Inflammatory Myopathy Associated with Anti-mitochondrial Antibody-negative Primary Biliary Cholangitis Diagnosed by a Liver Biopsy

Abstract

Anti-mitochondrial antibody (AMA)-associated myopathies represent a homogeneous disease entity with severe arrhythmia and slowly progressive proximal muscle weakness with lordotic posture, irrespective of the presence of primary biliary cholangitis (PBC). We herein report a case of myositis associated with PBC without AMAs. A 48-year-old woman presented with clinical features very similar to AMA-associated myositis, despite negative AMAs. PBC, ascertained by a liver biopsy performed based on mildly elevated liver enzymes, and the efficacy of steroid therapy on muscle weakness confirmed the diagnosis of immune-mediated myositis. When AMAs are negative, a liver biopsy is indispensable for diagnosing treatable PBC-associated myositis.

Introduction

Inflammatory myopathies associated with anti-mitochondrial antibodies (AMAs) are becoming recognized as a homogeneous disease entity, irrespective of the presence of primary biliary cholangitis (PBC) (1). Nevertheless, in the absence of AMAs and symptomatic PBC, the diagnosis of immune-mediated inflammatory myopathies may be missed, and treatment may be unsuccessful in many cases.

We herein report a case of PBC-associated myositis without AMAs or symptomatic PBC, although the clinical features were typical of the disease. A liver biopsy was indispensable for the diagnosis.

Case Report

A 48-year-old woman with no medical or family history was admitted. She was a non-smoker and did not drink alcohol. At 44 years old, she experienced difficulty riding a bicycle uphill and had concurrent palpitations and shortness of breath. At 45 years old, leg edema appeared, and at 46 years old, she had difficulty climbing stairs and lifting heavy objects. At 47 years old, she started to visit the Department of Cardiology at our hospital due to signs of heart failure, such as palpitations and leg edema. Diuretics, angiotensin receptor blockers, and beta-blockers were initiated sequentially. At 48 years old, she was admitted to our hospital due to difficulty walking on level ground.

Her height was 165 cm and her weight was 55 kg, with a body mass index of 19.9 kg/m². Her vital signs were as follows: blood pressure, 87/63 mmHg; pulse, 75 beats/minute (irregular); body temperature, 36.8°C; and oxygen saturation, 100% in room air. Bilateral leg indentation edema was prominent. A neurological examination revealed a marked lordotic posture and weakness of the neck and proximal limbs, with manual muscle testing (MMT) showing grades of 3 for neck flexors and 4 for deltoids and hamstrings. Her laboratory findings (Table) included slightly elevated hepatobiliary enzymes and moderately elevated muscle enzymes as follows: aspartate transaminase (AST), 38 U/L; alanine transaminase (ALT), 29 U/L;γ-glutamyl transpeptidase (γ-GTP), 135 U/L; creatine kinase (CK), 960 U/L; brain natriuretic peptide (BNP), 154 pg/mL. The blood count and other biochemical tests were normal. AMA (indirect immunofluorescence; IIF) and anti-mitochondrial M2 antibody (chemiluminescent enzyme immunoassay; CLEIA), as well as other myositis specific antibodies as shown below, were negative: transcription intermediary factor 1 (TIF1)-γ, melanoma differentiation-associated gene 5 (MDA5), Mi-2β, and signal recognition particle (SRP). The weak positivity of the anti-EJ antibody, one of the ARS antibodies, was considered nonspecific, as this case did not present the interstitial pneumonia or dermatomyositis that is characteristic of the antibody. Her low platelet count (81,000 /μL) was found to be due to secondary immune thrombocytopenia, but this value later normalized after Helicobacter pylori eradication.

Table.

Laboratory Findings on Admission.

Biochemistry

Hematology

Serology (continued)

Albumin

4.7

g/dL

White blood cell

4,400

/µL

sIL-2R

415

U/mL

LDH

294

U/L

Hemoglobin

11.7

g/dL

C3

124.6

mg/dL

AST

38

U/L

Platelet

8.1

×104/µL

C4

26.4

mg/dL

ALT

29

U/L

PT-INR

1.1

MPO-ANCA

<1.0

γ-GTP

135

U/L

APTT

28.7

s

PR3-ANCA

<1.0

Total bilirubin

0.7

mg/dL

ESR

31

mm/h

Rheumatoid factor

3

U/mL

BUN

18.3

mg/dL

Serology

SS-A Ab

<0.5

U/mL

Creatinine

0.57

mg/dL

CRP

0.1

mg/dL

Ro-52 Ab

(-)

Sodium

138

mEq/L

HIV Ab

(-)

LKM-1 Ab

(-)

Potassium

3.5

mEq/L

HTLV-1 Ab

(-)

AMA

<20

CK

960

U/L

STS

(-)

AMA-2

3.7

U/mL

LDL-C

115

mg/dL

Treponema pallidum

(-)

Jo-1 Ab

(-)

HDL-C

58

mg/dL

HBs Ag

(-)

PL-7 Ab

(-)

HbA1c

5.5

%

HCV Ab

(-)

PL-12 Ab

(-)

BNP

154

pg/mL

Antinuclear antibody

40

OJ Ab

(-)

TSH

4.6

μU/mL

Homogeneous

<40

EJ Ab

(1+)

FT4

1.9

ng/dL

Peripheral

<40

TIF1-γ Ab

(-)

ACE

15.4

U/L

Speckled

<40

MDA5 Ab

(-)

Aldolase

4.6

U/L

Nucleolar

<40

Mi-2 Ab

(-)

Lactic acid

6.2

mg/dL

Centromere

<40

Mi-2β Ab

(-)

Pyruvic acid

0.6

mg/dL

Granular

<40

SRP Ab

(-)

IgA

202

mg/dL

Nuclear envelope

40

Ku Ab

(-)

IgM

78

mg/dL

Cytoplasmic

(-)

PM-Scl100 Ab

(-)

IgG

958

mg/dL

Centromere Ab

<2.0

U/mL

PM-Scl75 Ab

(-)

dsDNA Ab

2.3

IU/mL

LDH: lactate dehydrogenase, AST: aspartate aminotransferase, ALT: alanine aminotransferase, γ-GTP: γ-glutamyl transpeptidase, BUN: blood urea nitrogen, CK: creatinine kinase, LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein cholesterol, HbA1c: hemoglobin A1c, BNP: brain natriuretic peptide, TSH: thyroid-stimulating hormone, FT4: free thyroxine, ACE: angiotensin converting enzyme, IgA: immunoglobulin A, IgM: immunoglobulin M, IgG: immunoglobulin G, PT-INR: prothrombin time international normalized ratio, APTT: activated partial thromboplastin time, ESR: erythrocyte sedimentation rate, CRP: C-reactive protein, HIV: human immunodeficiency virus, Ab: antibody, HTLV-1: human T-cell leukemia virus type 1, STS: serologic test for syphilis, HBs: hepatitis B surface, HCV: hepatitis C virus, dsDNA: double-stranded deoxyribonucleic acid, sIL-2R: soluble interleukin-2 receptor, C3: complement component 3, C4: complement component 4, MPO-ANCA: myeloperoxidase antineutrophil cytoplasmic antibody, PR3-ANCA: proteinase 3 antineutrophil cytoplasmic antibody, LKM-1: liver/kidney microsome type 1, AMA: anti-mitochondrial antibody, AMA-2: anti-mitochondrial M2 antibody, TIF1-γ: transcription intermediary factor 1-γ, SRP: signal recognition particle

An electrocardiogram showed frequent premature atrial contraction (PAC), premature ventricular contraction (PVC), and non-sustained ventricular tachycardia (NSVT). The cardiothoracic ratio was 60% on chest X-ray, and the left ventricular ejection fraction was 40% on echocardiography. Abdominal ultrasonography showed mildly increased liver echogenicity and hepatic parenchymal roughness. The respiratory function was normal, with a vital capacity (VC) of 3.15 L (%VC, 91.3%). Muscle computed tomography revealed muscular atrophy and fat replacement, markedly in the paraspinal muscles and mildly in the dorsal side of the upper and lower legs (Fig. 1). Electromyography showed fibrillation potentials, positive sharp waves, and small polyphasic short-duration motor unit action potentials in the left biceps brachii and deltoid muscles, which were compatible with a myopathic pattern.

Figure 1.

Muscle computed tomography images. Muscular atrophy and fat replacement are observed, markedly in paraspinal muscles (arrows) and mildly in the dorsal side of the upper and lower legs (arrowheads).

While we initially considered muscular dystrophy with myocardial involvement as a differential diagnosis, no pathological mutations in the lamin A/C gene were detected on laminopathy screening. A left deltoid muscle biopsy revealed fiber variation in size and scattered necrotic and regenerating fibers. Increased staining with anti-human leukocyte antigen (HLA)-ABC antibody, suggestive of inflammatory myopathy of chronic course, was noted but mild (Fig. 2). All other immunohistochemical stains showed normal patterns, including negative staining for membrane attack complex.

Figure 2.

Histopathology of the deltoid muscle. Fibers varied in size with scattered necrotic and regenerating fibers are observed, showing mildly increased expression of HLA-ABC antibody. HE: Hematoxylin and Eosin staining, HLA: anti-human leukocyte antigen. Scale bar=100 μm.

Although AMAs were negative, the characteristic distribution of muscle weakness and atrophy was typical of AMA-associated myositis. Since she had mild liver damage on blood tests and ultrasonography, we performed a liver biopsy. The result showed chronic cholangitis, hepatic lobular inflammation, and periportal fibrosis, leading to a histopathological diagnosis of PBC in the early stage (Scheuer's stage 1) (Fig. 3). At this point, we strongly suspected AMA-negative PBC-associated immune-mediated inflammatory myopathy.

Figure 3.

Histopathology of the liver. Chronic cholangitis, hepatic lobular inflammation, and periportal fibrosis are observed, leading to a histopathological diagnosis of primary biliary cholangitis in the early stage (Scheuer’s stage 1). Scale bar=100 μm.

After undergoing radiofrequency catheter ablation (RFCA) and receiving an implantable cardioverter-defibrillator (ICD) for severe arrhythmias, we initiated oral prednisolone (PSL) therapy for myositis at a dose of 60 mg (1 mg per kg body weight) daily. At week 2, CK levels normalized, and muscle weakness began to improve. After 1 month of treatment, we started tapering the dose of PSL by 5 mg weekly. Since she developed steroid psychosis while taking 45 mg of PSL, we immediately reduced the dose to 30 mg. She was discharged from the hospital after confirmation that her psychotic symptoms had stabilized. At three months after treatment initiation, MMT improved to grade 4 for neck flexors and 5 for deltoids and hamstrings. Her lordotic posture also showed an improving trend (Fig. 4). The favorable response to PSL confirmed the diagnosis of immune-mediated myositis. Administration of 600 mg/day of ursodeoxycholic acid (UDCA) was started along with PSL initiation, and the hepatobiliary enzyme levels subsequently normalized. While mild liver damage recurred at week 4 (maximum AST 84 U/L, ALT 150 U/L, γ-GTP 112 U/L), it resolved after PSL reduction. Three months after treatment initiation, hepatobiliary enzymes remained improved under 300 mg/day of UDCA (AST 19 U/L, ALT 17 U/L, γ-GTP 69 U/L). Cardiac complications did not change markedly after treatment initiation.

Figure 4.

The clinical course after treatment initiation. The patient underwent RFCA and ICD for severe arrhythmias. We initiated oral PSL therapy for myositis. At three months after treatment initiation, MMT scores improved to grade 4 for neck flexors and 5 for deltoids and hamstrings, which were 3 and 4 before treatment, respectively. RFCA: radiofrequency catheter ablation, ICD: implantable cardioverter-defibrillator, PSL: prednisolone, CK: creatine kinase, MMT: manual muscle testing

Discussion

PBC (formerly known as primary biliary cirrhosis) is a chronic inflammatory cholestatic liver disease that culminates in end-stage biliary cirrhosis when untreated. This disease predominantly affects women over 40 years old. Chronic immune-mediated biliary epithelial injury causes cholestasis, ductopenia, and progressive biliary fibrosis. It is clinically characterized by jaundice, pruritus, esophageal varices, ascites, and hepatic encephalopathy. PBC lacking these symptoms is called asymptomatic PBC and is associated with a good prognosis. Biochemical markers include increased serum alkaline phosphatase and γ-GTP. AMA positivity is observed in more than 90% of patients with PBC (2).

Regarding the association of PBC with inflammatory myopathies, there has been a growing body of literature since the first case was reported in detail by Uhl et al. in 1974 (3). Since a comprehensive study by Maeda et al. in 2012 (1), several large-scale case series have been reported, and it has become evident that AMA-positive myositis presents with homogeneous clinical features, regardless of the presence of PBC (4-7). AMA-positive myositis predominantly affects women over 40 years old, and 14% to 75% of the patients are reported to have PBC. AMA-positive myositis has a chronic, slowly progressive disease course, with patients experiencing several months to several years of weakness prior to presentation. It is characterized by muscle weakness and atrophy with proximal dominance, especially paraspinal muscle involvement with lordotic posture. The frequent association of cardiac complications, including severe arrhythmias and heart failure, is characteristic of this disease so it is not uncommon for patients to initially visit a department other than neurology.

Restrictive ventilatory impairment without interstitial pneumonia is also recognized with this disease. Indeed, Maeda et al. reported that 6 of 24 patients with AMAs had a VC of <80%, with 2 patients requiring respiratory support (1). The mean CK level is about 1,000 to 2,000 U/L. Muscle histopathology most commonly shows necrotic and/or regenerating fibers with or without inflammatory infiltrates. Findings of muscle atrophy and endomysial fibrosis are also noted, suggesting the long-term nature of the disease (1,6). There have also been reports of the infiltration of CD3 (8) or CD4-positive T cells (1), granulomatous inflammation (1), and the accumulation of abnormal mitochondria (9).

In the present case, the clinical course, distribution of muscle weakness, complications of severe arrhythmias, and muscle histopathological findings were all compatible with AMA-positive myositis, although AMAs were negative, and clinical symptoms of PBC were lacking. A liver biopsy was indispensable for diagnosing inflammatory myopathy associated with asymptomatic PBC. Based on the findings of a PubMed search performed in January 2022 using the terms (PBC) AND (myositis OR myopathy), this is the first case report in English of AMA-negative myositis associated with histopathologically diagnosed PBC, of which only one case has ever been reported in the Japanese literature (10). Since such a clinical feature is known as “AMA-positive myositis” rather than “PBC-associated myositis,” the diagnosis of autoimmune myositis is often overlooked when AMAs are negative, with patients missing out on the opportunity for immune-modulatory treatment because of a misdiagnosis of other diseases, such as muscular dystrophy with cardiomyopathy. Even if AMAs are negative, a proactive liver biopsy is essential for a definitive diagnosis and appropriate therapeutic intervention.

The role of AMAs is still unclear. Although they are regarded as serological hallmarks of PBC, they are not detectable in 10-22% of PBC patients when tested by IIF, nor in 5-10% even when more accurate immunoassays, such as a CLEIA, are used (11). The early phase of PBC may help explain the AMA negativity (12). However, the presence of AMAs can reportedly predate histological and biochemical manifestations by several years (13). Indeed, AMA-negative PBC patients are remarkably similar to AMA-positive subjects in their clinical, laboratory, and even histological features (11,14).

Even less is known concerning the relationship between AMAs and myositis. AMA-positive myositis is not always associated with PBC (1,4-7). In addition, AMA titers are not correlated with the disease activity or severity in myositis patients (7). The wide variety of skeletal and cardiac muscle histopathologies in AMA-associated myopathy (1,8,9) also leads to a lack of agreement as to whether this is a form of idiopathic inflammatory myopathy with secondary AMAs or a primary immune-mediated mitochondrial myopathy. Our case suggests that unknown factors other than AMAs may be intrinsic to the pathogenesis. Further studies are required to elucidate the relationship between myopathy, PBC, and AMAs.

This is a timely reminder that, in some cases, the typical clinical features of PBC-associated myositis require a liver biopsy to elucidate the diagnosis, even in the absence of antibodies or symptomatic PBC. It is essential not to overlook treatable autoimmune pathogeneses.

The authors state that they have no Conflict of Interest (COI).

Financial Support

This study was supported partly by Intramural Research Grant (2-5) for Neurological and Psychiatric Disorders of NCNP.