychia tric symptoms were nonspecific. Ceru loplasmin level was initially elevated to normal range . Liver biopsy showed early nonspecif ic cirrhosis; staining for copper did not show the dram atic effe cts expected with Wilson's Disease. Neurological examination , including NMR, was within normal limits . Kayser-Fleischer rings arc no longer considered pathognomi c. Urinary copper excretion helped to establish the diagnosis. J. Am. Acad. Child Adolesc. Psychiatry, 1990,29, 3:470-471. Key Words: Wilson's Disease, diagnosis , ceruloplasmin , psychiatri c symptoms, hepatic symptoms. " Wi lso n's Di sease is not suspected often enou gh by psychia trists," assert Scheinb erg and Sternlieb (1984) in the ir recent monograph on thi s rar e , ge netic , treatable disease of chro nic co pper to xicosis . Diagnosis in the early stages of the disease is extre me ly imp ort ant because the disease ha s a spec ific and effecti ve pharmacological treatment which can reli eve or pre vent the cl inical man ifestations of serious hepatic , neurological , and psychiatric symptoms before irreversible damage has been done. How ever, diagnosis is not alw ay s as easy as ha s been claimed by Laufer (19 79) . Dia gn ostic cri teria have cha nged over the ye ars . In the ea rly stages of the disease , it may be ext rem el y difficult to make the diagnosis , espec ially wi tho ut neurological signs. Fo r example , Kayser-Flei sch er rin gs are no lon ger co nsidered path ogn omic . Reli ance on ce ruloplasmin determination s ma y lead to a false nega tive diagnosi s . In a non symptom atic Wilson ' s Dise ase pati ent whose ceruloplasmin ha s actu all y been low for ye ars , ce rulop lasmin may be elevated to normal by copper-caused ac tive liver disease as the symptoms of the disease finally become man ife st (Sc heinberg and Sternlieb, 19 84) . Th e fo llow ing cas e illu strates some of the diagnostic pit fall s present in rea ch ing the conclusio n that a pati en t ha s earl y-stage Wilson' s Disease.
was deni ed by famil y and pati ent , thou gh she did admit to occasional alcohol usage , intoxication , and suicidal thoughts. On the WAIS-R she obtained a verba l IQ of 107 , performance IQ of 96 , and a resulting full-scale IQ of 102 . Initial diagnostic impression was (1) aty pical dep ression ; (2) person ality disord er with mix ed , borderline , and his trioni c features . Routi ne internal medicine con sultation rev ealed history of chro nic physical symptomato logy of the past years including vague arthralgia, fever, sor e throat , int er mittent diarrhea , cramping abdominal pain , and gastro ent eritis . Physical ex ami natio n revealed ex tre me obesity with abdominal tend ern ess in right and left upp er quadrant. Initial routine lab orator y stud ies showed abno rma l liver funct ion tests SOOT 131 , SOPT 324, CPK 78 7 , alkaline phosph atase 142 , and total bilirubin 1.8. Repeat liver function test co ntinued to be abnormal. T his prompted addi tiona l laboratory tests . Hepatit is B surface antigen and hep atiti s A 10M were negative . Rheumatoid factor titration (latex) wa s positive, 1:160, but more speci fic sheep cell agglutinin test wa s negative . Th yroid screen was within normal limits. Alkaline phosphatase elev ated at 142 : iso- enzymes heat sensitive , consistent with bone origin. Antinucl ear antibodies positive at a low titer of 1-40. Mono scree n negati ve . Initial ce ruloplas min was within normal ra nge at 28 rng/dl (no rmal 25-68 mg/dl). Repeat ceruloplasmin I week later was slightly abnormal at 24 mg/dl but still greater than 20 mg/dl . Rep eat SOPT and alkaline phosphatase co ntinued to be abnormal. Upper abdominal so nog ram was normal. Li ver biopsy sho we d fatty met am orphosis and non specific early cirrhosis, but no copper accumulations. Th e liver biopsy wa s restained spe ci fically for copper. Mild copper deposition was noted but was less than ex pec ted for Wil son's Disease . Corneal slit-lamp exami natio n rev ealed definit e Ka yser -Flei scher rin gs bilaterally , visible onl y with slit lamp exa mination. However , neurological examinat ion , including NMR examination and CAT- x-ray of head , was within normal limits . Tw ent y-four-hour urinary coppe r was 30 1 p .g/d (normal 1550 p.g/d ) . The pati ent was treated with peni cillamine for a total of 2 month s before developing thrombocytopenia (platelet count
Cas e History A 15-year-old bro wn- eyed fem ale was admitte d to the Bayl or U nive rs ity Me dical Cent er , Ad olescent Psych iatr y Unit wi th a history of impulsive, dram atic and viol ent behavior , ex treme con flict with her moth er, depression , de clining grades , and a recent suicide attempt. Drug abuse
Accepted Septe mber II . 1989. The author wishes to acknowledge Robert L. Fine, M .D . , whose consultation led to diag nosis , Burton Combes. M .D .. who aided in the diagnosis. and Dennis Kay . M.D ., who p erformed the ophthalmic examination. Request reprin ts fro m Dr . Crumley , 36 00 Gaston A ve .. Suite 808 . Dallas, TX 75246 . 0890-8567/90/2903-0470$02. 00/0 © 1990 by the America n Acade my of Child and Adolesce nt Psychiatry .
470
W ILSON' S DI SEASE-DIAGNOSTI C PITFALL S
79 ,000). T he parents requ ested treat ment with zinc as has been reported in the literature. The dia gnosis wa s co nfirmed at the Unive rsity of Michigan Hospital. Repea t ophthalmic exa mination revea led Kayser-Fleischer rings o .u . on slitlamp exami nation . Laboratory tests showed elev ated SOOT Ill , SGPT 207, and alka line phosphat ase 255 . Diagnosi s also based on low ser um ce rulop las min with elevat ed urinary copper. A liver biopsy revealed cirrhosis with staina ble copper con sistent with Wilson ' s Disease . Th e patie nt's 9-year-old brother tested nega tive for Wilson's Disease.
Discu ssion Appro ximatel y only 10- 25% of pati ents with Wilson' s Disease present with psychiatric disturbances as the first clinical manifestation , accord ing to Sch einberg and Sternlieb (1984). Though Wil son' s Dise ase generally first presents with either neur ological or psyc hiatric symptoms, hepatic presentation is common among those under 20 yea rs of age and is the most difficult to diagnose. Schei nberg and Sternlieb (198 4) emp hasized the importance of a thorough exami nation of psychiatric patient s (eve n neurologically asymptom atic patients ) with unexplained elevated live r enzymes. Routi ne cerulopl asmin screening of all psych iatric pa tient s who are admi tted and under age 30 has been reco mmended by Ca rtwright ( 1978). However, a more pract ica l sugges tion would be to screen psychia tric patien ts with signs of liver or neuro logical disea se , failure to respond to treatment, or family history of Wilson's Disease (Schei nberg and Stern lieb, 1984). Often, general rou tine screening results may pro vide thc clues that lead to diagnosis, as observed by Cr um ley ( 1986). In th is case , the initial clue was the rou tine screening examination , SMA 20 , whic h show ed elevated liver enzymes combined with pre senti ng psych iatric disorder. Cartwright ( 1978) described the pitfall of assum ing elev ated liver enzy mes as bein g the result of a medic ation and, thus , leadin g to the premature excl usion of a diag nosis of Wilson ' s Disease . Th e live r biopsy pointed to earl y cirrh osis but was nonspecific . Copper acc um ulation was obs erved but to a lesser degree than expected fo r Wi lso n' s Disease; however, this is typical of the liver in ea rly sta ges of Wi lson ' s Disea se (Scheinberg and Sternlieb, 1984) . In patients first presentin g with psychiatric symptoms, the clinica l picture is ex trem ely variable and nons pecific (Goldstein et al., 1968; Scheinberg and Sternlieb, 1984). Psychiatric symptoms are thought to occ ur eventually in almos t every pat ient with clini ca lly man ifest Wi lso n' s Disease . Her psych iatric symptoms alone would not have led to the diagnosis . It is questio nab le whet her her psyc hiatric symptom s were eve n related to Wilson ' s Disease at this early stage of the disease, especially in view of the norm al neurological examination (Medalia and Sch ienberg, 1989).
l .A m . Acad . Child Adolesc .Psv chiat ry, 29 :3 , May 1990
Neurological symptoms were not present and NMR showed no abnor malities in this ea rly stage of the disease . Thi s is co nsisten t with the findi ngs of S tarosta- Rube nstein ct al., ( 1987) , who found that asymp tomatic pa tien ts and patient s who presen ted wit h hepatic symptoms may not show NM R abnorm alities . However, patients presenting with neurological proble ms almost always show NM R abnormalities. NMR has been reported to be more sensitive than CAT -x-ray in the diagnosis of bra in abnormalities (Aisen ct al. , 1985). Physicians can not rely on a nor mal ce rulop lasmin level since 5% of pati en ts wit h Wi lso n's Disease may have the enz yme elevated to the normal range . Usuall y th is elevati on is temporary , but it may be susta ined through treatment. II' the ceruloplasmi n is greater than 20 mg/dl , hut less than 30 mg/d l, Sc hei nberg and Stcrnlieb ( 1984) e mp hasize that the diagnosis is not excluded. The determination of Wil son' s Disease could have been excluded in this case if dia gnosis had been based on the patie nt' s low nor ma l ce ru loplasmi n level. If Kay ser-Fleischer rings arc prese nt in the co rnea, physical exam ination may revea l thes e go lde n or greenishbrown rings in blue-eyed individua ls . Th e rings were not observed in this pat ien t o n rou tine ex aminatio n, partly because she was brow n-ey ed . The positive psychiatric symptoms, elev ated liver en zymes , liver biopsy in earl y stage or c irrhosis , and KayserFleischer rings were incon gruent wit h the low no rmal ce ruloplasmin levels. T his case illus trates the va lue of the recomm end ation of Scheinberg and Stern lieb ( 1984) that all psychiatric patients with unexplained and persistently e levated tra nsamin ase levels should have a ceruloplasmi n determi nation. If ceruloplasmi n level is greater than 20 mg/ dl but less than 30 mg/d l, then add itional ev aluation is still indicat ed with slit-lamp and meas urement of uri nary co pper (Scheinberg and Sternlieb, 1984).
References Aise n , A . E., Mart e l. W .. Gabri elson , T . O . cr al. ( !9H5), W ilson 's Disease of the brain. Radiology. 157 : 137- 14 1. Cart wright, G. E . (1978 ), Diagnosis of trea table Wil son's Disease. N . Engl. J, M cd .. 29H: 1347-1 350 . Crumley . F. E . ( 198 6) . A case for ro utine laborator y tests . .I . Alii . Acad. Child Psvchiatrv, 25:579 . Go ldste in N. P . . 'E wert j . c. , Ran dall R . V . & G ross J . B. ( I96 X), Psych iatric asp ects of Wil son' s Disea se (hcp atolcntic ular dcgcn cration ). Alii . .I . Psychiatry, 124 : 1555-1 56 1. Laufer M . W . , Shell y , T. ( 1979), Acu te and chro nic brain sy ndro mes . In: Basic Handb ook of Chil d Psych iatry, Vol. II. cd . .I. D . Ivospitz . New York: Ba sic Bo oks, pp . 395- 3 96 . Mcdalia , A . & Sc hienbcrg, I. H. (I9X9), Psychopatholo gy in patie nts with Wil son ' s Disea se . 1\111 . .I. Psy chiatry, 146:662- 664 . Sche inberg I. H. & Stern lieh I. ( 19H4) . Wilson 's Disease In: Major Problems in Int ern a l M edicine, Vo!. XX III. Philadelph ia: W . B. Saunders Co . . pp. 1-1 64. Starosta -Rubenstcin S. , Youn g A . B. , Kinin K. ct al . ( 1987) , Clinical assessm en t of 3 1 patients with W ilson' s Dicu sc . Arch , Neu ra l.. 44: 365- 370.
47 1
was deni ed by famil y and pati ent , thou gh she did admit to occasional alcohol usage , intoxication , and suicidal thoughts. On the WAIS-R she obtained a verba l IQ of 107 , performance IQ of 96 , and a resulting full-scale IQ of 102 . Initial diagnostic impression was (1) aty pical dep ression ; (2) person ality disord er with mix ed , borderline , and his trioni c features . Routi ne internal medicine con sultation rev ealed history of chro nic physical symptomato logy of the past years including vague arthralgia, fever, sor e throat , int er mittent diarrhea , cramping abdominal pain , and gastro ent eritis . Physical ex ami natio n revealed ex tre me obesity with abdominal tend ern ess in right and left upp er quadrant. Initial routine lab orator y stud ies showed abno rma l liver funct ion tests SOOT 131 , SOPT 324, CPK 78 7 , alkaline phosph atase 142 , and total bilirubin 1.8. Repeat liver function test co ntinued to be abnormal. T his prompted addi tiona l laboratory tests . Hepatit is B surface antigen and hep atiti s A 10M were negative . Rheumatoid factor titration (latex) wa s positive, 1:160, but more speci fic sheep cell agglutinin test wa s negative . Th yroid screen was within normal limits. Alkaline phosphatase elev ated at 142 : iso- enzymes heat sensitive , consistent with bone origin. Antinucl ear antibodies positive at a low titer of 1-40. Mono scree n negati ve . Initial ce ruloplas min was within normal ra nge at 28 rng/dl (no rmal 25-68 mg/dl). Repeat ceruloplasmin I week later was slightly abnormal at 24 mg/dl but still greater than 20 mg/dl . Rep eat SOPT and alkaline phosphatase co ntinued to be abnormal. Upper abdominal so nog ram was normal. Li ver biopsy sho we d fatty met am orphosis and non specific early cirrhosis, but no copper accumulations. Th e liver biopsy wa s restained spe ci fically for copper. Mild copper deposition was noted but was less than ex pec ted for Wil son's Disease . Corneal slit-lamp exami natio n rev ealed definit e Ka yser -Flei scher rin gs bilaterally , visible onl y with slit lamp exa mination. However , neurological examinat ion , including NMR examination and CAT- x-ray of head , was within normal limits . Tw ent y-four-hour urinary coppe r was 30 1 p .g/d (normal 1550 p.g/d ) . The pati ent was treated with peni cillamine for a total of 2 month s before developing thrombocytopenia (platelet count
Cas e History A 15-year-old bro wn- eyed fem ale was admitte d to the Bayl or U nive rs ity Me dical Cent er , Ad olescent Psych iatr y Unit wi th a history of impulsive, dram atic and viol ent behavior , ex treme con flict with her moth er, depression , de clining grades , and a recent suicide attempt. Drug abuse
Accepted Septe mber II . 1989. The author wishes to acknowledge Robert L. Fine, M .D . , whose consultation led to diag nosis , Burton Combes. M .D .. who aided in the diagnosis. and Dennis Kay . M.D ., who p erformed the ophthalmic examination. Request reprin ts fro m Dr . Crumley , 36 00 Gaston A ve .. Suite 808 . Dallas, TX 75246 . 0890-8567/90/2903-0470$02. 00/0 © 1990 by the America n Acade my of Child and Adolesce nt Psychiatry .
470
W ILSON' S DI SEASE-DIAGNOSTI C PITFALL S
79 ,000). T he parents requ ested treat ment with zinc as has been reported in the literature. The dia gnosis wa s co nfirmed at the Unive rsity of Michigan Hospital. Repea t ophthalmic exa mination revea led Kayser-Fleischer rings o .u . on slitlamp exami nation . Laboratory tests showed elev ated SOOT Ill , SGPT 207, and alka line phosphat ase 255 . Diagnosi s also based on low ser um ce rulop las min with elevat ed urinary copper. A liver biopsy revealed cirrhosis with staina ble copper con sistent with Wilson ' s Disease . Th e patie nt's 9-year-old brother tested nega tive for Wilson's Disease.
Discu ssion Appro ximatel y only 10- 25% of pati ents with Wilson' s Disease present with psychiatric disturbances as the first clinical manifestation , accord ing to Sch einberg and Sternlieb (1984). Though Wil son' s Dise ase generally first presents with either neur ological or psyc hiatric symptoms, hepatic presentation is common among those under 20 yea rs of age and is the most difficult to diagnose. Schei nberg and Sternlieb (198 4) emp hasized the importance of a thorough exami nation of psychiatric patient s (eve n neurologically asymptom atic patients ) with unexplained elevated live r enzymes. Routi ne cerulopl asmin screening of all psych iatric pa tient s who are admi tted and under age 30 has been reco mmended by Ca rtwright ( 1978). However, a more pract ica l sugges tion would be to screen psychia tric patien ts with signs of liver or neuro logical disea se , failure to respond to treatment, or family history of Wilson's Disease (Schei nberg and Stern lieb, 1984). Often, general rou tine screening results may pro vide thc clues that lead to diagnosis, as observed by Cr um ley ( 1986). In th is case , the initial clue was the rou tine screening examination , SMA 20 , whic h show ed elevated liver enzymes combined with pre senti ng psych iatric disorder. Cartwright ( 1978) described the pitfall of assum ing elev ated liver enzy mes as bein g the result of a medic ation and, thus , leadin g to the premature excl usion of a diag nosis of Wilson ' s Disease . Th e live r biopsy pointed to earl y cirrh osis but was nonspecific . Copper acc um ulation was obs erved but to a lesser degree than expected fo r Wi lso n' s Disease; however, this is typical of the liver in ea rly sta ges of Wi lson ' s Disea se (Scheinberg and Sternlieb, 1984) . In patients first presentin g with psychiatric symptoms, the clinica l picture is ex trem ely variable and nons pecific (Goldstein et al., 1968; Scheinberg and Sternlieb, 1984). Psychiatric symptoms are thought to occ ur eventually in almos t every pat ient with clini ca lly man ifest Wi lso n' s Disease . Her psych iatric symptoms alone would not have led to the diagnosis . It is questio nab le whet her her psyc hiatric symptom s were eve n related to Wilson ' s Disease at this early stage of the disease, especially in view of the norm al neurological examination (Medalia and Sch ienberg, 1989).
l .A m . Acad . Child Adolesc .Psv chiat ry, 29 :3 , May 1990
Neurological symptoms were not present and NMR showed no abnor malities in this ea rly stage of the disease . Thi s is co nsisten t with the findi ngs of S tarosta- Rube nstein ct al., ( 1987) , who found that asymp tomatic pa tien ts and patient s who presen ted wit h hepatic symptoms may not show NM R abnorm alities . However, patients presenting with neurological proble ms almost always show NM R abnormalities. NMR has been reported to be more sensitive than CAT -x-ray in the diagnosis of bra in abnormalities (Aisen ct al. , 1985). Physicians can not rely on a nor mal ce rulop lasmin level since 5% of pati en ts wit h Wi lso n's Disease may have the enz yme elevated to the normal range . Usuall y th is elevati on is temporary , but it may be susta ined through treatment. II' the ceruloplasmi n is greater than 20 mg/dl , hut less than 30 mg/d l, Sc hei nberg and Stcrnlieb ( 1984) e mp hasize that the diagnosis is not excluded. The determination of Wil son' s Disease could have been excluded in this case if dia gnosis had been based on the patie nt' s low nor ma l ce ru loplasmi n level. If Kay ser-Fleischer rings arc prese nt in the co rnea, physical exam ination may revea l thes e go lde n or greenishbrown rings in blue-eyed individua ls . Th e rings were not observed in this pat ien t o n rou tine ex aminatio n, partly because she was brow n-ey ed . The positive psychiatric symptoms, elev ated liver en zymes , liver biopsy in earl y stage or c irrhosis , and KayserFleischer rings were incon gruent wit h the low no rmal ce ruloplasmin levels. T his case illus trates the va lue of the recomm end ation of Scheinberg and Stern lieb ( 1984) that all psychiatric patients with unexplained and persistently e levated tra nsamin ase levels should have a ceruloplasmi n determi nation. If ceruloplasmi n level is greater than 20 mg/ dl but less than 30 mg/d l, then add itional ev aluation is still indicat ed with slit-lamp and meas urement of uri nary co pper (Scheinberg and Sternlieb, 1984).
References Aise n , A . E., Mart e l. W .. Gabri elson , T . O . cr al. ( !9H5), W ilson 's Disease of the brain. Radiology. 157 : 137- 14 1. Cart wright, G. E . (1978 ), Diagnosis of trea table Wil son's Disease. N . Engl. J, M cd .. 29H: 1347-1 350 . Crumley . F. E . ( 198 6) . A case for ro utine laborator y tests . .I . Alii . Acad. Child Psvchiatrv, 25:579 . Go ldste in N. P . . 'E wert j . c. , Ran dall R . V . & G ross J . B. ( I96 X), Psych iatric asp ects of Wil son' s Disea se (hcp atolcntic ular dcgcn cration ). Alii . .I . Psychiatry, 124 : 1555-1 56 1. Laufer M . W . , Shell y , T. ( 1979), Acu te and chro nic brain sy ndro mes . In: Basic Handb ook of Chil d Psych iatry, Vol. II. cd . .I. D . Ivospitz . New York: Ba sic Bo oks, pp . 395- 3 96 . Mcdalia , A . & Sc hienbcrg, I. H. (I9X9), Psychopatholo gy in patie nts with Wil son ' s Disea se . 1\111 . .I. Psy chiatry, 146:662- 664 . Sche inberg I. H. & Stern lieh I. ( 19H4) . Wilson 's Disease In: Major Problems in Int ern a l M edicine, Vo!. XX III. Philadelph ia: W . B. Saunders Co . . pp. 1-1 64. Starosta -Rubenstcin S. , Youn g A . B. , Kinin K. ct al . ( 1987) , Clinical assessm en t of 3 1 patients with W ilson' s Dicu sc . Arch , Neu ra l.. 44: 365- 370.
47 1
