Primary biliary cirrhosis (PBC) is a cholestatic liver disease, which is characterized by a chronic inflammatory destruction of intrahepatic bile ducts. It is a rare disorder whose precise etiology is still to be elucidated. Even though the liver is the principal target of PBC, other organ systems also might be affected. Muscular involvement has rarely been described in this disease, and in the majority of cases, muscular weakness has been interpreted as polymyositis. We report the case of a 48-year-old woman suffering from classic PBC, in association with a myopathy whose histological features are distinct from the cases reported before. We also performed a MEDLINE research for PBC and concomitant muscular diseases.A cirrose biliar primária (CBP) é uma doença hepática colestática crônica de etiologia desconhecida e rara. Apesar do principal órgão acometido na CBP ser o fígado, outros órgãos podem também ser afetados. O acometimento muscular raramente tem sido relatado em pacientes com CBP e na maioria destes casos, a fraqueza muscular tem sido interpretada como Polimiosite. Nós relatamos o caso de uma mulher de 48 anos com CBP e miopatia com achados histopatológicos distintos dos casos anteriormente descritos e fizemos uma revisão da literatura sobre o acometimento muscular na CBP

Arai, Milton Hideaki

Castro, Pedro Paulo Neves de

Domingues, Elaine Zamora

Hallack Neto, Abrahão Elias

Marie, Sueli K. Nagahashi

Meireles, Luiz Pedro

Migueletto, Bruno Cupertino

Stocker, Hartmut

English

A cirrose biliar primária (CBP) é uma doença hepática colestática crônica de etiologia desconhecida e rara. Apesar do principal órgão acometido na CBP ser o fígado, outros órgãos podem também ser afetados. O acometimento muscular raramente tem sido relatado em pacientes com CBP e na maioria destes casos, a fraqueza muscular tem sido interpretada como Polimiosite. Nós relatamos o caso de uma mulher de 48 anos com CBP e miopatia com achados histopatológicos distintos dos casos anteriormente descritos e fizemos uma revisão da literatura sobre o acometimento muscular na CBP.Primary biliary cirrhosis (PBC) is a cholestatic liver disease, which is characterized by a chronic inflammatory destruction of intrahepatic bile ducts. It is a rare disorder whose precise etiology is still to be elucidated. Even though the liver is the principal target of PBC, other organ systems also might be affected. Muscular involvement has rarely been described in this disease, and in the majority of cases, muscular weakness has been interpreted as polymyositis. We report the case of a 48-year-old woman suffering from classic PBC, in association with a myopathy whose histological features are distinct from the cases reported before. We also performed a MEDLINE research for PBC and concomitant muscular diseases

Cadernos Espinosanos (E-Journal)

165REV. HOSP. CLÍN. FAC. MED. S.PAULO 54(5):165-168, 1999SEPTEMBER-OCTOBERFrom the Department of Clinical Medicine,University of São Paulo School of Medicine,São Paulo - Brazil.PRIMARY BILIARY CIRRHOSIS AND MYOPATHY: ANUNCOMMON ASSOCIATIONBruno Cupertino Migueletto, Abrahão Elias Hallack Neto, Elaine ZamoraDomingues, Pedro Paulo Neves de Castro, Hartmut Stocker, Sueli K. NagahashiMarie, Luiz Pedro Meireles and Milton Hideaki AraiRHCFAP/ 2985MIGUELETTO, B. C. et al. - Primary biliary cirrhosis and myopathy: an uncommum association. Rev. Hosp. Clín. Fac. Med. S. Paulo 54 (5):165-168,1999.SUMMARY: Primary biliary cirrhosis (PBC) is a cholestatic liver disease, which is characterized by a chronic inflammatory destruction of intrahepaticbile ducts. It is a rare disorder whose precise etiology is still to be elucidated. Even though the liver is the principal target of PBC, other organ systemsalso might be affected. Muscular involvement has rarely been described in this disease, and in the majority of cases, muscular weakness has beeninterpreted as polymyositis. We report the case of a 48-year-old woman suffering from classic PBC, in association with a myopathy whose histologicalfeatures are distinct from the cases reported before. We also performed a MEDLINE research for PBC and concomitant muscular diseases.DESCRIPTORS: Primary biliary cirrhosis. Myopathy.Primary biliary cirrhosis (PBC) is arare disease, characterized by chroniccholestasis. Its etiology is still notentirely understood, but clinical,laboratory and histopathologic findingsstrongly suggest an autoimmune pro-cess. Histologically the disorder ischaracterized by an inflammatoryprocess that leads to the destruction ofintrahepatic bile ducts and results infibrosis of the portal tracts and finallyin hepatic failure. Up to 84% ofpatients with PBC also suffer from atleast one more disorder classified asauto immune, with Sjogren Syndrome,auto immune thyroiditis, and systemicsclerosis being the most frequent ones.Besides the liver, which is theprincipal target of PBC, other organsmight also be affected. However,muscular damage has rarely beenreported in patients with PBC, and inthese cases the nature of the myopathyhas been poorly characterized.We report the case of a patient withhistologically proven PBC withassociated muscular disease. We de-scribe the histologic features of thismyopathy.A MEDLINE research yieldedtwenty case reports on PBC in asso-ciation with muscular involvement,which was generally found to bepolymyositis.CASE  REPORTOur patient, a 48-year-old whitewoman, sought medical assistance be-cause of proximal muscular weaknessof upper and lower extremities that hadstarted four years earlier. She also com-plained of generalized prurigo as wellas darkening of her skin, principally ofher trunk and forearms, and hypertri-chosis of her arms, which had beentroubling her for two years. Eight yearsearlier, she had undergone total hyster-ectomy and bilateral oophorectomybecause of ovarian cysts. Estrogen re-placement was initiated and maintainedever since. In 1995 osteoporosis wasdiagnosed.The patient reported that she didnot drink alcohol on a regular basis andthat she had not received any trans-fusions.On physical examination she didnot show any stigmas of chronic liverdisease. She had no fever, she did nothave jaundice, and her liver wasnormal in size. Muscular strength wasgrade 4 in proximal muscles of upperand lower extremities. There were nofurther alterations on physical exam.Laboratory data acquired duringinvestigation include the following:AST 123U/L (10-30U/L), ALT 84 U/L (10-36 U/L), gGT 543 U/L (7-32 U/L), Alkaline Phosphatase 941 U/L (32-104 U/L), Creatine Kinase 380U/L(24-173U/L), LDH 465 U/L, Choles-terol 247 mg/dl. Serum immunoglo-bulins were increased: IgG 1767 mg/166REV. HOSP. CLÍN. FAC. MED. S.PAULO 54(5):165-168, 1999 SEPTEMBER-OCTOBERdl, (952-1538); IgA 703 mg/dl (153-359) IgM 617 mg/dl (73-171).Erythrocyte sedimentation rate was78 mm.Immunofluorescence was positiveshowing a granular cytoplasmic pattern(1:160).Anti-DNA, SSA, SSB, SM, andRNP autoantibodies were absent. Anti-smooth muscle and anti-liver-kidneyantibodies could not be detected.Serum complement was normal.Serologic testing for viral hepatitis wasnegative.Total serum bilirubin and fractionswere within normal range. There wereno alterations in coagulation tests.Serum albumine was 4.4 mg/dlTSH was 0.9 um/L (0.25-4.0).Antimitochondrial antibodies(AMA) were present (titre>1:320).ECG showed sinus rhythm withfrequent atrial and ventricular pre-mature complexes.Chest X-ray was normal.Bone densitometry of the lumbarspine and of the neck of femur confir-med the diagnosis of osteoporosis. (Tindex lumbar spine:-3.83 DP/ T indexneck of femur -4.06 DP)On abdominal ultrasonography, thepatient’s liver was found to be homo-geneously enlarged without evidenceof congestion of the bile tree.Liver biopsy (Microphotograph 1)showed moderate fibrous expansion ofthe portal tracts with preservation ofliver architecture. Portal tracts weredensely infiltrated with lymphocytes afew plasmocytes, and a significantnumber of neutrophils, with focalinvasion of the portal tracts. Prolife-ration of bile ductules was evident inthe periphery of portal tracts, and therewas discreet lobular inflammatoryactivity.The histopathologic findings werecompatible with chronic hepatobiliarydisease in moderate activity, suggestingprimary biliary cirrhosis.Focussing on the patient’s muscu-Fig. 1 - Liver biopsy: proliferation of bile ductules infiltrated with lymphocytes.Fig. 2 - Muscle biopsy. We found accentuated variation of muscle fiber size with the presence ofragged, rounded degenerating fibers.167REV. HOSP. CLÍN. FAC. MED. S.PAULO 54(5):165-168, 1999SEPTEMBER-OCTOBERlar weakness, we had an electromyo-graphy performed, which revealedchronic myopathy affecting all extre-mities with a clear proximal distri-bution pattern. The findings were com-patible with polymyositis. A biopsyspecimen (microphotograph 2) was ob-tained from the left brachial biceps. Onexamination we found accentuatedvariation of muscle fiber size with thepresence of ragged, rounded, degener-ating fibers, as well basophilic necroticfibers with subsarcolemmal vacuoles.Angular fibers were present with nucleicondensed into aggregates, a phenom-enon known as nuclear clumps. Wealso noted fibers with centrally locatednuclei. There was proliferation of con-nective tissue both in endomysium andperimysium.When stained for oxidative reac-tions, some fibers showed disarrange-ment. Occasional fibers showed in-creased granulation in the SDH stainthat indicated mitochondrial prolifera-tion. Numerous fibers were identifiedby the acid phosphatase reaction, indi-cating lysosomal activity. A few regen-erating fibers reacted positively whenstained with the alkaline phophatasereaction. We noted a slight predomi-nance of type one fibers.The final diagnosis was PBC withmuscular involvement.We initiated treatment with cho-lestyramine 4.0 g, p.o. three times aday, and ursodeoxycholic acid 300 mg,p.o. b.i.d., as well as calcium car-bonate, vitamin D, and alendronate forosteoporosis. The patient was dis-charged from hospital and is conti-nuing treatment on an outpatient basis.DISCUSSIONPBC is a rare, progressive, cho-lestatic liver disease of unknownetiology. Morphologically it is charac-terized by the destruction of intra-hepatic bile ductules. PBC is frequentlyassociated with other autoimmunedisorders. The most frequent ones areSjogren syndrome, rheumatoid ar-thritis, and systemic sclerosis (CRESTsyndrome).In this article we present the caseof a 48-year-old patient with PBC anda coexisting myopathy. The diagnosisof PBC was based on clinical data, onelevated levels of serum alkalinephosphatase, gGT, and IgM, as well asthe presence of circulating antimi-tochondrial antibodies (AMA). Thediagnosis was histologically confirmedby liver biopsy.Concerning the patient’s muscularweakness, we found elevated creatinekinase, alterations in EMG, and finallya highly pathologic muscular histology.Muscular disease in patients withPBC has been poorly defined. Thereare few articles in medical literaturethat deal with this subject. In 1993Varga and co-workers described twocases of asymptomatic PBC with asyndrome of severe progressive myo-pathy, cardiomyopathy, and gastro-intestinal dysmotility. They also re-viewed literature focussing on this rareassociation. They found most of theprevious reports describing focalmononuclear inflammatory infiltratesgenerally localized in the perivascularspaces, in addition to other alterationscompatible with inflammatory myopa-thy.In our case, there was little perivas-cular and endomysial inflammationexcept for rare fibers with mito-chondrial proliferation. These findingsare symptomatic of a mixture ofneurogenic and primary myogenicmuscular disorder.In spite of the patient’s proximalmuscular weakness, elevated levels ofcreatine kinase, and the results of EMGthat all suggested polymyositis, mus-cular biopsy did not reveal any charac-teristics of active inflammatory muscu-lar disease.The findings reveal a chronicprocess that is compatible with the longduration of the muscular disease. Sinceour patient underwent biopsy fouryears after the onset of her musculardisease, we must consider the possibi-lity of a different histologic pattern atthe beginning of the disease. Onpossibility includes a more distinctinflammatory pattern.The coexistence of PBC and mus-cular disease raises the possibility of acommon pathogenic mechanism forboth processes. PBC is associated withvarious immunologic abnormalities.Patients typically have elevated levelsof IgM, circulating immune com-plexes, and 90% of patients are positivefor antimitochondrial antibodies.Antimitochondrial antibodies mayalso be detected in patients with diffusemuscle weakness and mitochondrialabnormalities. In these cases, though,the specificity of these antibodies hasnot been defined yet, and the signifi-cance of this finding in diffuse muscleweakness and mitochondrial abnor-malities is still to be elucidated.According to Varga2 and co-workers, antimitochondrial antibodiesdirected against specific proteinspresent in the skeletal muscle and otherorgans could be responsible for thedevelopment of muscular disease inpatients with PBC.In this case, other primary andsecondary myopathies have to beexcluded. Autoimmune thyroiditis isvery frequent in patients with PBC;therefore, hyperthyroidism and hypo-thyroidism have to be ruled out ascauses of muscular weakness. Othercauses such as drug-induced myo-pathies, hyperparathyroidism, hyper-adrenalism, and other inflammatorymyopathies should be considered too.An interesting aspect of this case isthe patient’s osteoporosis confirmed bydensitometry. Osteoporosis is a fre-quent extra hepatic manifestation ofPBC. Even though it shares the histo-logic features of osteoporosis in post-168REV. HOSP. CLÍN. FAC. MED. S.PAULO 54(5):165-168, 1999 SEPTEMBER-OCTOBERmenopausal women, its pathogenicmechanism is unclear, and there is noconsensus on how to treat this con-dition. Besides her liver disease bilat-eral oophorectomy represents a furtherpredisposing factor for osteoporosis inour patient. Treatment with estrogensis usually avoided because of its well-known cholestatic effect.However, in a non-controlled,retrospective trial performed in 1994,Crippin and colleagues found thatoestrogen replacement in patients withPBC and osteoporosis did not worsencholestasis either clinically or bio-chemically.Another observation from thisstudy was that calcium and vitamin Dwere not sufficient for reverting boneloss in patients with PBC.In 1999 Olsson et al.5, whoanalyzed the effect of estrogens onosseous density in nine women withosteoporosis and PBC, found treatmentwith calcium and vitamin D to beeffective and safe. The small numberof patients in these trials, however,makes it difficult to recommendoestrogen treatment for all women withosteoporosis and PBC. In our case, weopted for treating osteoporosis withcalcium, vitamin D, and alendronateTreatment of myopathy generallyrequires the use of corticoids. In thiscase, however, benefits of an increasedmuscular strength have to be consi-dered against the risks of aggravatingthe patient’s osteoporosis in addition tothe other complications this treatmentmay cause.This article describes the case of apatient with PBC and myopathy, aninfrequent association, complicated byosteoporosis. The physiopathology ofthis association is still not understoodbut may be related to the presence ofantimitochondrial antibodies.RESUMO RHCFAP/2985MIGUELETTO, B. C. e col. - Cirrosebiliar primária e miopatia: uma raraassociação. Rev. Hosp. Clín.Fac. Med. S. Paulo 54 (5):165-168, 1999.A cirrose biliar primária (CBP) éuma doença hepática colestática crô-nica de etiologia desconhecida e rara.Apesar do principal órgão acometidona CBP ser o fígado, outros órgãospodem também ser afetados. O acome-timento muscular raramente tem sidorelatado em pacientes com CBP e namaioria destes casos, a fraqueza mus-cular tem sido interpretada comoPolimiosite. Nós relatamos o caso deuma mulher de 48 anos com CBP emiopatia com achados histopatológicosdistintos dos casos anteriormentedescritos e fizemos uma revisão daliteratura sobre o acometimento mus-cular na CBP.DESCRITORES: Cirrose biliarprimária. Miopatia.REFERENCES1. CULP KS, FLEMING CR, DUFFY J et al. - Autoimmune associationsin primary biliary cirrhosis. Mayo Clin Proc 1982; 57:365-370.2. VARGA J, PATTERSON TH, MUÑOZ S et al. - Myopathy withmitochondrial alterations in patients with primary biliary cirrhosisand antimitochondrial antibodies. Arthr Rheum 1993;36(10):1468-75.3. SIMPSON WG & NICKL NJ - Polymyositis associated with primarybiliary cirrhosis. J Ky Med Assoc 1995; 93 (3):93-94.4. CRIPPIN JS, JORGENSEN RA, DICKSON ER et al. - Hepaticosteodystrophy in primary biliary cirrhosis: effects of medicaltreatment. Am J Gastr 1994; 89(1):47-49.5. OLSSON R, MATTSSON LA, OBRANT K et al. - Estrogen-progestogen therapy for low bone density in primary biliarycirrhosis. Liver 1999; 19(3):188-92.Received for publication on the 24/08/99

Primary biliary cirrhosis and myopathy: an uncommon association

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Cirrose biliar primária e miopatia: uma rara associação

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Cirrose biliar primária e miopatia: uma rara associação

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