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Is Mitochondrial Antibody Diagnostic of Primary Biliary Cirrhosis?

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Is Mitochondrial Antibody Diagnostic of Primary Biliary Cirrhosis? Gut: first published as 10.1136/gut.22.2.136 on 1 February 1981. Downloaded from Guit, 1981, 22, 136-140 Is mitochondrial antibody diagnostic of primary biliary cirrhosis? LINDA E MUNOZ, H C THOMAS,* P J SCHEUER, DEBORAH DONIACH, AND SHEILA SHERLOCK From the Department of Medicine and Histopathology, Royal Free Hospital, London, and the Department ofImmunology, Middlesex Hospital Medical School, London SUMMARY In a series of 218 patients diagnosed as having primary bilary cirrhosis only nine ex- hibited a negative serum mitochondrial antibody. On examining additional specimens from these. patients, seven were found to be positive, giving a final incidence of greater than 99%. The two. patients whose sera remained negative for the mitochondrial antibody had liver histology com- patible with the diagnosis of primary biliary cirrhosis, but a firm diagnosis could not be reached. Three additional mitochondrial antibody positive subjects who were asymptomatic and exhibited. normal serum alkaline phosphatase were shown on liver biopsy to have stage I primary biliary- cirrhosis. The presence of a positive serum mitochondrial antibody in a patient with or without abnormalities in liver function tests strongly suggests the diagnosis of primary biliary cirrhosis. Primary biliary cirrhosis is a disease of unknown Free Hospital identified 218 patients with the diag- aetiology in which the epithelium of the intrahepatic nosis of primary biliary cirrhosis. In nine patients. biliary tree is destroyed by a chronic inflammatory mitochondrial antibody was negative at presenta- process characterised by the presence of granu- tion, the diagnosis being made on the basis of http://gut.bmj.com/ lomata. symptoms, biochemistry, and liver histology. Ad-- The incidence of mitochondrial antibody in ditional specimens from these patients were ex- patients diagnosed on the basis of a suggestive amined for the presence of mitochondrial antibody. clinical history, cholestatic liver function tests, The original specimens were not available for re- raised serum IgM, and a compatible histological testing and in general the repeat specimen was appearance has varied from 83 to 98%.1-6 When obtained within one to five years. primary biliary cirrhosis was diagnosed at the Three additional subjects were included in the on September 28, 2021 by guest. Protected copyright. presymptomatic stage, mitochondrial antibody was study. All were mitochondrial antibody positive- present in 90 to 100% of cases.7 8 with normal alkaline phosphatase and IgM. These To investigate further the specificity of the re- patients were studied clinically, biochemically, lationship of the mitochondrial antibody to primary serologically, and histologically for stigmata of biliary cirrhosis, we have tested a large group of primary biliary cirrhosis. patients who, on clinical, biochemical, and histo- logical grounds, have this disease. We have also SEROLOGY examined three apparently normal subjects who were Mitochondrial, smooth muscle, nuclear, and thyroid mitochondrial antibody positive, for the presence autoantibodies were done in two laboratories (Royal of liver disease. Free Hospital and Middlesex Hospital). Mitochon- drial, smooth muscle, and nuclear autoantibodies. Methods were detected by indirect immunofluorescence. Rat PATIENTS kidney, stomach, and liver were used as substrate A review of the clinical and liver biopsy material at the Royal Free Hospital. At the Middlesex from January 1973 to December 1977 at the Royal Hospital human thyroid, submaxillary gland, and kidney, as well as rat liver and kidney, were used as *Address for correspondence and reprint requests: H C Thomas, Department of Medicine, Royal Free Hospital, Pond Street, London substrate. Cryostat sections were made. After drying NW3 2QG, United Kingdom. the slide at room temperature for one hour, the tissue: Received for publication 18 August 1980 was covered with 1/10 (Royal Free Hospital) and, 136 Gut: first published as 10.1136/gut.22.2.136 on 1 February 1981. Downloaded from Is mitochondrial antibody diagnostic ofprimary biliary cirrhosis? 137 undiluted sera as well as 1/10 (Middlesex Hospital) Table 1 Autoantibody titres for screening. Positive samples were titrated. After Case Substrate: 30 minutes at room temperature, the slides were no. Human thyroid submaxillary gland and kidney; rat stomach; washed twice in Coons buffer for five minutes, liver and kidney fixed in absolute alcohol for three minutes, rinsed in MA* SMA NA Thyro- Thyro- .Coons buffer, and then FITC antibody was added globulin microsomal and left for 30 minutes. Duplicate unfixed slides were 10 tested. Positive and negative controls were used. 2 10 10 for mito- 3 0-10 10 40 Two patients who remained negative 4 0-1 10 'chondrial antibody on retesting by immunofluor- 5 10 10 10 40 escence were also tested by complement fixation 6 40-160 7 40-160 10 12802 'XICF) using anti-C3 conjugate. 8 10-20 10 Thyroid (thyroglobulin and microsomal) auto- 9 40-80 10 40 antibodies were detected by a haemagglutination *Results on retesting at the Royal Free Hospital and Middlesex test using sheep red cells coated with human thyroid Hospital. antigens (Wellcome Laboratories and Fujizoki MA: mitochondrial antibody. SMA: smooth muscle antibody. Pharmaceutical Co Ltd). NA: nuclear antibody. 'HISTOLOGICAL EXAMINATION also found to be positive at the Middlesex Hospital. Liver biopsies were processed and stained by routine The titres found were similar in all the patients except method. The rhodanine stain was used to demon- in patients 6 and 7, in whom mitochondrial antibody strate copper, and the orcein stain for copper- was found to be positive in a titre on 40 at the Royal associated protein. Both were semi-quantitatively Free Hospital, whereas at the Middlesex Hospital it graded from 0 to + + + +. Indirect immuno- was found to be 160. Patients 3 and 4 who remained peroxidase testing for alpha 1 antitrypsin was negative at the Royal Free Hospital were found to carried out. be positive in a very low titre-10 and undiluted serum respectively-at the Middlesex Hospital. Results There was no difference in the titres obtained when were used. Two rat and human substrates patients http://gut.bmj.com/ MITOCHONDRIAL ANTIBODY NEGATIVE (patients 1-2) remained mitochondrial antibody PRIMARY BILIARY CIRRHOSIS negative on retesting in both laboratories. On retesting additional serum specimens (obtained Smooth muscle and nuclear antibodies were 12 to 60 months after the first specimen) from the present mostly in low titres. Thyroid autoantibodies nine mitochondrial antibody negative patients, five were found only occasionally. Patient 5 had thyro- patients were found to be positive at the Royal Free globulin antibodies and patient 7 had thyroid Hospital (patients 5-9) (Table 1). These patients were microsomal antibodies both in high titres (Table 1). on September 28, 2021 by guest. Protected copyright. Table 2 Main features found in two female patients who remained negative for mitochondrial antibody on retesting Patient 1 Patient 2 Age (yr) 56 34 History (yr) 2 3 Symptoms and signs at presentation Itching, RUQ pain, weight loss Itching, jaundice, hepatosplenomegaly, spider naevi Pi phenotype MM MS ,Other autoimmune disease Sicca syndrome Dermatomyositis RTA RTA Diabetes mellitus Total bilirubin (5-17 Lmol/l (0-8-1-2 mg%)) 18 (1-3) 15 (1.1) SGOT (4-15 IU) 52 109 Alkaline phosphatase (3-13 KAU) 164 119 Alpha I antitrypsin ( > 1-9 g/l ( > 190 mg °)) 2-4 (240) 1.7 (166) IgM (0 7-2-8 g/l (70-280 mg %)) 1.1 (105) 1.0 (102) IgG (8-18 g/l (800-1800 mg%)) 12-6 (1260) 10.8 (1080) IgA (0.9-4.5 g/l (90-450 mg %)) 3-2 (320) 1-7 (170) Liver biopsy Latest stage of PBC seen 3 3 Copper and CAP' staining + +1++ +/+ + PAS-diastase resistant globules Negative Negative Immunoperoxidase for alpha 1 antitrypsin Negative Inconclusive 'Copper associated protein. Gut: first published as 10.1136/gut.22.2.136 on 1 February 1981. Downloaded from 138 Munoz, Thomas, Scheuer, Doniach, and Sherlock The nine patients who were initially negative for Hospital three years later. She had itching, jaundi ce mitochondrial antibody had a clinical history, hepatosplenomegaly, and spider naevi (Table 2 > LFTs, and histological changes suggestive of primary SGOT and alkaline phosphatase were raised. Im- biliary cirrhosis when first presenting to medical munoglobulins were normal and a mild decrease in care. They were all females and the mean age was 48 serum alpha 1 antitrypsin was noted 1-7 g/l (166 years (34 to 70 years). IgM was raised in five patients. mg%). Renal tubular acidosis was also diagnosed Patient 4 had low serum levels of alpha 1 antitrypsin and one year later she developed dermatomyositis. (0.9 g/l (92 mg%) normal, 1.9 g/l (190 mg%)). Liver She was then treated with prednisolone and later biopsy of this patient showed some PAS-diastase cyclophosphamide but showed no improvement. resistant globules in hepatocytes. It was not possible She developed complete heart block, right pleural to make additional studies as there was no follow-up effusion, and pulmonary consolidation. One year in this patient. Extrahepatic bile ducts were shown later she was diagnosed as having diabetes mellitus. to be clear in all the patients. Three liver biopsies were done and in all the histology The liver biopsies of the nine patients were was compatible with late PBC. No cholestasis was randomised and reviewed by a single observer. A seen. Copper and copper-associated protein were total of 16 liver biopsies were reviewed. There was found to be mildly increased by rhodanine and no marked differences between the patients who orcein staining respectively.10 Pas-diastase resistant remained negative for serum mitochondrial antibody globules were absent and immunoperoxidase exami- and the patients who were found to be positive for mation for alpha 1 antitrypsin was inconclusive this antibody on retesting. All the patients had (Table 2). The phenotype by acid starch gel electro- stage 3 or 4 of primary biliary cirrhosis.9 phoresis was MS.
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