COMMENTARY
LICHEN PLANUS AND THE LIVER ALEREDO REBORA, M.D.
progressively to cirrhosis. Serum transaminases, gammaglutamyl transpeptidases, and IgG may be elevated. Various autoantibodies help classification. Chronic active hepatitis is presently divided into autoimmune type 1 CAH (once named lupoid CAH) with antinuclear antibodies and liver membrane antibodies as markers; autoimmune type 2 witb liver-kidney-microsomal (LKM) antibodies; autoimmune type 3 with autoantibodies directed to a soluble liver antigen (LSA); and CAH associated with high titers of anti-smooth muscle or anti-actin antibodies (SMA). Actually, three kinds of antiLKM antibody can be detected: the anti-LKMl that is found in autoimmune CAH, the anti-LKM2 in ticrynafeninduced hepatitis, and the anti-LKM3 typical of the delta hepatitis. In addition, post-viral CAH follows acute viral hepatitis due to HBV, HCV, and other viruses.
The association of lichen planus (LP) with a chronic liver disease (CLD) that may result in cirrhosis has been reported with increasing frequency over the last decade. The largest work has been conducted by the Italian Group for Epidemiologic Studies in Dermatology (GISED) on 577 newly diagnosed LP patients and 1008 controls.' It confirmed tbat patients with a history of CLD or of acute viral hepatitis, and those who actually have high levels of transaminases or HBsAg present in their blood have at least double the risk of developing LP than the general population, irrespective of their age, sex, and alcohol consumption. In patients who underwent liver biopsy, sucb risk is more than five-fold higher. This study—while confirming that LP may be significantly accompanied by a CLD with a distinctive tendency to cirrhosis (cryptogenic cirrhosis was diagnosed in 7 LP patients |1.2%] versus 2 controls |0.27|) — failed to assess its real nature. In this article, I shall try to set the state of our knowledge on this topic, which, besides casting new light on the nature of the skin disease, may turn it into an invaluahle clue for prognosing and monitoring the liver disorder.
Primary Biliary Cirrhosis This is a chronic disease of unknown etiology in which mononucleates destroy the small intrahepatic bile ducts causing a progressive cholestasis. Along with the classic pattern of pruritus, skin pigmentation, and eventual jaundice, many oligosymptomatic patients exist. Serum alkaline phosphatase and IgM are almost invariably elevated. Anti-mitochondrial antibodies are present in 90% of cases and define two serologic subsets: one rather benign (anti-M9- and/or anti-M2-positive) and one progressive (anti-M2-, -M4- and -M8-positive). The detection of MHC class II antigens on bile duct epithelia and the analysis of cellular immune reaction in vitro and in vivo suggest an activation of cytotoxic T cells against an infectious agent.
CHRONIC LIVER DISEASES ASSOCIATED WITH LICHEN l'LANUS
A number of different chronic liver pathologies have been found to be associated with LP: chronic active hepatitis (CAM), primary biliary cirrbosis (PBC), primary sclerosing cholangitis (PSC), Wilson's disease, hemochromatosis, and alpha-1-antitrypsin deficiency. Chronic Active Hepatitis
Primary Sclerosing Cholangitis
This is a chronic inflammatory disease in which T-lymphocytes infiltrate the portal spaces and destroy the first lines of the surrounding hepatocytes devastating the normal architecture of the hepatic lobule in the very same way as lichenoid infiltrate damages epidermis. Phases of activity alternate with remissions (chronic persistent hepatitis), but tbe ensuing fibrosclerosis leads
This is a chronic cholestatic disease that frequently associates with ulcerative colitis (30%), Sjogren syndrome (40%), and Crohn's disease (13%), suggesting an immunologic pathogenesis. The process is due to inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts. Alkaline pbospbatase, gammaglutamyl transpeptidase, total and 7-alpha-hydroxylated bile acids in the blood, and copper in the urine are constantly elevated.
From the Department of Dermatology, University of Genoa School of Medicine, Genoa, Italy.
Miscellany
Address for correspondence: Alfredo Rebora, M.D., Department of Dermatology, University of Genoa School of Medicine, Genoa, Italy.
Hepatolenticular degeneration (Wilson's disease) is an autosomal recessive metabolic disorder of copper that ac392
Lichen Planus and the Liver Rebora
cumulates first in the liver and is then released in circulation, filling and damaging brain, cornea, bones, and kidneys through its toxic activity on enzymes, particularly on those with -SH groups. While young adults have neurologic ahnormalities, a nonspecific liver disease begins in infancy with symptoms of CAH and cirrhosis. Primary hemochromatosis is an inherited metabolic disease in which iron overloads the liver and heart resulting in cirrhosis and myocardial sclerosis. More than 90% of patients are men and often develop symptoms after the age of 40. An inborn deficiency of a-1-antitrypsin leading to at least a 40% decrease in its plasma level may occur in 1 in 1000 Europeans and result in an unimpeded elastolysis in major organs, especially the lung and liver. Fulminant juvenile cirrhosis or a slowly progressive liver damage, which may present in adult life as cirrhosis and occasionally as hepatoma, are possible outcomes.
eruption following HBV vaccination," and of association of LP witb hepatocarcinoma,'^ whose etiologic relationship with both HBV and HCV is well known. Recently, 87 LP patients have been screened for anti-HBV, anti-HCV, and anti-LKMl antibodies, which are said to accompany the false positive anti-HCV results.'-' Twenty-six (30%) patients had anti-HBV antibodies and 12 (14%) had antiHCV antibodies. Three patients were also HBsAg positive, and four had both anti-HBV and anti-HCV antibodies. Overall, 44% of LP patients had anti-HBV and/or -HCV antibodies; none had anti-LKMl antibodies. Anti-HBV antibodies were evenly distributed among LP patients irrespective of having CLD or not, whereas anti-HCV antibodies were significantly more frequent (47% versus 4%) in LP patients with CLD (Table 1). Primary Biliary Cirrhosis The association of PBC with LP was first reported in 1982,'''-'-'' but some patients had been treated with penicillamine, a drug that may cause exacerbation of existing LP. All of them, however, had antimitochondrial antibodies, as requested for diagnosis. Other anecdotal LP/PBC patients without any association with penicillamine were reported later,"'""* but their prevalence among LP patients must he exceedingly rare, at least in Latin countries, if the GISED study, for example, found one PBC in either LP patients or controls (0.2% vs. 0.1%).' In the aforementioned study,** no definite cases of PBC were found, and overall, clinical and laboratory findings described a CLD witb a definite prevalence of the signs of necrosis (transaminases and gamma-glutamyl transpeptidases) over those of cholestasis (bilirubinemia and alkaline phosphatase). IgM values were less frequently raised than IgC ones, and antimitochondrial antibodies were found only in a minority of cases versus more than 20% of anti-smooth muscle antibodies. Tbcse findings fulfilled CAH diagnostic criteria more closely than PBC ones. In a recent study on a very small series," antimitochondrial antibodies were found in 1 in 30 of ordinary LP patients; the positive patient had no liver disorder whatsoever. The main factor suggesting that LP may be noncoincidentally associated with PBC is the occurrence of a LPlike eruption and a PBC-like disorder in graft-verstishost disease (GVHD).-" In acute GVHD, skin is involved by a maculopapular pruritic rasb, often progressing to
EVIDENCE OE ASSOCIATION WITH LICHEN PLANUS
Autoimmune Chronic Active Hepatitis After the first papers,'-' several anecdotal cases associated LP and erosive LP with CAH. Later on, a retrospective study on 44 LP patients revealed that five (11.3%) had laboratory features and liver bioptic findings of CAH.'' A number of papers bave been published, only some of which, especially in Latin countries, confirm the association.-^ In the GlSF.D work,' 16 LP patients had their liver biopsied (2.8%) versus five controls (0.5%), and in three (0.5%) versus one (0.1%) was CAH diagnosed. Recently, several odontologic papers confirmed that LP of the oral mucosa has a peculiar tendency to be associated witb CAH.''-^ In particular, in Spain, an uncontrolled survey on 65 patients with oral LP revealed that 22 (33.8%) of them had clinical and analytic signs of CLD.'' Liver biopsy was performed on 17 patients, and CAH was found in two (3.1% at least), while PBC was not found. Cirrhosis was diagnosed in seven patients. In another study, 50 LP patients with CLD were studied by liver echograms and biopsies whenever possible and followed up for no less than 1 year.** Tbe disease proved to be severe enough to induce a decrease of prothrombinemia in 22% and of tbe tbrombocyte count in 34% of cases. Sonographic diagnoses were mild in most of the patients, although in 13 cases a severe chronic hepatopathy and in four of them CAH were signaled. With liver biopsy, CAH or CAH-cirrhosis were diagnosed in 7 of 12 cases.
Table 1. Prevalence of Anti-HBV and -HCV Antibodies Antibodies Anti-HBV
Post-Viral Chronic Active Hepatitis With CLD Without CLD Total
The prevalence of HBsAg in LP patients' has been mentioned before. In addition, there are reports of high prevalence of anti-HBV antibodies in LP patients,''-'" of LP
7 20 27
Anti-HCV
9 3 12
Negative 6 46 52
Total 68*
' 4 patients had both anti-lilic: and I lev Ah. c m = chronic liver disease.
393
International journal of Dermatology Vol. 31, No. 6, June 1992
ers LP as a multi-organ disease and the liver disorder as but a part of it. Whicb one of the liver epithelial cells is affected depends probably on tbe genetic predisposition and on the prevalence of the HBV or HCV infections in the geographic area. In areas where such infections are prevailing, the lichenoid attack may be mainly directed on the hepatocytes and results in CAH; elsewhere, the attack may be mostly directed on the intrahepatic biliary epitbelium and more rarely on the extrahepatic one, resulting in PBC or PSC. Other environmental factors may determine the end-result of the liver disease.
erythroderma. Liver dysfunction includes hyperbilirubinemia and increased alkaline phosphatase and aminotransferase values. Pathologic changes feature a selective epithelial damage of epidermis and intestinal crypts, and segmental disruption of small bile ducts. In chronic GVHD, the skin eruption affects 80% of patients and, initially, closely resembles LP with a cbronic cholestatic liver disease, occurring again in 80% of cases. Gastrointestinal involvement is rare, but a sicca syndrome is quite a constant feature. Primary Sclerosing Cholangitis One single patient bas been described with LP and PSC.^' The prevalence of such association is unknown.
REEERENCES
Miscellany
1.
One single patient with LP and Wilson's disease^^ had a probable relationship with a D-penicillamine treatment. Another patient has been reported with hemochromatosis,^^ and one had CLD possibly due to a-1-antitrypsin deficiency.^'*
2.
3. 4.
DISCUSSION
Growing evidence suggests that LP is a multi-organ disease involving at least skin, gut,^' and liver." CAH, PBC, and PSC, which have a similar pathology, are the liver diseases that may he associated noncoincidentally. GVHD is a good in vivo model of this process sharing the same visceral involvement and immunopathogenetic mechanism. This consists in the expression of MHC class II antigens by the epithelial cells that are then attacked and destroyed by activated T cells. The role of circulating antibodies is unclear, but they may activate an antibody-dependent cell cytotoxicity or may simply be directed to by-products of the epitheliocyte destruction. The cytolytic activity of suppressor T cells on target cells has heen recently challenged, and the role of soluble mediators, sucb as the tumor necrosis factor a released by T cells, bas been suggested.^" The origin of such a process is unknown, but the variety of hepatic disorders suggests that a number of antigenic determinants including drugs,^'' by-products of the liver damage, and those resulting from as different disorders as Wilson's disease, hemochromatosis, and a-1antitrypsin deficiency may induce LP as a stereotype skin reaction. Whether an infectious agent is active is still unclear, but strong suggestions come from the high prevalence of HBV and HCV infections among LP patients.**-" Anti-HCV antibodies have recently been found in up to 40% of CAH, but also in 42% of PBC and in 7% of PSC," though with remarkable geographic differences.^* The main question, namely whether PBC or CAH is associated with LP, though important from the therapeutic point of view, becomes irrelevant if one consid-
5.
6.
7.
8.
9.
10.
11. 12.
13.
14.
15.
394
Gruppo Italiano Studi Epidemiologici in Dermatologia. Lichen planus and liver disease: a multicentre case-control study. BMj 1990; 300:227-230. Rebora A, Patri PL, Rampini F, et al. Erosive lichen planus and cirrhotic hepatitis. Ital Gen Rev Dermatol 1978; 15:123-127. Rebora A. Lichen planus and the liver. Lancet 1981; ii: 805-806. Rongioletti F, Rebora A. Chronic active hepatitis and lichen planus. A retrospective survey. Acta Derm Venereol (Stockh) 1984; 64:52-56. Rebora A, Rongioletti F, Grosshans E. Le syndrome lichen-hepatite. Ann Dermatol Venereol 1985; 112: 27-32. Blanchereau C, Pulik M. Oral erosive lichen planus: think of chronic liver disease. Actual Odontostomatol (Paris) 1990; 44:89-94. Olmo JA del, Bagan JV, Rodrigo JM, et al. Oral lichen planus and hepatic cirrhosis. Ann Intern Med 1989; 110:666. Robert E, Rongioletti E, Rebora A. Clinical and laboratory features of 50 patients with lichen planus and a chronic liver disease. G Ital Dermatol Venereol 1991; 126:1-4. Cottoni F, Solinas A, Piga MR, et al. Lichen planus, chronic liver diseases, and immunologic involvement. Arch Dermatol Res 1 988; 280(suppl):S55-S60. Ayala F, Balato N, Santoianni P. Lichen planus and related disorders. A seven-year study. Ital Gen Rev Dermatol 1988; 25:49-54. Ciaccio M, Rebora A. Lichen planus following HBV vaccination: a coincidence? BrJ Dermatol 1990; \11A1A. Virgili A, Robert E, Rebora A. Hepatocellular carcinoma and lichen planus. Report of two cases. Dermatology 1992; 184:137-138. Divano MC, Parodi A, Rebora A. Lichen planus, liverkidney-microsomal antibodies and hepatitis C virus antibodies. Dermatology (in press). Graham Brown RA, Sarkany I, Sherlock S. Lichen planus and primary biliary cirrhosis. Br J Dermatol 1982; 106:699-703. Powell FC, Rogers RS, Dickson ER. Lichen planus, primary biliary cirrhosis and penicillamine. Br J Dermatol 1982; 107:617.
Lichen Planus and the Liver Rehora
Sowden IM, Cartwright PH, Green JR, Leonard JN. Isolated lichen planus of the nails associated with primary biliary cirrhosis. Br J Dermatol 1989; 121: 659-662. Strauss RA, Fattore L, Soltani K. The association of mucocutaneous lichen planus and chronic liver disease. Oral Surg Oral Med Oral Pathol 1989; 68:406-410.
23.
18.
Graham Brown RA, Sarkany I. Lichen sclerosus et atrophicus with primary biliary cirrhosis and lichen planus. IntJ Dermatol 1986; 25:317.
25.
19.
McDonagh AJ, Leyva-Leon F, Gawkrodger DJ, Ward AM. Lichen planus is not commonly a skin marker of primary biliary cirrhosis. Dermatologica 1990; 180:1 II.
26.
Ferrara JLM, Deeg HJ. Graft-versus-host disease. N Engl J Med 1991; 324:667-674. Jorge A, Findor J, Esley C, Brunch E. Primary sclerosing cholangitis. Z Gastroenterol 1988; 26:322-330.
27.
16.
17.
20. 21. 22.
24.
Solinas A, Tocco A, Deplano A, et al. Chronic hepatitis, immunopathology and relationship with lichen planus. Ital Gen Rev Dermatol 1988; 25:44-48.
28.
Ayala F, Balato N, Mazzanti R, Romanelli RG. Lichen planus and chronic hepatitis in a patient with a-l-antitrypsin deficiency. Ital Gen Rev Dermatol 1988; 25: 123-125. Rainero C, Dubois D, Lacour JPh, Ortonne JP. Association lichen cutaneo-muqueux erosif-hemochromatose primitive. lime rencontre franco-italienne de la Riviera de dermatologie clinique. Sanremo 1990. Abstracts, 57. Gruppo Italiano Studi Epidemiologici in Dermatologia. Fpidemiological evidence of the association between lichen planus and two immune-related diseases. Arch Dermatol 1991; 127:688-691. Kurumaji Y, Miyazaki K. Tiopronin-induced lichenoid eruption in a patient with liver disease and positive patch test reaction to drugs with sulphydryl group. J Dermatol 1990; 17:1 76-1 8'"i. Schrupf E, Elgjo K, Fausa O, et al. The significance of anti-hepatitis C virus antibodies measured in chronic liver disease. Scand J Gastroenterol 1990; 25:1 169-1174. Brind AM, Codd AA, Cohen BJ, et al. Low prevalence of antibody to hepatitis C virus in north east England. J Med Virol 1990; 32:243-248.
"Their own Agenda." Edward M. Shapiro, M.D., Houston, Texas. Oil painting—first place. American Academy of Dermatology Art Exhibit, Dallas, Texas, 1991. Photograph courtesy of Dermik Laboratories, Inc. 395
LICHEN PLANUS AND THE LIVER ALEREDO REBORA, M.D.
progressively to cirrhosis. Serum transaminases, gammaglutamyl transpeptidases, and IgG may be elevated. Various autoantibodies help classification. Chronic active hepatitis is presently divided into autoimmune type 1 CAH (once named lupoid CAH) with antinuclear antibodies and liver membrane antibodies as markers; autoimmune type 2 witb liver-kidney-microsomal (LKM) antibodies; autoimmune type 3 with autoantibodies directed to a soluble liver antigen (LSA); and CAH associated with high titers of anti-smooth muscle or anti-actin antibodies (SMA). Actually, three kinds of antiLKM antibody can be detected: the anti-LKMl that is found in autoimmune CAH, the anti-LKM2 in ticrynafeninduced hepatitis, and the anti-LKM3 typical of the delta hepatitis. In addition, post-viral CAH follows acute viral hepatitis due to HBV, HCV, and other viruses.
The association of lichen planus (LP) with a chronic liver disease (CLD) that may result in cirrhosis has been reported with increasing frequency over the last decade. The largest work has been conducted by the Italian Group for Epidemiologic Studies in Dermatology (GISED) on 577 newly diagnosed LP patients and 1008 controls.' It confirmed tbat patients with a history of CLD or of acute viral hepatitis, and those who actually have high levels of transaminases or HBsAg present in their blood have at least double the risk of developing LP than the general population, irrespective of their age, sex, and alcohol consumption. In patients who underwent liver biopsy, sucb risk is more than five-fold higher. This study—while confirming that LP may be significantly accompanied by a CLD with a distinctive tendency to cirrhosis (cryptogenic cirrhosis was diagnosed in 7 LP patients |1.2%] versus 2 controls |0.27|) — failed to assess its real nature. In this article, I shall try to set the state of our knowledge on this topic, which, besides casting new light on the nature of the skin disease, may turn it into an invaluahle clue for prognosing and monitoring the liver disorder.
Primary Biliary Cirrhosis This is a chronic disease of unknown etiology in which mononucleates destroy the small intrahepatic bile ducts causing a progressive cholestasis. Along with the classic pattern of pruritus, skin pigmentation, and eventual jaundice, many oligosymptomatic patients exist. Serum alkaline phosphatase and IgM are almost invariably elevated. Anti-mitochondrial antibodies are present in 90% of cases and define two serologic subsets: one rather benign (anti-M9- and/or anti-M2-positive) and one progressive (anti-M2-, -M4- and -M8-positive). The detection of MHC class II antigens on bile duct epithelia and the analysis of cellular immune reaction in vitro and in vivo suggest an activation of cytotoxic T cells against an infectious agent.
CHRONIC LIVER DISEASES ASSOCIATED WITH LICHEN l'LANUS
A number of different chronic liver pathologies have been found to be associated with LP: chronic active hepatitis (CAM), primary biliary cirrbosis (PBC), primary sclerosing cholangitis (PSC), Wilson's disease, hemochromatosis, and alpha-1-antitrypsin deficiency. Chronic Active Hepatitis
Primary Sclerosing Cholangitis
This is a chronic inflammatory disease in which T-lymphocytes infiltrate the portal spaces and destroy the first lines of the surrounding hepatocytes devastating the normal architecture of the hepatic lobule in the very same way as lichenoid infiltrate damages epidermis. Phases of activity alternate with remissions (chronic persistent hepatitis), but tbe ensuing fibrosclerosis leads
This is a chronic cholestatic disease that frequently associates with ulcerative colitis (30%), Sjogren syndrome (40%), and Crohn's disease (13%), suggesting an immunologic pathogenesis. The process is due to inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts. Alkaline pbospbatase, gammaglutamyl transpeptidase, total and 7-alpha-hydroxylated bile acids in the blood, and copper in the urine are constantly elevated.
From the Department of Dermatology, University of Genoa School of Medicine, Genoa, Italy.
Miscellany
Address for correspondence: Alfredo Rebora, M.D., Department of Dermatology, University of Genoa School of Medicine, Genoa, Italy.
Hepatolenticular degeneration (Wilson's disease) is an autosomal recessive metabolic disorder of copper that ac392
Lichen Planus and the Liver Rebora
cumulates first in the liver and is then released in circulation, filling and damaging brain, cornea, bones, and kidneys through its toxic activity on enzymes, particularly on those with -SH groups. While young adults have neurologic ahnormalities, a nonspecific liver disease begins in infancy with symptoms of CAH and cirrhosis. Primary hemochromatosis is an inherited metabolic disease in which iron overloads the liver and heart resulting in cirrhosis and myocardial sclerosis. More than 90% of patients are men and often develop symptoms after the age of 40. An inborn deficiency of a-1-antitrypsin leading to at least a 40% decrease in its plasma level may occur in 1 in 1000 Europeans and result in an unimpeded elastolysis in major organs, especially the lung and liver. Fulminant juvenile cirrhosis or a slowly progressive liver damage, which may present in adult life as cirrhosis and occasionally as hepatoma, are possible outcomes.
eruption following HBV vaccination," and of association of LP witb hepatocarcinoma,'^ whose etiologic relationship with both HBV and HCV is well known. Recently, 87 LP patients have been screened for anti-HBV, anti-HCV, and anti-LKMl antibodies, which are said to accompany the false positive anti-HCV results.'-' Twenty-six (30%) patients had anti-HBV antibodies and 12 (14%) had antiHCV antibodies. Three patients were also HBsAg positive, and four had both anti-HBV and anti-HCV antibodies. Overall, 44% of LP patients had anti-HBV and/or -HCV antibodies; none had anti-LKMl antibodies. Anti-HBV antibodies were evenly distributed among LP patients irrespective of having CLD or not, whereas anti-HCV antibodies were significantly more frequent (47% versus 4%) in LP patients with CLD (Table 1). Primary Biliary Cirrhosis The association of PBC with LP was first reported in 1982,'''-'-'' but some patients had been treated with penicillamine, a drug that may cause exacerbation of existing LP. All of them, however, had antimitochondrial antibodies, as requested for diagnosis. Other anecdotal LP/PBC patients without any association with penicillamine were reported later,"'""* but their prevalence among LP patients must he exceedingly rare, at least in Latin countries, if the GISED study, for example, found one PBC in either LP patients or controls (0.2% vs. 0.1%).' In the aforementioned study,** no definite cases of PBC were found, and overall, clinical and laboratory findings described a CLD witb a definite prevalence of the signs of necrosis (transaminases and gamma-glutamyl transpeptidases) over those of cholestasis (bilirubinemia and alkaline phosphatase). IgM values were less frequently raised than IgC ones, and antimitochondrial antibodies were found only in a minority of cases versus more than 20% of anti-smooth muscle antibodies. Tbcse findings fulfilled CAH diagnostic criteria more closely than PBC ones. In a recent study on a very small series," antimitochondrial antibodies were found in 1 in 30 of ordinary LP patients; the positive patient had no liver disorder whatsoever. The main factor suggesting that LP may be noncoincidentally associated with PBC is the occurrence of a LPlike eruption and a PBC-like disorder in graft-verstishost disease (GVHD).-" In acute GVHD, skin is involved by a maculopapular pruritic rasb, often progressing to
EVIDENCE OE ASSOCIATION WITH LICHEN PLANUS
Autoimmune Chronic Active Hepatitis After the first papers,'-' several anecdotal cases associated LP and erosive LP with CAH. Later on, a retrospective study on 44 LP patients revealed that five (11.3%) had laboratory features and liver bioptic findings of CAH.'' A number of papers bave been published, only some of which, especially in Latin countries, confirm the association.-^ In the GlSF.D work,' 16 LP patients had their liver biopsied (2.8%) versus five controls (0.5%), and in three (0.5%) versus one (0.1%) was CAH diagnosed. Recently, several odontologic papers confirmed that LP of the oral mucosa has a peculiar tendency to be associated witb CAH.''-^ In particular, in Spain, an uncontrolled survey on 65 patients with oral LP revealed that 22 (33.8%) of them had clinical and analytic signs of CLD.'' Liver biopsy was performed on 17 patients, and CAH was found in two (3.1% at least), while PBC was not found. Cirrhosis was diagnosed in seven patients. In another study, 50 LP patients with CLD were studied by liver echograms and biopsies whenever possible and followed up for no less than 1 year.** Tbe disease proved to be severe enough to induce a decrease of prothrombinemia in 22% and of tbe tbrombocyte count in 34% of cases. Sonographic diagnoses were mild in most of the patients, although in 13 cases a severe chronic hepatopathy and in four of them CAH were signaled. With liver biopsy, CAH or CAH-cirrhosis were diagnosed in 7 of 12 cases.
Table 1. Prevalence of Anti-HBV and -HCV Antibodies Antibodies Anti-HBV
Post-Viral Chronic Active Hepatitis With CLD Without CLD Total
The prevalence of HBsAg in LP patients' has been mentioned before. In addition, there are reports of high prevalence of anti-HBV antibodies in LP patients,''-'" of LP
7 20 27
Anti-HCV
9 3 12
Negative 6 46 52
Total 68*
' 4 patients had both anti-lilic: and I lev Ah. c m = chronic liver disease.
393
International journal of Dermatology Vol. 31, No. 6, June 1992
ers LP as a multi-organ disease and the liver disorder as but a part of it. Whicb one of the liver epithelial cells is affected depends probably on tbe genetic predisposition and on the prevalence of the HBV or HCV infections in the geographic area. In areas where such infections are prevailing, the lichenoid attack may be mainly directed on the hepatocytes and results in CAH; elsewhere, the attack may be mostly directed on the intrahepatic biliary epitbelium and more rarely on the extrahepatic one, resulting in PBC or PSC. Other environmental factors may determine the end-result of the liver disease.
erythroderma. Liver dysfunction includes hyperbilirubinemia and increased alkaline phosphatase and aminotransferase values. Pathologic changes feature a selective epithelial damage of epidermis and intestinal crypts, and segmental disruption of small bile ducts. In chronic GVHD, the skin eruption affects 80% of patients and, initially, closely resembles LP with a cbronic cholestatic liver disease, occurring again in 80% of cases. Gastrointestinal involvement is rare, but a sicca syndrome is quite a constant feature. Primary Sclerosing Cholangitis One single patient bas been described with LP and PSC.^' The prevalence of such association is unknown.
REEERENCES
Miscellany
1.
One single patient with LP and Wilson's disease^^ had a probable relationship with a D-penicillamine treatment. Another patient has been reported with hemochromatosis,^^ and one had CLD possibly due to a-1-antitrypsin deficiency.^'*
2.
3. 4.
DISCUSSION
Growing evidence suggests that LP is a multi-organ disease involving at least skin, gut,^' and liver." CAH, PBC, and PSC, which have a similar pathology, are the liver diseases that may he associated noncoincidentally. GVHD is a good in vivo model of this process sharing the same visceral involvement and immunopathogenetic mechanism. This consists in the expression of MHC class II antigens by the epithelial cells that are then attacked and destroyed by activated T cells. The role of circulating antibodies is unclear, but they may activate an antibody-dependent cell cytotoxicity or may simply be directed to by-products of the epitheliocyte destruction. The cytolytic activity of suppressor T cells on target cells has heen recently challenged, and the role of soluble mediators, sucb as the tumor necrosis factor a released by T cells, bas been suggested.^" The origin of such a process is unknown, but the variety of hepatic disorders suggests that a number of antigenic determinants including drugs,^'' by-products of the liver damage, and those resulting from as different disorders as Wilson's disease, hemochromatosis, and a-1antitrypsin deficiency may induce LP as a stereotype skin reaction. Whether an infectious agent is active is still unclear, but strong suggestions come from the high prevalence of HBV and HCV infections among LP patients.**-" Anti-HCV antibodies have recently been found in up to 40% of CAH, but also in 42% of PBC and in 7% of PSC," though with remarkable geographic differences.^* The main question, namely whether PBC or CAH is associated with LP, though important from the therapeutic point of view, becomes irrelevant if one consid-
5.
6.
7.
8.
9.
10.
11. 12.
13.
14.
15.
394
Gruppo Italiano Studi Epidemiologici in Dermatologia. Lichen planus and liver disease: a multicentre case-control study. BMj 1990; 300:227-230. Rebora A, Patri PL, Rampini F, et al. Erosive lichen planus and cirrhotic hepatitis. Ital Gen Rev Dermatol 1978; 15:123-127. Rebora A. Lichen planus and the liver. Lancet 1981; ii: 805-806. Rongioletti F, Rebora A. Chronic active hepatitis and lichen planus. A retrospective survey. Acta Derm Venereol (Stockh) 1984; 64:52-56. Rebora A, Rongioletti F, Grosshans E. Le syndrome lichen-hepatite. Ann Dermatol Venereol 1985; 112: 27-32. Blanchereau C, Pulik M. Oral erosive lichen planus: think of chronic liver disease. Actual Odontostomatol (Paris) 1990; 44:89-94. Olmo JA del, Bagan JV, Rodrigo JM, et al. Oral lichen planus and hepatic cirrhosis. Ann Intern Med 1989; 110:666. Robert E, Rongioletti E, Rebora A. Clinical and laboratory features of 50 patients with lichen planus and a chronic liver disease. G Ital Dermatol Venereol 1991; 126:1-4. Cottoni F, Solinas A, Piga MR, et al. Lichen planus, chronic liver diseases, and immunologic involvement. Arch Dermatol Res 1 988; 280(suppl):S55-S60. Ayala F, Balato N, Santoianni P. Lichen planus and related disorders. A seven-year study. Ital Gen Rev Dermatol 1988; 25:49-54. Ciaccio M, Rebora A. Lichen planus following HBV vaccination: a coincidence? BrJ Dermatol 1990; \11A1A. Virgili A, Robert E, Rebora A. Hepatocellular carcinoma and lichen planus. Report of two cases. Dermatology 1992; 184:137-138. Divano MC, Parodi A, Rebora A. Lichen planus, liverkidney-microsomal antibodies and hepatitis C virus antibodies. Dermatology (in press). Graham Brown RA, Sarkany I, Sherlock S. Lichen planus and primary biliary cirrhosis. Br J Dermatol 1982; 106:699-703. Powell FC, Rogers RS, Dickson ER. Lichen planus, primary biliary cirrhosis and penicillamine. Br J Dermatol 1982; 107:617.
Lichen Planus and the Liver Rehora
Sowden IM, Cartwright PH, Green JR, Leonard JN. Isolated lichen planus of the nails associated with primary biliary cirrhosis. Br J Dermatol 1989; 121: 659-662. Strauss RA, Fattore L, Soltani K. The association of mucocutaneous lichen planus and chronic liver disease. Oral Surg Oral Med Oral Pathol 1989; 68:406-410.
23.
18.
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"Their own Agenda." Edward M. Shapiro, M.D., Houston, Texas. Oil painting—first place. American Academy of Dermatology Art Exhibit, Dallas, Texas, 1991. Photograph courtesy of Dermik Laboratories, Inc. 395
