[Pathology in Autoimmune Hepatitis] --- 自己免疫性肝炎の病理組織所見に関する論文です --- 1998.4.17 by T. Morizane, MD 以下の文献のうち１のBachらの論文で述べられていることは内田先生の講演で述べられていることと非常に近い内容です。一般に自己免疫性肝炎の病理組織所見の特徴は自己免疫性肝炎の国際診断基準に含まれているBridging necrosis, Rosetting of liver cells, Plasma cellの高度の浸潤などとされており、Biliary changeは逆にAIHを否定する所見の一つとされています。しかし、これらが果たして正しいのかきちんとした解析が必要だと思います。
Bachの論文からそれぞれの組織所見の頻度を表にまとめてみました。
AIH CH C Cirrhosis 90% 58% Bile duct change 91% 40% Bile duct loss 91% 20% Steatosis 72% 19% Lymphoid cell aggregation (follicles)
within portal tracts49% 10% Severe lobular necrosis and inflammation 76% 38% Piecemeal necrosis 81% 10% Multinucleated hepatocytes 29% 6% Broad areas of parenchymal collapse 76% 6% また文献２のCzajaらの論文ではAIHとCH C, CH Bを比較ししています。
さらにCH BはAIH、CH Cと比べてground-glass hepatocytes の頻度が有意に高く(36% vs. 0%, P = 0.001) multinucleated giant cells の頻度も有意に高い(54% vs. 2%, P = 0.0001) と述べています。
AIH CH C P value Portal lymphoid aggregates 42% 76% 0.02 Steatosis 16% 52% 0.006 Severe periportal hepatitis 23% 0% 0.02 Moderate to severe plasma cell infiltration of the portal tracts 66% 21% 0.005 Lobular hepatitis 47% 16% 0.04 また慢性肝炎のNomenclatureに関するSpecial Article（Ishak K, Baptista A, Bianchi L, et al: Histological grading and staging of chronic hepatitis. J Hepatol 1995; 22: 696-699)やUchida T: Pathology of hepatitis C. Intervirology 1994; 37: 126-132.も参考にしてください。
1. Bach N, Thung SN, Schaffner F: The histological features of chronic hepatitis C and autoimmune chronic hepatitis: a comparative analysis. Hepatology 1992;15:572-7.Before the availability of serological markers for hepatitis C, the morphological features of this diagnosis, which represents most non-A, non-B hepatitis, could not be confirmed. We examined biopsy specimens from 50 patients with chronic hepatitis C and 21 patients with autoimmune chronic hepatitis. Each biopsy specimen was graded on 19 different histological features. The results indicated that at the time of biopsy, the average age of patients with chronic hepatitis C was 46 yr vs. 36 yr for autoimmune chronic hepatitis. Cirrhosis was seen more frequently in autoimmune chronic hepatitis (90%) than in hepatitis C (58%). Features more commonly observed in chronic hepatitis C were bile duct damage (91% vs. 40%), bile duct loss (91% vs. 20%), steatosis (72% vs. 19%) and lymphoid cell aggregation (follicles) within portal tracts (49% vs. 10%). Severe lobular necrosis and inflammation (76% vs. 38%), piecemeal necrosis (81% vs. 10%), multinucleated hepatocytes (29% vs. 6%) and broad areas of parenchymal collapse (76% vs. 6%) were seen more often in autoimmune chronic hepatitis. Exclusion of five patients with autoimmune chronic hepatitis who received immunosuppression before biopsy accentuated these differences. In conclusion, morphological criteria, in addition to serological data, may be useful for differentiating chronic hepatitis C from autoimmune chronic hepatitis, which histologically is a more aggressive disease.
2. Czaja AJ, Carpenter HA: Sensitivity, specificity, and predictability of biopsy interpretations in chronic hepatitis [see comments] Gastroenterology 1993;105:1824-32.
BACKGROUND: To determine the frequency of individual histological findings in different types of chronic hepatitis and to assess the sensitivity, specificity, and predictability of histological patterns in distinguishing these types, liver biopsy specimens were examined from 86 patients with autoimmune hepatitis (43 patients), chronic hepatitis B (11 patients), chronic hepatitis C (21 patients), and cryptogenic hepatitis (11 patients). METHODS: Specimens were examined under code by a single hepatopathologist, and predefined histological features were sought. A histological diagnosis was rendered based on composite changes. RESULTS: Patients with chronic hepatitis C had a higher frequency of portal lymphoid aggregates (76% vs. 42%, P = 0.02) and steatosis (52% vs. 16%, P = 0.006) than patients with autoimmune hepatitis, whereas the latter patients more commonly had severe periportal hepatitis (23% vs. 0%, P = 0.02), moderate to severe plasma cell infiltration of the portal tracts (66% vs. 21%, P = 0.005), and lobular hepatitis (47% vs. 16%, P = 0.04). Patients with chronic hepatitis B had a higher frequency of ground-glass hepatocytes (36% vs. 0%, P = 0.001) and multinucleated giant cells (54% vs. 2%, P = 0.0001) than those with autoimmune hepatitis and chronic hepatitis C. The histological diagnoses for these clinical entities had high specificity (81%-99%) and predictability (62%-91%) but low sensitivity (36%-57%). CONCLUSIONS: Autoimmune hepatitis, chronic hepatitis B, and chronic hepatitis C have characteristic individual histological features. Histological patterns based on these features have high specificity and predictability but low sensitivity.
3. Krawitt EL: Autoimmune hepatitis. N Engl J Med 1996;334:897-903.
4. Te HS, Koukoulis G, Ganger DR: Autoimmune hepatitis: a histological variant associated with prominent centrilobular necrosis. Gut 1997;41:269-71.
A patient presented with pruritus and recent elevation of aminotransferases. The case fulfilled most of the criteria for the diagnosis of autoimmune hepatitis and achieved clinical and complete biochemical response to steroid therapy. However, the liver biopsy specimen revealed an unusual histological pattern consisting of severe centrilobular necrosis demarcated by a thin rim of hepatitic reaction. In contrast, the portal tracts appeared almost normal. This histological appearance has not been associated with autoimmune hepatitis. This presentation and the histology may represent an early pattern of autoimmune injury to the liver.
5. Lachaux A, Bertrand Y, Bouvier R, Dumont C, Pinzaru M, Hermier M: Intravenous immunoglobulin therapy in an infant with autoimmune hemolytic anemia associated with necrotic hepatitis and peliosis. J Pediatr Gastroenterol Nutr 1996;22:99-102.
6. Burgart LJ, Batts KP, Ludwig J, Nikias GA, Czaja AJ: Recent-onset autoimmune hepatitis. Biopsy findings and clinical correlations [published erratum appears in Am J Surg Pathol 1995 Nov;19(11):1341] Am J Surg Pathol 1995;19:699-708.
Whereas the histologic findings in clinically 'chronic' autoimmune hepatitis have been well established, with piecemeal necrosis as a hallmark lesion, the histologic findings of clinically 'acute' or recent-onset autoimmune hepatitis remain undefined. The goal of this study was to define more fully the liver histomorphology in patients with recent-onset autoimmune hepatitis. Twenty-six patients were identified at our institution who had well-characterized autoimmune hepatitis and had undergone a liver biopsy within 6 months of clinical presentation. A detailed histologic evaluation revealed evidence of chronic liver disease in 25 (of 26) patients despite the lack of correlating clinical chronicity. The histologic evidence of chronicity included, in addition to a portal lymphoplasmacytic infiltrate, bridging (septal) fibrosis (11 patients) and overt cirrhosis (four patients). Eighteen of these 25 cases with evidence of chronicity also showed zone 2 and 3 lobular hepatitis, including disarray and hepatocyte necrosis. A single case showed lobular hepatitis with confluent hepatocyte necrosis (submassive hepatocellular necrosis), but no evidence of chronic liver disease. Although autoimmune hepatitis remains in the differential diagnosis of lobular hepatitis, these data show that most patients with autoimmune hepatitis who undergo biopsy early in its clinical course will have histologic evidence of chronic liver disease. Most of these patients probably have a lobular 'flare' in disease activity, which likely precipitated the clinical presentation. The findings herein reinforce the concept that autoimmune hepatitis is by definition a chronic disease and supports the proposal that the modifier 'chronic' be eliminated from autoimmune hepatitis.
7. Vyberg M: The hepatitis-associated bile duct lesion. Liver 1993;13:289-301.
8. Pappo O, Yunis E, Jordan JA, Jaffe R, Mateo R, Fung J, Demetris AJ: Recurrent and de novo giant cell hepatitis after orthotopic liver transplantation. Am J Surg Pathol 1994;18:804-13.
This study examines the clinical and pathologic course of seven patients who developed giant cell hepatitis (GCH) after liver transplantation. Five of these patients also had GCH as their native liver disease and experienced a particularly aggressive course because of recurrent disease, beginning 1-21 months after transplantation. Two died and another two required hepatic retransplantation because of recurrent GCH; one of them had GCH recurrence in a second liver allograft. A remaining patient with recurrent GCH is alive 6 years after transplantation. Follow-up of the two patients who developed de novo GCH between 8 and 24 months after hepatic transplantation showed active micronodular cirrhosis in one and persistent giant cell transformation in the other at 4 years. All of the patients were serologically negative for hepatitis C virus, hepatitis B virus, and human immunodeficiency virus before transplantation. One patient became positive for hepatitis C virus after transplantation. Two patients had an associated autoimmune syndrome, which could have been accounted for by the GCH. None had a history of drug exposure. Interestingly, human papilloma virus (HPV) type 6 was detected by PCR analysis of liver tissues with GCH from one of three cases before and three of four cases after transplantation. This small series shows that GCH occurs in liver allografts, but it is uncommon. Documentation of recurrent disease in five of seven patients suggests that GCH in a subgroup of patients may be related to a transmissible agent, or that a particular recipient may injure livers in a way that elicits a giant cell reaction.
9. Martins EB, Graham AK, Chapman RW, Fleming KA: Elevation of gamma delta T lymphocytes in peripheral blood and livers of patients with primary sclerosing cholangitis and other autoimmune liver diseases. Hepatology 1996;23:988-93.
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that is possibly an autoimmune disease. Although gamma delta T cells represent a small proportion of the total T-cell population in healthy individuals, there is evidence to suggest a role for these cells in autoimmunity. Accordingly, the aim of this study was to investigate the population of gamma delta T cells in patients with PSC, compared with other chronic liver diseases. An elevation in the percentage and absolute numbers of gamma delta T cells was found in the peripheral blood of patients with PSC (8.66% and 0.13 x 10(-6)/L [P < .01 and < .05, respectively]) and autoimmune hepatitis (AIH) (8.03% and 0.13 x 10(-6)/L [both P < 0.001]) compared with controls (4.10% and 0.06 x 10(-6)/L). We also found an elevation in the percentage and absolute numbers of gamma delta T cells in the portal areas of patients with PSC (10.55% and 4.33 [P < .001 and < .001, respectively]), AIH (7.16% and 4.55 [P = .001 and < .001, respectively]), and primary biliary cirrhosis (PBC) (5.57% and 3.49 [P = .008 and < .001, respectively]) when compared with controls (2.23% and 0.81). These findings suggest a role for gamma delta T cells in the mechanism of immune damage in autoimmune liver diseases.
10. Freni MA, Artuso D, Gerken G, Spanti C, Marafioti T, Alessi N, Spadaro A, Ajello A, Ferrau O: Focal lymphocytic aggregates in chronic hepatitis C: occurrence, immunohistochemical characterization, and relation to markers of autoimmunity. Hepatology 1995;22:389-94.
Intrahepatic lymphocytic aggregates are observed in chronic hepatitis C as well as in autoimmune chronic hepatitis. Autoantibodies and autoimmune manifestations may occur in hepatitis C. It has been suggested that the lymphocytic aggregates play a role in the liver injury of chronic hepatitis C by an immune-mediated mechanism. We studied the occurrence of intrahepatic lymphocytic aggregates and of autoantibodies in a consecutive series of 128 patients with chronic hepatitis C. For the phenotypic characterization of the lymphocytic aggregates cryostat sections and microwaved paraffin embedded sections were immunostained with monoclonal antibodies directed against T cell subsets, B cells, killer/natural killer cells, follicular dendritic cells, and macrophages. Autoantibodies were tested by immunofluorescence (antinuclear, anti-smooth muscle, antimitochondrial) and by enzyme-linked immunosorbent assay (anti-soluble liver antigen, anti-liver/kidney microsome, anti-human receptor for asialoglycoprotein). Focal lymphocytic aggregates in portal tracts were observed in 76 of 128 (59%) patients. The cellular composition of the aggregates was constant: a core of B cells mixed with many T helper/inducer lymphocytes, and an outer ring was prominently formed by T suppressor/cytotoxic lymphocytes. A germinal center was rarely identifiable. The presence of lymphocytic aggregates was inversely correlated with the degree of fibrosis. Lymphocytic aggregates appeared more frequently in chronic persistent and chronic active hepatitis in comparison with cirrhosis and in the presence of bile duct damage. No correlation was found between lymphocytic aggregates and autoantibodies or other markers of autoimmunity. The lymphocytic aggregates are frequent in chronic hepatitis C. Their cellular composition is similar to that of primary lymphoid follicles in lymph nodes. Their presence does not seem to be correlated with features of autoimmunity.
11. Goldstein NS, Kodali VP, Gordon SC: Histologic spectrum of cryptogenic chronic liver disease and comparison with chronic autoimmune and chronic type C hepatitis. Am J Clin Pathol 1995;104:567-73.
Most histologic studies of cryptogenic chronic liver disease were done before the discovery of hepatitis C, and therefore encompass the histologic spectrum of this disease. The authors report the histopathologic findings of 18 liver biopsies of presumed cryptogenic chronic liver disease patients and compared them to chronic autoimmune hepatitis and hepatitis C virus biopsies. Severe bridging fibrosis or cirrhosis was present in 55%. Eighty percent of biopsies had minimal necroinflammatory activity including those with cirrhosis; 20% had moderate activity. Histologic distinction from chronic hepatitis C was difficult in the minimally active cryptogenic chronic liver disease biopsies because 20% of biopsies had portal lymphoid follicles and 33% had macrovesicular steatosis. Chronic autoimmune hepatitis had more parenchymal necroinflammatory activity and plasma cells than did either cryptogenic chronic liver disease or chronic hepatitis C biopsies. These findings suggest that one form of cryptogenic chronic liver disease is a persistent, low grade hepatitis that can progress to cirrhosis despite an innocuous histopathologic appearance. Pathologists should be aware that cryptogenic chronic liver disease biopsies may have minimal histologic abnormalities. These biopsies should not be reported as normal. Such cases require long-term clinical follow-up.