897
Section ofDermatology REFERENCES Di Ferrante N, Leachman R D, Angelini P, Donnelly P V, Francis G & Almazan A (1975) Connective Tissue Research 3, 49 Pinnell S R, Krane S M, Kenzora J E & Glimcher M J (1972) New England Journal of Medicine 286, 1013 Pope F M, Martin G R, Lichtenstein J R, Pentdnnen R, Gerson B, Rowe D W & McKusick V A (1975) Proceedings of the National Academy ofSciences of the USA 72, 1314 Pope F M, Martin G R & McKusick V A (1977) Journal of Medical Genetics 14, 200-204 Sussman M D, Lichtenstein J R, Nigra T P, Martin G R & McKusick V A (1974) Journal of Bone and Joint Surgery 56A, 1228-1231
Fig 2 Skin histology showing diffuse granulomata with slight necrobiosis Cutaneous Granulomata with Primary Biliary Cirrhosis J P H Byrne MRcpi, A M G Cochrane MRCP, D I Williams FRCP and R Williams FRCP (Kipg's College Hospital and Medical School, Denmark Hill, London SE5 9RS)
test, negative; antimitochondnal antibodies 1: 320 Barium swallow showed no cesophageal varices; Schirmer's test abnormal, suggesting keratoconjunctivitis sicca. Technetium scan showed hepatomegaly with a patchy uptake and increased For two years Mrs E S, aged 74, had a generalized splenic uptake. Chest X-ray was normal with no pruritus which was associated for the last year with evidence of hilar lymphadenopathy or fibrosis. a widespread sheeted papular eruption on the Skin biopsy (Fig 2), taken from the back, revealed trunk and limbs. On examination there was slight granulomata in the dermis consisting of monuclear generalized hyperpigmentation and a sheeted glis- cells, epithelioid cells and Langhan's type giant tening flesh-coloured papular eruption affecting cells. Liver biopsy (Dr B Portmann, Fig 3) showed the upper chest, back and arms (Fig 1). Liver changes consistent with primary biliary cirrhosis palpable 6 cm and spleen 3 cm below the costal (PBC), namely enlargement of portal tracts with ill-defined granulomata; focal collections of margin; no clinical jaundice or xanthelasma. lymphocytes and plasma cells around small bile Investigations: HB, 10.2 g/dl; WBC, 3000 cells/pl; ducts, the epithelial cells of which were swollen and platelets, 143 000/pl; ESR, 90 mm/hr; partial abnormal; piecemeal necrosis; and extensive thromboplastin time 16 s (control 13 s); bilirubin, fibrosis. 14 pmol/l; alkaline phosphatase, 850 iu/l (normal 30-85 iu/l); aspartate aminotransferase, 157 iu/l Treatment (normal 50 iu/l); IgM, 6.0 g/l (normal 0.5-1.7 g/l); One sachet of cholestyramine every day for prurIgG, 29.4 g/l (normal 5-16 g/l); IgA, 1.7 g/l (nor- itis; methyl cellulose eye drops and monthly inmal 1.4-4.2 g/1); Kveim test, negative; Mantoux jections of vitamins A, D and K. ~~~~~~~~~ra :
Fig 1 Extensive confluent papular eruption on the chest
Fig 3 Liver biopsy showing granulomata chronic inflammatory reaction around the bile ducts, piecemeal
necrosis andportal tract fibrosis
898
Proc. roy. Soc. Med. Volume 70 December 1977
Comment The presence of pruritus, hepatosplenomegaly, antimitochondrial antibodies, elevated IgM and alkaline phosphatase, and the histological appearances of the liver are all characteristic of PBC. The negative Kveim test, normal chest X-ray and serum calcium, and age of the patient are all against a diagnosis of sarcoidosis. The skin eruption is more compatible with a diagnosis of generalized granuloma annulare (Stankler & Leslie 1967) than with sarcoidosis or PBC. Granuloma annulare, a condition of unknown etiology, is characterized histologically by the presence of diffuse palisading granulomata surrounding areas of collagen necrosis. The clinical appearance of granuloma annulare is that of smooth firm papules which may coalesce to form rings or as widespread disseminated papules as in the present case. A relationship between the disseminated form and diabetes mellitus has been noted by Romaine et al. (1968). Recently, Dahl et al. (1977) noted the presence of deposits of immunoglobulin M, C3 and fibrin in the dermal blood vessels and at the dermoepidermal junction in cases of granuloma annulare, leading them to suggest that this condition may represent an immunoglobulinmediated chronic vasculitis. Although extrahepatic granulomata have been demonstrated in PBC in lung parenchyma, abdominal lymph nodes and the omentum (Stanley et al. 1972), to our knowledge granulomata in the skin have never been reported. To complicate interpretation even further, we have previously reported the association of PBC with Kveim positive sarcoidosis (Karlish et al. 1969) and have recently seen a further case. Dicken et al. (1969) mentioned a case of generalized granuloma annulare which also showed hepatic granulomata, and for this reason they favoured the diagnosis of sarcoidosis. Our patient's skin eruption is compatible with generalized granuloma annulare and the presence of granulomata is a feature common to both granuloma annulare and PBC. Although immunofluorescent studies of the skin and liver were not done in our patient, it is possible to hypothesize that circulating complexes involving IgM, which is elevated in PBC, lodge in the skin causing a vasculitis with subsequent granulomatous formation. Some support for this comes from a case report by Rai et al. (1977) in which they describe details of a woman with PBC who also had IgMassociated cutaneous capillaritis and membranous glomerulonephritis. They felt that immunological reactions in the skin may have been responsible for the pruritis. We are unable to explain satisfactorily the rapid disappearance of the eruption within a few days of starting cholestyramine therapy, as it was too rapid an effect to implicate a bile salt
lowering effect. Perhaps cholestyramine has an effect on immune complexes of which we are unaware. REFERENCES Dahl M V, Ullman S & Goltz R W (1977) Archives ofDermatology 113, 463-467 Dicken C H, Carrington S G & Winkelman R K (1969) Archives of Dermatology 99, 536-563 Karlish A J, Thompson R P H & Williams R (1969) Lancet ii, 599 Rai G S, Hamlyn A N, Dahl M G C, Morley A R & Wilkinson R (1977) British Medical Journal i, 817-819 Romaine R, Rudner E J & Altman J (1968) Archives ofDermatology 98, 152-154 Stankler L & Leslie G (1967) Archives of Dermatology 95, 509-513 Stanley N N, Fox R A, Whimster W F et al (1972) New England Journal of Medicine 287, 1283
Professor E Wilson Jones: If I had been shown this patient's slides without being given any clinical information, I would have diagnosed granuloma annulare with a fair degree of confidence. The only unusual aspect was the relatively large number of multinucleate giant cells, but these are sometimes a feature of granuloma annulare. I do not think that sarcoidosis is at all likely and I am unable to relate the skin problem to her primary biliary cirrhosis.
The following cases were also presented:
Xanthomata and Histiocytosis Dr J P H Byrne (for Dr R H Marten and Dr P J Watkins) (King's College Hospital, London SE5 9RS)
Cryptococcosis Dr E Cronin and Dr R McKenzie (St John's Hospitalfor Diseases of the Skin, Lisle Street, London WC2H 7BJ) Eosinophilic Fasciitis Dr M R Klaber (for Dr N A Thorne) (The London Hospital, London El 2AD) Necrobiotic Nodules Dr Joanna Ward (Charing Cross Hospital, London W6 8RF)
Sarcoidosis with Tenosynovitis and Widespread Cutaneous Involvement Dr D A Burns (for Dr I Sarkany) (Royal Free Hospital, London NW3 2QG) ? Lichen Planus or Lupus Erythematosus Dr T J Ryan
(Institute ofDermatology, London WC2) Essential Progressive Telangiectasia Dr S Peiris (for Dr R H Marten) (King's College Hospital, London SE5 9RS)
Section ofDermatology REFERENCES Di Ferrante N, Leachman R D, Angelini P, Donnelly P V, Francis G & Almazan A (1975) Connective Tissue Research 3, 49 Pinnell S R, Krane S M, Kenzora J E & Glimcher M J (1972) New England Journal of Medicine 286, 1013 Pope F M, Martin G R, Lichtenstein J R, Pentdnnen R, Gerson B, Rowe D W & McKusick V A (1975) Proceedings of the National Academy ofSciences of the USA 72, 1314 Pope F M, Martin G R & McKusick V A (1977) Journal of Medical Genetics 14, 200-204 Sussman M D, Lichtenstein J R, Nigra T P, Martin G R & McKusick V A (1974) Journal of Bone and Joint Surgery 56A, 1228-1231
Fig 2 Skin histology showing diffuse granulomata with slight necrobiosis Cutaneous Granulomata with Primary Biliary Cirrhosis J P H Byrne MRcpi, A M G Cochrane MRCP, D I Williams FRCP and R Williams FRCP (Kipg's College Hospital and Medical School, Denmark Hill, London SE5 9RS)
test, negative; antimitochondnal antibodies 1: 320 Barium swallow showed no cesophageal varices; Schirmer's test abnormal, suggesting keratoconjunctivitis sicca. Technetium scan showed hepatomegaly with a patchy uptake and increased For two years Mrs E S, aged 74, had a generalized splenic uptake. Chest X-ray was normal with no pruritus which was associated for the last year with evidence of hilar lymphadenopathy or fibrosis. a widespread sheeted papular eruption on the Skin biopsy (Fig 2), taken from the back, revealed trunk and limbs. On examination there was slight granulomata in the dermis consisting of monuclear generalized hyperpigmentation and a sheeted glis- cells, epithelioid cells and Langhan's type giant tening flesh-coloured papular eruption affecting cells. Liver biopsy (Dr B Portmann, Fig 3) showed the upper chest, back and arms (Fig 1). Liver changes consistent with primary biliary cirrhosis palpable 6 cm and spleen 3 cm below the costal (PBC), namely enlargement of portal tracts with ill-defined granulomata; focal collections of margin; no clinical jaundice or xanthelasma. lymphocytes and plasma cells around small bile Investigations: HB, 10.2 g/dl; WBC, 3000 cells/pl; ducts, the epithelial cells of which were swollen and platelets, 143 000/pl; ESR, 90 mm/hr; partial abnormal; piecemeal necrosis; and extensive thromboplastin time 16 s (control 13 s); bilirubin, fibrosis. 14 pmol/l; alkaline phosphatase, 850 iu/l (normal 30-85 iu/l); aspartate aminotransferase, 157 iu/l Treatment (normal 50 iu/l); IgM, 6.0 g/l (normal 0.5-1.7 g/l); One sachet of cholestyramine every day for prurIgG, 29.4 g/l (normal 5-16 g/l); IgA, 1.7 g/l (nor- itis; methyl cellulose eye drops and monthly inmal 1.4-4.2 g/1); Kveim test, negative; Mantoux jections of vitamins A, D and K. ~~~~~~~~~ra :
Fig 1 Extensive confluent papular eruption on the chest
Fig 3 Liver biopsy showing granulomata chronic inflammatory reaction around the bile ducts, piecemeal
necrosis andportal tract fibrosis
898
Proc. roy. Soc. Med. Volume 70 December 1977
Comment The presence of pruritus, hepatosplenomegaly, antimitochondrial antibodies, elevated IgM and alkaline phosphatase, and the histological appearances of the liver are all characteristic of PBC. The negative Kveim test, normal chest X-ray and serum calcium, and age of the patient are all against a diagnosis of sarcoidosis. The skin eruption is more compatible with a diagnosis of generalized granuloma annulare (Stankler & Leslie 1967) than with sarcoidosis or PBC. Granuloma annulare, a condition of unknown etiology, is characterized histologically by the presence of diffuse palisading granulomata surrounding areas of collagen necrosis. The clinical appearance of granuloma annulare is that of smooth firm papules which may coalesce to form rings or as widespread disseminated papules as in the present case. A relationship between the disseminated form and diabetes mellitus has been noted by Romaine et al. (1968). Recently, Dahl et al. (1977) noted the presence of deposits of immunoglobulin M, C3 and fibrin in the dermal blood vessels and at the dermoepidermal junction in cases of granuloma annulare, leading them to suggest that this condition may represent an immunoglobulinmediated chronic vasculitis. Although extrahepatic granulomata have been demonstrated in PBC in lung parenchyma, abdominal lymph nodes and the omentum (Stanley et al. 1972), to our knowledge granulomata in the skin have never been reported. To complicate interpretation even further, we have previously reported the association of PBC with Kveim positive sarcoidosis (Karlish et al. 1969) and have recently seen a further case. Dicken et al. (1969) mentioned a case of generalized granuloma annulare which also showed hepatic granulomata, and for this reason they favoured the diagnosis of sarcoidosis. Our patient's skin eruption is compatible with generalized granuloma annulare and the presence of granulomata is a feature common to both granuloma annulare and PBC. Although immunofluorescent studies of the skin and liver were not done in our patient, it is possible to hypothesize that circulating complexes involving IgM, which is elevated in PBC, lodge in the skin causing a vasculitis with subsequent granulomatous formation. Some support for this comes from a case report by Rai et al. (1977) in which they describe details of a woman with PBC who also had IgMassociated cutaneous capillaritis and membranous glomerulonephritis. They felt that immunological reactions in the skin may have been responsible for the pruritis. We are unable to explain satisfactorily the rapid disappearance of the eruption within a few days of starting cholestyramine therapy, as it was too rapid an effect to implicate a bile salt
lowering effect. Perhaps cholestyramine has an effect on immune complexes of which we are unaware. REFERENCES Dahl M V, Ullman S & Goltz R W (1977) Archives ofDermatology 113, 463-467 Dicken C H, Carrington S G & Winkelman R K (1969) Archives of Dermatology 99, 536-563 Karlish A J, Thompson R P H & Williams R (1969) Lancet ii, 599 Rai G S, Hamlyn A N, Dahl M G C, Morley A R & Wilkinson R (1977) British Medical Journal i, 817-819 Romaine R, Rudner E J & Altman J (1968) Archives ofDermatology 98, 152-154 Stankler L & Leslie G (1967) Archives of Dermatology 95, 509-513 Stanley N N, Fox R A, Whimster W F et al (1972) New England Journal of Medicine 287, 1283
Professor E Wilson Jones: If I had been shown this patient's slides without being given any clinical information, I would have diagnosed granuloma annulare with a fair degree of confidence. The only unusual aspect was the relatively large number of multinucleate giant cells, but these are sometimes a feature of granuloma annulare. I do not think that sarcoidosis is at all likely and I am unable to relate the skin problem to her primary biliary cirrhosis.
The following cases were also presented:
Xanthomata and Histiocytosis Dr J P H Byrne (for Dr R H Marten and Dr P J Watkins) (King's College Hospital, London SE5 9RS)
Cryptococcosis Dr E Cronin and Dr R McKenzie (St John's Hospitalfor Diseases of the Skin, Lisle Street, London WC2H 7BJ) Eosinophilic Fasciitis Dr M R Klaber (for Dr N A Thorne) (The London Hospital, London El 2AD) Necrobiotic Nodules Dr Joanna Ward (Charing Cross Hospital, London W6 8RF)
Sarcoidosis with Tenosynovitis and Widespread Cutaneous Involvement Dr D A Burns (for Dr I Sarkany) (Royal Free Hospital, London NW3 2QG) ? Lichen Planus or Lupus Erythematosus Dr T J Ryan
(Institute ofDermatology, London WC2) Essential Progressive Telangiectasia Dr S Peiris (for Dr R H Marten) (King's College Hospital, London SE5 9RS)
