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Human Antibodies 22 (2013) 87–93 DOI 10.3233/HAB-140275 IOS Press
Autoimmune hepatitis in a Jamaican cohort spanning 40 years Karen Roye-Greena,∗, Rohan Willisa , Nathlee Mc Morrisa , Jacqueline Dawsona, Dwight Whittleb , Everard Bartonb and Monica Smiklea a
b
Departments of Microbiology, The University of the West Indies, Mona, Jamaica, West Indies Departments of Medicine, The University of the West Indies, Mona, Jamaica, West Indies
Abstract. BACKGROUND: The prevalence and characteristics of autoimmune hepatitis (AIH) in black populations are not well documented. OBJECTIVES: To describe the clinical and laboratory features of AIH in patients presenting at a Jamaican hospital, 1969–2009. METHODS: A retrospective review of hospital records was done and patients were classified by the revised international scoring system. RESULTS: Fifty patients satisfied criteria for diagnosis of AIH type-1 and most presented late at hospital. Almost one third of cases presented with chronic liver disease (32%) while 8% presented with fulminant hepatic failure and 2% with acute liver disease. Jaundice (92%) was the most common presenting feature. Other associated autoimmune diseases (10%) systemic lupus erythematosus and insulin dependent diabetes mellitus, were found. All patients (100%) had abnormal liver biochemical tests, 81% had hypergammaglobulinaemia and 82% AIH associated autoantibodies. The prevalence of autoantibodies increased with age (P = 0.05). Liver biopsy, performed in 33 cases, showed chronic hepatitis (45%), cirrhosis (24%) chronic hepatitis with bridging necrosis (15%), chronic hepatitis with rosetting (6%) and nonspecific findings (10%). Patients were treated with prednisone with or without azathioprine. Relapse occurred in 4% and death 6%. CONCLUSION: Autoimmune hepatitis is rare in Jamaicans and prognosis is similar to that reported in developed countries. Keywords: Autoimmune hepatitis, antinuclear antibodies, smooth muscle antibodies, scoring system, Jamaica
1. Introduction Autoimmune hepatitis (AIH) is characterized by female predominance, presence of liver specific and non-liver specific autoantibodies, hypergammaglobulinaemia and periportal hepatitis. Most patients show good response to immunosuppressive therapy but the disease can progress to cirrhosis and liver failure despite immunosuppressive treatment. Autoimmune hepatitis may be defined as an unresolving inflamma∗ Corresponding author: Karen Roye-Green, Microbiology Department, The University of the West Indies, Mona, Kingston 7, Jamaica, West Indies. Tel.: 876 9772206; Fax: 876 977 9553; E-mail: [email protected].
tion and necrosis of the liver of unknown aetiology. However both environmental and genetic factors are thought to be involved. When the diagnosis of AIH is made it is implied that there is the exclusion of hepatitis of known causes [8,15,16,20]. Autoimmune hepatitis may be associated with other autoimmune diseases. Much of what is known about AIH was derived from studies involving patients of European Caucasoid or Japanese extraction though the disease affects other ethnic groups. The available information indicates that there is diversity in the prevalence, presenting features and outcome of AIH in different ethnic groups. Consequently it has been suggested that diagnostic criteria developed in Caucasian populations may not apply in different ethnic groups and geographical regions [7,8,13,15,30,35].
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K. Roye-Green et al. / Autoimmune hepatitis in a Jamaican cohort spanning 40 years
Accurate diagnosis of AIH is critical since prompt institution of immunosuppressive agents can be lifesaving [8]. Investigations to exclude other causes of chronic liver disease should be performed in patients with suspected AIH. There is now a revised scoring system that allows a reproducible and standardized approach to diagnose AIH as definite and probable cases [15,16]. Recently a simplified diagnostic scoring system was added to ease clinical application [13]. It has been reported that the revised original scoring system has greater sensitivity for diagnosis of AIH whereas the simplified scoring system has superior specificity and accuracy [8]. Autoimmune hepatitis may be further classified as types 1 and 2 based on autoantibody profile. Type 1, the predominant form is characterized by the presence of antinuclear (ANA) and anti-smooth muscle antibodies (ASMA) whereas type 2 is defined by the absence of these antibodies and the presence of liver kidney microsomal antibody – type1(LKM-1) and anti-cytosol antibody type-1(LCI1). Type 2 AIH is thought to occur mainly in children [1,8,20]. Jamaica is a developing country, with a predominantly Black population of 2.7 million. In this paper we report on the features of AIH in patients who presented at a Jamaican hospital over a 40 year period.
Table 1 Age distribution of 50 patients with autoimmune hepatitis (AIH) in Jamaica Age group (years) 0–14 15–20 21–30 31–40 >40
AIH cases Definite Probable 10 7 4 5 5 2 1 4 3 9
Total 17 9 7 5 12
ing double immunodiffusion tests [12,27]. Sera were screened for hepatitis A, B, and C virus infection by commercially prepared enzyme immunoassays (Abbott Diagnostics, Abbott Park), and also by counterimmunoelectrophoresis (CIE) in case of hepatitis B [24]. Serum total globulin, immunoglobulin concentrations, routine liver function tests and haematological parameters including complete blood counts (CBC), erythrocyte sedimentation rate (ESR), prothrombin time (PT), partial thromboplastin time (PTT) were determined by standard procedures using commercially available reagents and automated systems [4, 14]. Abdominal ultrasound was done. Percutaneous needle liver biopsy was done when possible based on clinical and laboratory parameters. 2.1. Statistical analysis
2. Materials and methods The study was conducted at the University Hospital of the West Indies (UHWI), a tertiary referral hospital, situated in Kingston Jamaica, after ethical approval was obtained. The hospital records of patients with autoimmune liver disease who presented at the hospital between 1969–2009 were reviewed, retrospectively. A standardized data abstraction form was used to collect data pertaining to demographic, clinical and laboratory parameters in each patient. The revised scoring system developed by the International Autoimmune Hepatitis Group (IAIHG) was used to classify patients as having definite or probable autoimmune hepatitis [15]. Immunofluorescence tests (IFT) were used to detect antinuclear antibodies (ANA), smooth muscle antibodies (SMA), liver kidney microsomal (LKM), antineutrophil cytoplasmic antibodies (ANCA) and antimitochondrial antibodies (AMA) in serum samples collected from each patient [13,18,33]. The ANA positive sera were tested for anti-dsDNA antibody using the Farr assay or Crithidia luciliae-IFT and antibodies to extractable nuclear antigens (ENA) us-
Data were analyzed using SPSS. Version 8 software and compared by Chi square analysis and Fisher’s exact test as necessary.
3. Results Of 64 patients with autoimmune liver disease seen at UHWI during the 40 year period under review 50 patients fulfilled the revised scoring system proposed by IAIHG for diagnosis of definite or probable AIH. The 14 patients who did not meet the criteria for diagnosis of AIH included 6 patients who had serological evidence of viral hepatitis with positive autoantibody tests, 3 patients with AMA and 7 patients whose laboratory investigations were inadequate. These 14 patients were excluded from further analysis. Of 50 patients who met the IAIHG criteria for diagnosis 22 (44%) patients were classified as definite (pre-treatment score > 15) and the remaining 28 (56%) probable (pre-treatment score 10–15) cases of AIH. The demographic and clinical features of the 50 patients with definite or probable AIH are sum-
K. Roye-Green et al. / Autoimmune hepatitis in a Jamaican cohort spanning 40 years Table 2 Clinical features at presentation in 50 patients with autoimmune hepatitis (AIH) Symptoms and signs Abdominal pain Vomiting Diarrhoea Pruritus Anorexia Weight loss Arthralgia Jaundice Ascites Peripheral oedema Encephalopathy Fever Hepatomegaly Splenomegaly Sickle cell anaemia Syncopy Oesphageal varices Dark urine/hematuria Melena Myalgia Glomerulonephritis Lymphadenopathy Pancreatitis Peritonitis Pulmonary embolism Bronchopneumonia
Number (%) 22 (44) 18 (36) 3 (6) 9 (18) 3 (6) 3 (6) 5 (10) 46 (92) 20 (40) 1 (2) 4 (8) 5 (10) 7 (14) 7 (14) 4 (8) 1 (2) 9 (18) 10 (20) 1 (2) 1 (2) 7 (14) 2 (4) 1 (2) 1 (2) 3 (6) 2 (4)
marized in Tables 1 and 2, respectively. As shown in Table 1, the mean age at diagnosis was 28.6 years (range 11 months- 69 years), the majority were female (39/50,78%; female: male ratio 3.6:1) and about a third (17/50, 34%) of cases were diagnosed in children who were 14 years of age and under. The mean duration of symptoms at presentation (shown in Table 2) was 4.3 years (range 1 month −23 years). The most common presenting clinical features among the 50 patients were jaundice (92%), abdominal pain (44%), ascites (40%) and vomiting (36%) (also shown in Table 2). Sixteen (32%) patients presented with chronic liver disease, 4 (8%) with fulminant hepatic failure and 1 (2%) as acute liver disease. Oesophageal varices with variceal haemorrhage were present in 18% of patients on presentation and this reflects the number of patients diagnosed with chronic liver disease. Concurrent other autoimmune diseases were observed in 5 (10%) patients including 3 (6%) patients with systemic lupus erythematosus (SLE) and 2 (4%) patients with insulin dependent diabetes mellitus (IDDM). Other underlying conditions noted were sickle cell disease in 3 (6%) patients and paediatric acquired immunodeficiency syndrome (PAIDS) in 1 (2%) patient.
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Table 3 Laboratory findings in 50 patients with autoimmune hepatitis∗ Frequency of laboratory parameter Liver function test (38) Normal 0 Abnormal 38 White blood count (34) Normal 19 Elevated 10 Decreased 4 Increased PT/PTT 12 Serum complement C3/C4 (2) Decreased 2 Erythrocyte sedimentation rate (12) Elevated 8 Normal 4 Total serum globulin (32) Elevated 23 Normal 9 Serum immunoglobulin IgG (21) Elevated 16 Normal 5 Serum immunoglobulin IgA (21) Elevated 1
ANA 25/44 ASMA 18/33 GPA 2/33 P -ANCA 14/29 C -ANCA 2/29 Rheumatoid Factor 2/25 Liver Histology (30) No evidence of CAH 0 Evidence of CAH 13 Abdominal ultrasound (18) Normal 7 Abnormal 11
Numbers in parentheses are available totals. ANA = antinuclear antibody, ASMA = anti-smooth muscle antibody, GPA = gastric parietal cell antibody, ANCA = antineutrophil cytoplasmic antibody, CAH = chronic active hepatitis.
The laboratory parameters are shown in Table 3. All patients (38/38, 100%), for whom these results were available, had abnormal liver function tests, 72% (23/32) elevated total serum globulin and 81% (17/21) had hypergammaglobulinaemia. The results of autoantibody testing performed on sera were available for 44 (88%) patients of whom 36 (82%) were positive for at least 1 autoantibody. The prevalence of ANA (57%, 25/44), ASMA (18/33, 55%) and ANCA (16/29, 55%, including 14 patients with p-ANCA and 2 with cANCA) were comparable. As shown in Table 4 an increasing trend in the prevalence of autoantibodies with age (p = 0.05) was observed. The ANCA did not occur without ANA or SMA in serum from any patient. Sera from 2 patients had significant, low titre of rheumatoid factor. Gastric parietal cell antibodies (GPA) were present in serum samples from 2 patients. Of 50 patients with AIH 33 (66%) underwent liver biopsy including 30 patients who had liver biopsy before treatment and 3 patients who had liver biopsy after coagulation tests became normal. Repeat liver biopsy was done in 15% (5/33) of patients. Liver histology showed chronic hepatitis in 45% (15/33), cirrhosis in 24% (8/33), chronic hepatitis with bridging necrosis in 15% (5/33) and chronic hepatitis with rosetting in 6% (2/33) while biopsy findings were nonspecific in the remaining 10% (3/33) of patients. The available
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Table 4 Prevalence of autoantibodies in 44 cases of autoimmune hepatitis (AIH) by age Age group (N) 0–14 (17) 15–30 (13) > 31 (14) Total 44
Autoantibody positive (%) 13 (78) 10 (77) 13 (93) 36 (82)
data on treatment of AIH showed that 21 patients were started on prednisone to which azathioprine was added in 10 patients. Relapse was noted in 4% (2/50) of patients. Death was noted for 3 (6%) patients including the PAIDS patient whose AIH was observed to have followed a rapidly severe course, an adult patient who succumbed to hepatic encephalopathy 10 years after diagnosis of AIH and follow-up management, the third patient was an adult who died 3 days after presenting to hospital . There was no record of any patient receiving a liver transplant but 1 patient had cholecystectomy. There also was no record of hepatocellular carcinoma (HCC) among the 50 cases of AIH.
4. Discussion As reported with most populations autoimmune hepatitis appears to be rare in Jamaicans considering that only 50 cases were identified from our hospital records over a 40 year period [35]. Epidemiologic studies have been limited however in the United States prevalence rates of less than 5/100,000 population have been reported for chronic active hepatitis. Likewise it has also been reported that the incidence of type 1 AIH among Caucasoid populations of Europe and North America ranges from 0.1 to 1.9/100,000 per year and that the disease is considerably less frequent in Japan [2,6]. On the other hand some of the highest prevalence rates of AIH have been reported in aboriginal North Americans and these were much higher compared the Norwegian population [2,25]. The cohort of AIH patients reported in the present study are representative of those who presented with clinical disease and were seen at a tertiary care hospital. Asymptomatic and milder forms of AIH have been described which may progress if untreated but improve quickly with therapy. It now appears that AIH is asymptomatic in a substantial proportion of patients at presentation and that an even higher proportion of individuals have mild disease [1,8,15, 35]. In one study in Alaskan natives it was noted that persons presenting with mild disease or no symptoms were more likely to have moderate to severe fibrosis on
liver biopsy compared to those presenting with jaundice [10]. In the present study AIH was identified in Jamaicans of all age groups with comparable frequencies. However the mean age at presentation was younger than that reported in Caucasoid series. Certain non- white groups of patients including African- American, South American, African and Asian were observed to be younger than their white counterparts at presentation. However in one relatively large multiethnic cohort which included Whites, Hispanics and Asians age at diagnosis was similar among all groups [7,8,15,17,19, 35]. The reported female predominance in AIH also was observed as female out-numbered male patients almost 4 folds [7,8,10,17,25,35]. The tendency for late presentation at hospital, in keeping with the insidious onset of disease, had been observed in Western countries and was also evident in the present study [7,15,23,30]. A substantial proportion of patients had manifestations of advanced liver disease at presentation and this finding is in agreement with previous reports on AIH in certain non-caucasoid ethnic groups. In contrast Japanese patients are reported to have typically mild late onset disease [7,8,10, 17,25,35]. The prevalence of cirrhosis at presentation in the Jamaican patients, being 23%, was much closer to the 29–38% reported in Caucasian and Asians than the 85% prevalence rate reported in Afro-Americans with AIH [7,8,17,31,35]. While cirrhosis correlates with poorer outcomes in most studies other large studies of AIH have shown that the presence of cirrhosis at diagnosis did not decrease long term survival expectations [7,12]. The prevalence of jaundice, in this Jamaican cohort, at presentation was over 90%. This figure was much higher than that observed in European and North American Caucasian series. It is also higher than that reported in cohorts from Iran and India where jaundice was reported in 60% and 55% of patients, respectively [22,34]. The prevalence of other characteristic presenting clinical features of AIH were in accordance with published reports [16,17]. The laboratory results were mostly comparable with those documented for AIH in other ethnic groups [13, 15,16,35]. Abnormal liver function tests were the most common laboratory finding at presentation. Elevated serum globulin concentration was common and in resource constrained settings this test might be considered a useful, inexpensive screening test or surrogate of the IgG mediated hypergammaglobulinaemia which is characteristic of AIH. The prevalence of ANA.
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Fig. 1. Age group distribution of autoantibodies in patients with AIH. (Colours are visible in the online version of the article; http://dx.doi.org/ 10.3233/HAB-140275)
ASMA and LKM-1, the classical autoantibodies observed in this Jamaican series was similar to that reported other ethnic groups and the 87% prevalence reported in Caucasian patients with AIH [8,29]. However the significant increasing prevalence of autoantibodies with age and the tendency for older patients to have ASMA, as far as we are aware, have not been reported in other studies of AIH. These findings are not readily explained as autoantibodies are not believed to have a pathogenic role in AIH. Autoantibody negative cases of AIH have been recognized as a non-classical phenotype in which patients are clinically indistinguishable from those with classical disease, including HLAtypes, and also respond to corticosteroids [8]. In the general healthy population there is also an increasing prevalence of autoantibodies with age. Previous studies have shown that ANA are rarely found in healthy Jamaicans whereas ASMA are more common, appearing in similar prevalence and distribution compared to other ethnic groups [27]. Based on autoantibody profile type 1 AIH was present in over 80% of patients and type 2 was not identified in our series of patients. Although childhood cases of AIH were well represented, cases of type 2 AIH were not identified. The observation that the classical autoantibodies were less prevalent in children 14 years and under and that ANCA, included in the revised AIHIG criteria, was more common in this age group warrants further autoantibody studies in patients in this age group to confirm the absence of type 2 AIH [15].
Type 2 AIH is reported to be rare in North Americans and is also less common in certain European populations compared to others but appears to be represented in a short series of AIH of non- European Caucasoid ethnic origin described by Zolfino et al. [17,35] Autoimmune thyroiditis, synovitis, ulcerative colitis, coeliac disease, Sjögrens syndrome, autoimmune diabetes and various rheumatic conditions have been reported as concurrent extrahepatic autoimmune disorders in 17–48% of patients with AIH [8,26,35]. Systemic lupus erythematosus and insulin dependent diabetes mellitus were the associated other autoimmune disorders found in this series of Jamaican patients with AIH. This finding was not entirely surprising as SLE is not uncommon in Jamaica and previous studies have pointed to common genetic predisposing factors to both organ specific and non-organ specific autoimmune disease in Jamaicans [21,28]. An additional 2 patients tested positive for rheumatoid factors yet systemic rheumatic disease was not documented in these patients. The tendency for extrahepatic autoimmune disorders and the genetic predisposing factors in AIH have been discussed [8,35]. Untreated AIH progresses to liver cirrhosis with resulting liver failure which needs liver transplantation [7]. Recent reviews have emphasized that AIH responds to immunosuppressive treatment, whatever the degree of liver impairment [7]. None of the patients in our study received liver transplantation. Only 3 patients were documented as having died. This mortality rate is similar to that observed in Hispanics and
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Whites but is lower than that reported in Asians in one multi-ethnic study in the US [7,8]. One study involving patients of African descent with a high prevalence of cirrhosis reported that the response to therapy is good although higher doses of prednisone were required to maintain remission. Similarly a smaller study involving fewer Black patients also suggested that management of such patients is challenging and may require alternative or more aggressive treatment strategies [7, 17]. Although the standard treatment regimens for AIH were followed the available data do not allow the authors to comment further on response to therapy in this Jamaican cohort. There was no reported incidence of associated HCC in the 50 patients. This is consistent with the notion that progress to HCC is rare in AIH unlike that of other chronic liver diseases [21]. Some limitations of the study include its retrospective design and the attending drawbacks including missing hospital records, the extensive time period of the review during which there was continuing improvement in clinical and laboratory services at our hospital. For example, certain types of autoantibody testing were more recently introduced. In conclusion the clinical, laboratory and epidemiological features of autoimmune liver disease in Jamaica are similar to that observed in developed countries. Important areas of concern include the late stage at which some patients presented at hospital. Prospective follow-up studies are needed to assess progress, outcome and the place of liver transplant in Jamaicans with AIH.
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Human Antibodies 22 (2013) 87–93 DOI 10.3233/HAB-140275 IOS Press
Autoimmune hepatitis in a Jamaican cohort spanning 40 years Karen Roye-Greena,∗, Rohan Willisa , Nathlee Mc Morrisa , Jacqueline Dawsona, Dwight Whittleb , Everard Bartonb and Monica Smiklea a
b
Departments of Microbiology, The University of the West Indies, Mona, Jamaica, West Indies Departments of Medicine, The University of the West Indies, Mona, Jamaica, West Indies
Abstract. BACKGROUND: The prevalence and characteristics of autoimmune hepatitis (AIH) in black populations are not well documented. OBJECTIVES: To describe the clinical and laboratory features of AIH in patients presenting at a Jamaican hospital, 1969–2009. METHODS: A retrospective review of hospital records was done and patients were classified by the revised international scoring system. RESULTS: Fifty patients satisfied criteria for diagnosis of AIH type-1 and most presented late at hospital. Almost one third of cases presented with chronic liver disease (32%) while 8% presented with fulminant hepatic failure and 2% with acute liver disease. Jaundice (92%) was the most common presenting feature. Other associated autoimmune diseases (10%) systemic lupus erythematosus and insulin dependent diabetes mellitus, were found. All patients (100%) had abnormal liver biochemical tests, 81% had hypergammaglobulinaemia and 82% AIH associated autoantibodies. The prevalence of autoantibodies increased with age (P = 0.05). Liver biopsy, performed in 33 cases, showed chronic hepatitis (45%), cirrhosis (24%) chronic hepatitis with bridging necrosis (15%), chronic hepatitis with rosetting (6%) and nonspecific findings (10%). Patients were treated with prednisone with or without azathioprine. Relapse occurred in 4% and death 6%. CONCLUSION: Autoimmune hepatitis is rare in Jamaicans and prognosis is similar to that reported in developed countries. Keywords: Autoimmune hepatitis, antinuclear antibodies, smooth muscle antibodies, scoring system, Jamaica
1. Introduction Autoimmune hepatitis (AIH) is characterized by female predominance, presence of liver specific and non-liver specific autoantibodies, hypergammaglobulinaemia and periportal hepatitis. Most patients show good response to immunosuppressive therapy but the disease can progress to cirrhosis and liver failure despite immunosuppressive treatment. Autoimmune hepatitis may be defined as an unresolving inflamma∗ Corresponding author: Karen Roye-Green, Microbiology Department, The University of the West Indies, Mona, Kingston 7, Jamaica, West Indies. Tel.: 876 9772206; Fax: 876 977 9553; E-mail: [email protected].
tion and necrosis of the liver of unknown aetiology. However both environmental and genetic factors are thought to be involved. When the diagnosis of AIH is made it is implied that there is the exclusion of hepatitis of known causes [8,15,16,20]. Autoimmune hepatitis may be associated with other autoimmune diseases. Much of what is known about AIH was derived from studies involving patients of European Caucasoid or Japanese extraction though the disease affects other ethnic groups. The available information indicates that there is diversity in the prevalence, presenting features and outcome of AIH in different ethnic groups. Consequently it has been suggested that diagnostic criteria developed in Caucasian populations may not apply in different ethnic groups and geographical regions [7,8,13,15,30,35].
c 2013 – IOS Press and the authors. All rights reserved ISSN 1093-2607/13/$27.50
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Accurate diagnosis of AIH is critical since prompt institution of immunosuppressive agents can be lifesaving [8]. Investigations to exclude other causes of chronic liver disease should be performed in patients with suspected AIH. There is now a revised scoring system that allows a reproducible and standardized approach to diagnose AIH as definite and probable cases [15,16]. Recently a simplified diagnostic scoring system was added to ease clinical application [13]. It has been reported that the revised original scoring system has greater sensitivity for diagnosis of AIH whereas the simplified scoring system has superior specificity and accuracy [8]. Autoimmune hepatitis may be further classified as types 1 and 2 based on autoantibody profile. Type 1, the predominant form is characterized by the presence of antinuclear (ANA) and anti-smooth muscle antibodies (ASMA) whereas type 2 is defined by the absence of these antibodies and the presence of liver kidney microsomal antibody – type1(LKM-1) and anti-cytosol antibody type-1(LCI1). Type 2 AIH is thought to occur mainly in children [1,8,20]. Jamaica is a developing country, with a predominantly Black population of 2.7 million. In this paper we report on the features of AIH in patients who presented at a Jamaican hospital over a 40 year period.
Table 1 Age distribution of 50 patients with autoimmune hepatitis (AIH) in Jamaica Age group (years) 0–14 15–20 21–30 31–40 >40
AIH cases Definite Probable 10 7 4 5 5 2 1 4 3 9
Total 17 9 7 5 12
ing double immunodiffusion tests [12,27]. Sera were screened for hepatitis A, B, and C virus infection by commercially prepared enzyme immunoassays (Abbott Diagnostics, Abbott Park), and also by counterimmunoelectrophoresis (CIE) in case of hepatitis B [24]. Serum total globulin, immunoglobulin concentrations, routine liver function tests and haematological parameters including complete blood counts (CBC), erythrocyte sedimentation rate (ESR), prothrombin time (PT), partial thromboplastin time (PTT) were determined by standard procedures using commercially available reagents and automated systems [4, 14]. Abdominal ultrasound was done. Percutaneous needle liver biopsy was done when possible based on clinical and laboratory parameters. 2.1. Statistical analysis
2. Materials and methods The study was conducted at the University Hospital of the West Indies (UHWI), a tertiary referral hospital, situated in Kingston Jamaica, after ethical approval was obtained. The hospital records of patients with autoimmune liver disease who presented at the hospital between 1969–2009 were reviewed, retrospectively. A standardized data abstraction form was used to collect data pertaining to demographic, clinical and laboratory parameters in each patient. The revised scoring system developed by the International Autoimmune Hepatitis Group (IAIHG) was used to classify patients as having definite or probable autoimmune hepatitis [15]. Immunofluorescence tests (IFT) were used to detect antinuclear antibodies (ANA), smooth muscle antibodies (SMA), liver kidney microsomal (LKM), antineutrophil cytoplasmic antibodies (ANCA) and antimitochondrial antibodies (AMA) in serum samples collected from each patient [13,18,33]. The ANA positive sera were tested for anti-dsDNA antibody using the Farr assay or Crithidia luciliae-IFT and antibodies to extractable nuclear antigens (ENA) us-
Data were analyzed using SPSS. Version 8 software and compared by Chi square analysis and Fisher’s exact test as necessary.
3. Results Of 64 patients with autoimmune liver disease seen at UHWI during the 40 year period under review 50 patients fulfilled the revised scoring system proposed by IAIHG for diagnosis of definite or probable AIH. The 14 patients who did not meet the criteria for diagnosis of AIH included 6 patients who had serological evidence of viral hepatitis with positive autoantibody tests, 3 patients with AMA and 7 patients whose laboratory investigations were inadequate. These 14 patients were excluded from further analysis. Of 50 patients who met the IAIHG criteria for diagnosis 22 (44%) patients were classified as definite (pre-treatment score > 15) and the remaining 28 (56%) probable (pre-treatment score 10–15) cases of AIH. The demographic and clinical features of the 50 patients with definite or probable AIH are sum-
K. Roye-Green et al. / Autoimmune hepatitis in a Jamaican cohort spanning 40 years Table 2 Clinical features at presentation in 50 patients with autoimmune hepatitis (AIH) Symptoms and signs Abdominal pain Vomiting Diarrhoea Pruritus Anorexia Weight loss Arthralgia Jaundice Ascites Peripheral oedema Encephalopathy Fever Hepatomegaly Splenomegaly Sickle cell anaemia Syncopy Oesphageal varices Dark urine/hematuria Melena Myalgia Glomerulonephritis Lymphadenopathy Pancreatitis Peritonitis Pulmonary embolism Bronchopneumonia
Number (%) 22 (44) 18 (36) 3 (6) 9 (18) 3 (6) 3 (6) 5 (10) 46 (92) 20 (40) 1 (2) 4 (8) 5 (10) 7 (14) 7 (14) 4 (8) 1 (2) 9 (18) 10 (20) 1 (2) 1 (2) 7 (14) 2 (4) 1 (2) 1 (2) 3 (6) 2 (4)
marized in Tables 1 and 2, respectively. As shown in Table 1, the mean age at diagnosis was 28.6 years (range 11 months- 69 years), the majority were female (39/50,78%; female: male ratio 3.6:1) and about a third (17/50, 34%) of cases were diagnosed in children who were 14 years of age and under. The mean duration of symptoms at presentation (shown in Table 2) was 4.3 years (range 1 month −23 years). The most common presenting clinical features among the 50 patients were jaundice (92%), abdominal pain (44%), ascites (40%) and vomiting (36%) (also shown in Table 2). Sixteen (32%) patients presented with chronic liver disease, 4 (8%) with fulminant hepatic failure and 1 (2%) as acute liver disease. Oesophageal varices with variceal haemorrhage were present in 18% of patients on presentation and this reflects the number of patients diagnosed with chronic liver disease. Concurrent other autoimmune diseases were observed in 5 (10%) patients including 3 (6%) patients with systemic lupus erythematosus (SLE) and 2 (4%) patients with insulin dependent diabetes mellitus (IDDM). Other underlying conditions noted were sickle cell disease in 3 (6%) patients and paediatric acquired immunodeficiency syndrome (PAIDS) in 1 (2%) patient.
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Table 3 Laboratory findings in 50 patients with autoimmune hepatitis∗ Frequency of laboratory parameter Liver function test (38) Normal 0 Abnormal 38 White blood count (34) Normal 19 Elevated 10 Decreased 4 Increased PT/PTT 12 Serum complement C3/C4 (2) Decreased 2 Erythrocyte sedimentation rate (12) Elevated 8 Normal 4 Total serum globulin (32) Elevated 23 Normal 9 Serum immunoglobulin IgG (21) Elevated 16 Normal 5 Serum immunoglobulin IgA (21) Elevated 1
ANA 25/44 ASMA 18/33 GPA 2/33 P -ANCA 14/29 C -ANCA 2/29 Rheumatoid Factor 2/25 Liver Histology (30) No evidence of CAH 0 Evidence of CAH 13 Abdominal ultrasound (18) Normal 7 Abnormal 11
Numbers in parentheses are available totals. ANA = antinuclear antibody, ASMA = anti-smooth muscle antibody, GPA = gastric parietal cell antibody, ANCA = antineutrophil cytoplasmic antibody, CAH = chronic active hepatitis.
The laboratory parameters are shown in Table 3. All patients (38/38, 100%), for whom these results were available, had abnormal liver function tests, 72% (23/32) elevated total serum globulin and 81% (17/21) had hypergammaglobulinaemia. The results of autoantibody testing performed on sera were available for 44 (88%) patients of whom 36 (82%) were positive for at least 1 autoantibody. The prevalence of ANA (57%, 25/44), ASMA (18/33, 55%) and ANCA (16/29, 55%, including 14 patients with p-ANCA and 2 with cANCA) were comparable. As shown in Table 4 an increasing trend in the prevalence of autoantibodies with age (p = 0.05) was observed. The ANCA did not occur without ANA or SMA in serum from any patient. Sera from 2 patients had significant, low titre of rheumatoid factor. Gastric parietal cell antibodies (GPA) were present in serum samples from 2 patients. Of 50 patients with AIH 33 (66%) underwent liver biopsy including 30 patients who had liver biopsy before treatment and 3 patients who had liver biopsy after coagulation tests became normal. Repeat liver biopsy was done in 15% (5/33) of patients. Liver histology showed chronic hepatitis in 45% (15/33), cirrhosis in 24% (8/33), chronic hepatitis with bridging necrosis in 15% (5/33) and chronic hepatitis with rosetting in 6% (2/33) while biopsy findings were nonspecific in the remaining 10% (3/33) of patients. The available
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Table 4 Prevalence of autoantibodies in 44 cases of autoimmune hepatitis (AIH) by age Age group (N) 0–14 (17) 15–30 (13) > 31 (14) Total 44
Autoantibody positive (%) 13 (78) 10 (77) 13 (93) 36 (82)
data on treatment of AIH showed that 21 patients were started on prednisone to which azathioprine was added in 10 patients. Relapse was noted in 4% (2/50) of patients. Death was noted for 3 (6%) patients including the PAIDS patient whose AIH was observed to have followed a rapidly severe course, an adult patient who succumbed to hepatic encephalopathy 10 years after diagnosis of AIH and follow-up management, the third patient was an adult who died 3 days after presenting to hospital . There was no record of any patient receiving a liver transplant but 1 patient had cholecystectomy. There also was no record of hepatocellular carcinoma (HCC) among the 50 cases of AIH.
4. Discussion As reported with most populations autoimmune hepatitis appears to be rare in Jamaicans considering that only 50 cases were identified from our hospital records over a 40 year period [35]. Epidemiologic studies have been limited however in the United States prevalence rates of less than 5/100,000 population have been reported for chronic active hepatitis. Likewise it has also been reported that the incidence of type 1 AIH among Caucasoid populations of Europe and North America ranges from 0.1 to 1.9/100,000 per year and that the disease is considerably less frequent in Japan [2,6]. On the other hand some of the highest prevalence rates of AIH have been reported in aboriginal North Americans and these were much higher compared the Norwegian population [2,25]. The cohort of AIH patients reported in the present study are representative of those who presented with clinical disease and were seen at a tertiary care hospital. Asymptomatic and milder forms of AIH have been described which may progress if untreated but improve quickly with therapy. It now appears that AIH is asymptomatic in a substantial proportion of patients at presentation and that an even higher proportion of individuals have mild disease [1,8,15, 35]. In one study in Alaskan natives it was noted that persons presenting with mild disease or no symptoms were more likely to have moderate to severe fibrosis on
liver biopsy compared to those presenting with jaundice [10]. In the present study AIH was identified in Jamaicans of all age groups with comparable frequencies. However the mean age at presentation was younger than that reported in Caucasoid series. Certain non- white groups of patients including African- American, South American, African and Asian were observed to be younger than their white counterparts at presentation. However in one relatively large multiethnic cohort which included Whites, Hispanics and Asians age at diagnosis was similar among all groups [7,8,15,17,19, 35]. The reported female predominance in AIH also was observed as female out-numbered male patients almost 4 folds [7,8,10,17,25,35]. The tendency for late presentation at hospital, in keeping with the insidious onset of disease, had been observed in Western countries and was also evident in the present study [7,15,23,30]. A substantial proportion of patients had manifestations of advanced liver disease at presentation and this finding is in agreement with previous reports on AIH in certain non-caucasoid ethnic groups. In contrast Japanese patients are reported to have typically mild late onset disease [7,8,10, 17,25,35]. The prevalence of cirrhosis at presentation in the Jamaican patients, being 23%, was much closer to the 29–38% reported in Caucasian and Asians than the 85% prevalence rate reported in Afro-Americans with AIH [7,8,17,31,35]. While cirrhosis correlates with poorer outcomes in most studies other large studies of AIH have shown that the presence of cirrhosis at diagnosis did not decrease long term survival expectations [7,12]. The prevalence of jaundice, in this Jamaican cohort, at presentation was over 90%. This figure was much higher than that observed in European and North American Caucasian series. It is also higher than that reported in cohorts from Iran and India where jaundice was reported in 60% and 55% of patients, respectively [22,34]. The prevalence of other characteristic presenting clinical features of AIH were in accordance with published reports [16,17]. The laboratory results were mostly comparable with those documented for AIH in other ethnic groups [13, 15,16,35]. Abnormal liver function tests were the most common laboratory finding at presentation. Elevated serum globulin concentration was common and in resource constrained settings this test might be considered a useful, inexpensive screening test or surrogate of the IgG mediated hypergammaglobulinaemia which is characteristic of AIH. The prevalence of ANA.
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Fig. 1. Age group distribution of autoantibodies in patients with AIH. (Colours are visible in the online version of the article; http://dx.doi.org/ 10.3233/HAB-140275)
ASMA and LKM-1, the classical autoantibodies observed in this Jamaican series was similar to that reported other ethnic groups and the 87% prevalence reported in Caucasian patients with AIH [8,29]. However the significant increasing prevalence of autoantibodies with age and the tendency for older patients to have ASMA, as far as we are aware, have not been reported in other studies of AIH. These findings are not readily explained as autoantibodies are not believed to have a pathogenic role in AIH. Autoantibody negative cases of AIH have been recognized as a non-classical phenotype in which patients are clinically indistinguishable from those with classical disease, including HLAtypes, and also respond to corticosteroids [8]. In the general healthy population there is also an increasing prevalence of autoantibodies with age. Previous studies have shown that ANA are rarely found in healthy Jamaicans whereas ASMA are more common, appearing in similar prevalence and distribution compared to other ethnic groups [27]. Based on autoantibody profile type 1 AIH was present in over 80% of patients and type 2 was not identified in our series of patients. Although childhood cases of AIH were well represented, cases of type 2 AIH were not identified. The observation that the classical autoantibodies were less prevalent in children 14 years and under and that ANCA, included in the revised AIHIG criteria, was more common in this age group warrants further autoantibody studies in patients in this age group to confirm the absence of type 2 AIH [15].
Type 2 AIH is reported to be rare in North Americans and is also less common in certain European populations compared to others but appears to be represented in a short series of AIH of non- European Caucasoid ethnic origin described by Zolfino et al. [17,35] Autoimmune thyroiditis, synovitis, ulcerative colitis, coeliac disease, Sjögrens syndrome, autoimmune diabetes and various rheumatic conditions have been reported as concurrent extrahepatic autoimmune disorders in 17–48% of patients with AIH [8,26,35]. Systemic lupus erythematosus and insulin dependent diabetes mellitus were the associated other autoimmune disorders found in this series of Jamaican patients with AIH. This finding was not entirely surprising as SLE is not uncommon in Jamaica and previous studies have pointed to common genetic predisposing factors to both organ specific and non-organ specific autoimmune disease in Jamaicans [21,28]. An additional 2 patients tested positive for rheumatoid factors yet systemic rheumatic disease was not documented in these patients. The tendency for extrahepatic autoimmune disorders and the genetic predisposing factors in AIH have been discussed [8,35]. Untreated AIH progresses to liver cirrhosis with resulting liver failure which needs liver transplantation [7]. Recent reviews have emphasized that AIH responds to immunosuppressive treatment, whatever the degree of liver impairment [7]. None of the patients in our study received liver transplantation. Only 3 patients were documented as having died. This mortality rate is similar to that observed in Hispanics and
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Whites but is lower than that reported in Asians in one multi-ethnic study in the US [7,8]. One study involving patients of African descent with a high prevalence of cirrhosis reported that the response to therapy is good although higher doses of prednisone were required to maintain remission. Similarly a smaller study involving fewer Black patients also suggested that management of such patients is challenging and may require alternative or more aggressive treatment strategies [7, 17]. Although the standard treatment regimens for AIH were followed the available data do not allow the authors to comment further on response to therapy in this Jamaican cohort. There was no reported incidence of associated HCC in the 50 patients. This is consistent with the notion that progress to HCC is rare in AIH unlike that of other chronic liver diseases [21]. Some limitations of the study include its retrospective design and the attending drawbacks including missing hospital records, the extensive time period of the review during which there was continuing improvement in clinical and laboratory services at our hospital. For example, certain types of autoantibody testing were more recently introduced. In conclusion the clinical, laboratory and epidemiological features of autoimmune liver disease in Jamaica are similar to that observed in developed countries. Important areas of concern include the late stage at which some patients presented at hospital. Prospective follow-up studies are needed to assess progress, outcome and the place of liver transplant in Jamaicans with AIH.
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