Liver transplantation in autoimmune liver diseases

Liver transplantation is indicated for terminal phases of autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis. Indications for transplantation in autoimmune liver diseases are similar to those used in other acute or chronic liver diseases. Therapeutic advances have reduced the need for transplantation for autoimmune hepatitis and primary biliary cirrhosis but not for primary sclerosing cholangitis. Overall, outcomes of transplantation for autoimmune liver diseases are excellent. However, recurrence of autoimmune liver diseases in the allograft has variable impacts on graft and patient survivals. Treatment of recurrent diseases requires changes in immunosuppression or addition of ursodeoxycholic acid. Among autoimmune liver diseases, only autoimmune hepatitis occurs de novo in recipients transplanted for other diseases. Patients transplanted for autoimmune hepatitis or primary sclerosing cholangitis are at risk for reactivation or de novo onset of ulcerative colitis. Better understanding of the pathogenesis of recurrent autoimmune liver diseases is needed to devise effective means of prevention and treatment.     

48例疑难肝病临床与病理分析

目的：评价肝活组织穿刺检查对疑难肝病的诊断价值。方法对48例临床不能确诊的疑难肝病患者行肝活组织穿刺检查,分析其临床与病理组织学特点。结果48例疑难肝病患者中,肝脏占位性病变24例（其中肝细胞癌7例,转移性肝癌7例,胆管细胞癌2例,肝脓肿3例,慢性肝炎重度1例,肝结核1例,肝海绵状血管瘤1例,未能确诊2例;慢性肝炎与肝硬化鉴别困难者12例（慢性肝炎轻度3例,慢性肝炎中度4例,慢性肝炎重度1例,早期肝纤维化1例,肝硬化3例）;隐源性肝炎5例（急性淤胆型肝炎1例,慢性肝炎中度4例）;隐源性肝硬化3例（结节性肝硬化1例,特发性门静脉高压2例）;慢性肝炎中度伴结节性肝硬化1例;急性淤胆型肝炎1例;自身免疫性肝病1例（原发性胆汁性肝硬化）;肝脏寄生虫病1例。病理组织学确诊46例。结论疑难肝病中以肝脏占位性病变多见,其中以原发性肝癌与转移性肝癌最常见。对疑难肝病行肝活组织穿刺检查可明显提高诊断率。     

Case Report: Multiple Cancers: Hepatocellular carcinoma and adenocarcinomas of the common bile duct and the gall-bladder in a woman with primary biliary cirrhosis

We present a case of primary biliary cirrhosis associated with simultaneous triple cancers: a hepatocellular carcinoma and adenocarcinomas of the common bile duct and gall-bladder. A 70 year old Japanese woman, who had been diagnosed with primary biliary cirrhosis (stage 2 by Scheuer) 15 years before, was admitted to Koseiren Kamo Hospital in a comatose state. Laboratory data were as follows: the ammonia level was high (164.0 μg/dL), the antimitochondrial antibody showed a 320-fold increase, a high level of alpha-fetoprotein was indicated (2677 ng/mL), hepatitis B surface antigen was negative and hepatitis C antibody by enzyme immunoassay was negative, although a test for the RNA of hepatitis C virus by polymerase chain reaction was positive (10^3.5 copies/50 μL). The patient's condition gradually worsened and the patient died of liver failure. Autopsy showed triple cancers in the liver (hepatocellular carcinoma; trabecular type, moderately differentiated), the common bile duct (well-differentiated papillary adenocarcinoma) and the gall-bladder (well-differentiated papillary adenocarcinoma) with primary biliary cirrhosis (stage 4). Primary biliary cirrhosis has been believed to be a low risk for the development of hepatocellular carcinoma, despite the high risk of extrahepatic malignancy. The simultaneous occurrence of triple cancers with primary biliary cirrhosis, to the best of our knowledge, has never been reported. The present case may provide additional evidence for a predisposition to malignancy in primary biliary cirrhosis.     

Hepatocellular carcinoma in patients with autoimmune liver diseases: two case reports and literature review

Background and aims: Hepatocellular carcinoma has been reported as a rare complication of autoimmune liver diseases. We describe herein two patients with this neoplasia associated with autoimmune hepatitis and primary biliary cirrhosis, and we also review the literature.Cases report: The first case corresponds to a 49-year-old woman presented for evaluation of right upper abdominal pain. She had been diagnosed with autoimmune hepatitis 4 years before. Alpha-fetoprotein was markedly elevated and an abdominal MRI showed a 10 cm × 9.0 cm mass. She received transarterial chemoembolization, and currently the disease has progressed to the lungs and bones, and she is on supportive care. The second case corresponds to a 68-year-old woman presented for evaluation of a liver mass found in a screening ultrasound. She had been diagnosed with primary biliary cirrhosis 5 years previously. At admission alpha-fetoprotein was 1000 ng/mL and an abdominal MRI revealed a 4 cm × 3 cm liver tumor. She was treated with percutaneous radiofrequency ablation getting complete response, and currently she has no evidence of neoplastic disease. These two patients constitute the only cases of hepatocellular carcinoma associated to autoimmune liver diseases that have been attended in our Institute.Conclusion: These cases highlight that hepatocellular carcinoma secondary to autoimmune hepatitis and primary biliary cirrhosis, although rare, can occur in the absence of coexistent viral hepatitis, or excessive alcohol consumption. The utility of screening for hepatocellular carcinoma in autoimmune liver diseases is still not defined.     

Non-invasive markers for the prediction of fibrosis in chronic hepatitis C infection.

Liver fibrosis occurs as a result of chronic liver injury and is the hallmark of chronic liver disease. The final stage of progressive liver fibrosis is cirrhosis, which is implicated in portal hypertension, end-stage liver disease and hepatocellular carcinoma. Liver biopsy has historically been the gold standard test for the assessment of liver fibrosis for liver diseases such as viral hepatitis, autoimmune hepatitis and primary biliary cirrhosis. Improved serological tests have enhanced the diagnosis of these conditions and reduced the need for liver biopsy. Liver biopsy is unpopular among patients and clinicians. It is associated with morbidity and mortality, and in addition is subject to sampling error, inter- and intra-observer variability. There is therefore a need for non-invasive markers of liver fibrosis that are accurate, reliable, cheap and easy to use. The aim of this review is to examine the different non-invasive methods that can be used to estimate the severity of fibrosis. The methods evaluated include clinical examination, routine laboratory investigations, imaging tests, specialized tests of liver function and finally serum extra-cellular matrix markers of fibrosis. The review mainly focuses on fibrogenesis in the context of chronic hepatitis C infection.     

Graft dysfunction mimicking autoimmune hepatitis following liver transplantation in adults

In children, a type of graft dysfunction associated with autoimmune features has been described. We have identified 7 adult liver-transplant (LT) recipients from a series of over 1,000 consecutive transplant recipients who presented between 0.3 years and 7.2 years following transplantation with characteristic symptoms, autoantibody profiles, and histologic findings of autoimmune disease. The indications for transplantation were Ecstasy overdose, alcohol-related cirrhosis, primary sclerosing cholangitis (PSC) (2), primary biliary cirrhosis (PBC), hepatitis C cirrhosis, and cryptogenic cirrhosis. Two patterns of de novo autoantibody development were noted; anti-liver-kidney-microsome (LKM) antibody development at high titer in association with an aspartate transaminase (AST) > 500 and antinuclear (ANA) and antismooth muscle (AMA) antibody development at titers >1/80 with lower AST levels. All cases had elevated IgG. Liver biopsies showed changes of an autoimmune-type hepatitis with portal and periportal hepatitis in association with a marked infiltrate of plasma cells, lymphocytes, and bridging collapse. Two patients lost their grafts because of the disease. Patients were treated with reintroduction of steroids and azathioprine in cases in which it had been withdrawn. Major histocompatibility class I and II mismatching did not incur risk. Eight of 12 liver allografts were acquired from either DRB*0301- or DRB*0401-positive donors, and 4 recipients were DRB*0301-positive. This series illustrates that both symptoms and histologic findings of graft dysfunction compatible with autoimmune hepatitis (AIH) exist in adult LT recipients. Graft loss may be a consequence. This entity may represent a specific type of rejection that should currently be classified as "graft dysfunction mimicking autoimmune hepatitis."     

Multifocal hepatocellular carcinoma and precancerous lesions in a patient with autoimmune hepatitis-related cirrhosis

A 44-year-old woman with a 29-year history of autoimmune hepatitis (AIH) received a living donor liver transplant for multifocal hepatocellular carcinoma (HCC) and cirrhosis in 2007. Her initial laboratory workup at our institution in 1996 revealed a positive antismooth muscle antibody with a titer of 1:640. Serum electrophoresis showed a monoclonal gamma globulin spike with elevated IgG, IgA, and IgM. The patient was negative for hepatitis B and hepatitis C (HCV) by serology and serum polymerase chain reaction. She was treated with corticosteroids and azathioprine, but her disease progressed. In 1997, a liver needle biopsy revealed cirrhosis and a focus of small cell change. In 2004, a 2-cm exophytic mass was detected on magnetic resonance imaging. Follow-up imaging in 2005 and 2006 showed growth of the exophytic mass and development of new tumors. The exophytic mass was treated with ethanol ablation and she received a transplant. Examination of the explant revealed multiple high-grade dysplastic nodules and four moderately differentiated HCCs, one of which is arising in a high-grade dysplastic nodule. We believe this to be the first case in the English literature documenting the presence of preneoplastic lesions in an HCV-negative patient with AIH who developed HCC.     

Recurrence of autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis after liver transplantation

Liver transplantation (LT) is the standard therapeutic approach for the treatment of end-stage acute and chronic autoimmune liver disease as autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Results of liver transplantation in these indications are good with a patient survival after LT at 5 years of 85%. However several series have reported a possible recurrence of primary autoimmune liver disease after liver transplantation. Concerning all these three autoimmune liver diseases, recurrence of the disease on the graft may have multiple clinical, biochemical, histological and radiological expression influenced by different factors as the diagnostic methods used, the degree of immunosuppression and the genetic background of the recipient. We would like with this overview to describe the different pattern of recurrence of these autoimmune liver disease, their potential influence on the liver graft and their therapeutic management.     

Pantoprazole induces severe acute hepatitis

A female patient receiving pantoprazole during a corticosteroid therapy for encephalomyelitis disseminata developed severe acute hepatitis one month after initiation of pantoprazole treatment. Other causes of hepatic dysfunction including viral hepatitis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, haemochromatosis or Wilson's disease were excluded. Liver biopsy showed severe hepatic lesions with extensive necroses of the parenchyma. One week after discontinuation of pantoprazole the liver function began to improve and gradually the patient fully recovered. One year earlier the patient had been treated with pantoprazole before and had developed a milder form of hepatitis then. This case argues for an idiosyncratic hepatocellular damage caused by pantoprazole.     

Long-term follow-up of serum N-terminal propeptide of collagen type III levels in patients with chronic liver disease

To evaluate the diagnostic and prognostic significance of the N-terminal propeptide of collagen Type III (Col 1-3) in chronic liver disease, the peptide level was measured in the serum of 4 patients with primary biliary cirrhosis, 5 with chronic persistent hepatitis, 12 with chronic active hepatitis, and 1 with autoimmune hepatitis, for a period of 2 to 10 years and compared with liver function and histology. In primary biliary cirrhosis, Col 1-3 peptide levels were always elevated, regardless of medical therapy; however, after liver transplantation in one patient, the Col 1-3 peptide level decreased. In chronic persistent hepatitis, the peptide level fluctuated around the upper limit of normal. Among patients with chronic active hepatitis, the Col 1-3 peptide level normalized in 2 patients during remission, but was elevated in 7 patients who developed cirrhosis. Only in a patient with autoimmune hepatitis was the Col 1-3 peptide level normal, although the patient developed cirrhosis during prednisone therapy. When prednisone was withdrawn, the Col 1-3 peptide level increased. The data suggest that the serum Col 1-3 peptide may estimate the course of liver fibrosis in chronic liver disease and has prognostic value, particularly in chronic active hepatitis. Persistent elevation suggests ongoing fibrosis and development of cirrhosis; normalization suggests remission.     

Primary Hepatocellular Carcinoma with Hepatitis B Virus Infection in a 16-Year-Old Noncirrhotic Patient

Primary hepatocellular carcinoma metastasizing to abdominal lymph nodes and to the left lung was observed in a 16-year-old male patient. No clinically apparent chronic liver disease preceded the carcinoma and no signs of cirrhosis were detectable in the nonneoplastic liver. Hepatitis B surface antigen, hepatitis B e antigen and antibody to hepatitis B core antigen were found to be positive in the serum. By immunohistochemistry (peroxidase-antiperoxidase technique) hepatitis B surface antigen could be demonstrated in the nontumorous liver parenchyma, but not in the primary hepatocellular carcinoma itself. Serum alpha-fetoprotein was only moderately elevated (75 ng/ml), but immunohistochemically primary hepatocellular carcinoma revealed a considerable number of alpha-fetoprotein-containing cells, whereas nontumorous parenchyma did not. Carcinoembryonic antigen could be demonstrated immunohistochemically in some tumor cells of a lymph node metastasis, but not in the primary tumor or in the nontumorous liver parenchyma. We propose that primary hepatocellular carcinoma developed in this case in a symptomless hepatitis B virus carrier without preceding cirrhosis, an we exclude a simultaneous acute hepatitis B.     

Liver transplantation: the Italian experience

BACKGROUND: Liver transplantation is the standard treatment for patients with end-stage liver disease no longer responsive to conventional medical treatment AIMS: To report the long-term experience of liver transplantation in Italy. PATIENTS AND METHODS: Data were obtained retrospectively by means of a multiple-item form collected from 15 Italian liver transplant centres. The filing centre was centralized. RESULTS: A total of 3323 liver transplants were performed on 3026 patients, with a cumulative proportional survival of 72.4%. Three, 5 and 10 years' patient survival rates were 72.3%, 68.8% and 61.3%, respectively. The most common indication for liver transplantation were hepatitis B virus (+/- hepatitis D virus)- and hepatitis C virus-related cirrhosis (59.4%). Excellent survival rates were observed particularly in controversial indications, such as alcoholic cirrhosis, hepatitis B virus-related cirrhosis and hepatocellular carcinoma. Retransplantation was required in 8.9% of the cases. The overall prevalence of acute cellular rejection episodes was 43.5%. In our study population, primary non-function and disease recurrence were the most common causes of graft failure (28.7% and 25.4%, respectively). Infections and/or sepsis were the most common causes of death after transplantation (42%). CONCLUSION: This study confirms that patients with controversial indications to liver transplantation such as alcoholic cirrhosis, HBV-related cirrhosis and hepatocellular carcinoma can achieve excellent survival when properly selected.     

Hepatic reactive lymphoid hyperplasia in a patient with primary biliary cirrhosis

Reactive lymphoid hyperplasia (RLH) of the liver is an extremely rare lesion characterized by the proliferation of non-neoplastic lymphocytes forming follicles. Hepatic RLH is known to be associated with gastrointestinal carcinoma and autoimmune diseases including primary biliary cirrhosis (PBC). We report a case of hepatic RLH in a patient with PBC and gastric cancer. A 68 year old Japanese woman with a 10 year history of liver enzyme abnormality was admitted. Laboratory testing revealed that her anti-mitochondrial antibody was markedly elevated. Five mo after the diagnosis of PBC, she was found to have gastric cancer. Abdominal computed tomography disclosed a liver nodule in S8, suggesting metastatic gastric carcinoma. Histopathologically, the resected liver lesion comprised of a nodular proliferation of small lymphocytes with lymphoid follicles. This is the first reported case of hepatic RLH in a patient with both PBC and gastric cancer. Pre-operative diagnosis of hepatic RLH by clinical imaging is extremely difficult. Therefore, a needle biopsy could be useful to make a diagnosis of hepatic RLH, especially to differentiate from metastatic gastrointestinal carcinoma.     

Overlap syndrome of autoimmune hepatitis and primary biliary cirrhosis triggered by fluvastatin

Although statins are generally well-tolerated drugs, recent cases of autoimmune hepatitis (AIH) associated with their use have been reported. A 59-year-old Japanese man reported with liver damage, which appeared one month after beginning treatment with fluvastatin and continued after discontinuation of the drug. Although drug-induced liver injury was possible, positive autoantibody tests (antinuclear antibodies >1/1280, anti-mitochondrial M2 antibodies 21 index value) also suggested autoimmune liver disease. Liver biopsy findings were consistent with an overlap of autoimmune hepatitis and primary biliary cirrhosis. Treatment with prednisone and ursodeoxycholic acid led to a good response. In this patient, manifestation of AIH and primary biliary cirrhosis overlap syndrome was possibly triggered by statin use. Autoimmune liver disease should be considered as a possible diagnosis in patients with evidence of prolonged liver damage after discontinuation of statins.     

A unique combination of celiac disease, mesenteric lymph node cavitation, splenic atrophy and necrotizing hepatitis

We report on a patient who was diagnosed six years before with celiac disease, with a current combined problem of asplenism, mesenteric cysts and elevated liver function tests. The implications of splenic atrophy mimic those of post-splenectomy patients. Mesenteric lymph node cavitation is a rare complication of celiac disease that is most often associated with splenic atrophy. The pathogenesis is unknown. The clinical implications of the cavitated mesenteric lymph nodes are unclear. The association of celiac disease with liver disease was reported many years ago, but only recently these associations have been more clearly defined. Liver involvement shows a clinical spectrum varying from nonspecific reactive hepatitis, chronic active hepatitis, steatohepatitis to frank cirrhosis. Associations with autoimmune hepatitis, autoimmune cholangitis, primary biliary cirrhosis and primary sclerosing cholangitis have been described. In our patient, we found no obvious cause for the necrotizing hepatitis and the negative auto-antibodies made it impossible to firmly establish the diagnosis of autoimmune hepatitis. The causal relationship with celiac disease, if any, remains unproven.     

Hepatocellular carcinoma in a patient with precirrhotic primary biliary cirrhosis

Hepatocellular carcinoma is generally associated with long-standing chronic liver disease of diverse etiology, most commonly HBsAg-positive chronic active hepatitis, hemochromatosis, or alcoholic liver disease. Patients with primary biliary cirrhosis have only rarely developed a subsequent hepatocellular carcinoma. We report such a patient, a 77-year-old woman with an early, precirrhotic stage of primary biliary cirrhosis who developed a hepatoma.     

Significance of the iron and copper content of the liver for the differential diagnosis of chronic liver diseases

Liver iron and copper concentrations were estimated in 395 patients undergoing hepatological examination. Relations to clinical, morphological and laboratory data were evaluated. Liver iron concentrations were not significantly different in chronic hepatitis of viral, toxic or immunological origin. Liver iron levels exceeding 100 mg/100 g dry liver tissue (normal range up to 300 mg/100 g) were only found in idiopathic hemochromatosis (n = 8), in a patient with prophyria cutanea tarda and in a multiple transfused patient who suffered from aplastic anemia. Liver copper content was significantly increased in primary biliary cirrhosis compared to chronic hepatitis of other origin. Apart from untreated Wilson's disease (n = 3) copper levels higher than 25 mg/100 g dry liver tissue (normal range up to 6 mg/100 g) were measured in chronic active hepatitis B (n = 2), primary biliary cirrhosis (n = 9) and in chronic hepatitis of uncertain origin (n = 3). Therefore excess accumulation of copper in the liver was typical of Wilson's disease but less diagnostic than severely elevated liver iron stores of idiopathic hemochromatosis.     

Celiac disease-associated autoimmune cholangitis

There is an association between celiac disease (CD) and primary biliary cirrhosis, but there is little information regarding the association between CD and autoimmune cholangitis (antimitochondrial antibody-negative primary biliary cirrhosis). We describe a case of a 60-yr-old woman with chronic serum liver biochemistry elevations, recent onset of pruritus, and unexplained iron deficiency anemia. Liver biopsy was suggestive of stage 1 primary biliary cirrhosis, but serum antimitochondrial antibody testing was negative. Subsequent evaluation revealed CD based on markedly elevated antiendomysial antibody titers and characteristic histological features on mucosal biopsies. Initiation of a gluten-free diet led to resolution of iron deficiency anemia, pruritus, and elevated serum liver biochemistries. This suggests that CD may play a direct role in the development of autoimmune cholangitis. Additionally, normalization of hepatic biochemistries may be achieved without the use of immunosuppressive agents in some patients. CD should be considered in all patients diagnosed with autoimmune cholangitis as a gluten-free diet may avoid the need for immunosuppressive therapy in affected patients.     

Cirrhosis and autoimmune liver disease:Current understanding

Primary biliary cirrhosis(PBC),primary sclerosing cholangitis(PSC) and autoimmune hepatitis(AIH) constitute the classic autoimmune liver diseases(AILDs).While AIH target the hepatocytes,in PBC and PSC the targets of the autoimmune attack are the biliary epithelial cells.Persistent liver injury,associated with chronic AILD,leads to un-resolving inflammation,cell proliferation and the deposition of extracellular matrix proteins by hepatic stellate cells and portal myofibroblasts.Liver cirrhosis,and the resultant loss of normal liver function,inevitably ensues.Patients with cirrhosis have higher risks or morbidity and mortality,and that in the decompensated phase,complications of portal hypertension and/or liver dysfunction lead to rapid deterioration.Accurate diagnosis and monitoring of cirrhosis is,therefore of upmost importance.Liver biopsy is currently the gold standard technique,but highly promising non-invasive methodology is under development.Liver transplantation(LT) is an effective therapeutic option for the management of endstage liver disease secondary to AIH,PBC and PSC.LT is indicated for AILD patients who have progressed to end-stage chronic liver disease or developed intractable symptoms or hepatic malignancy;in addition,LT may also be indicated for patients presenting with acute liver disease due to AIH who do not respond to steroids.     

Overlap syndrome of primary biliary cirrhosis and autoimmune hepatitis with unusual initial presentation as fulminant hepatic failure

Autoimmune hepatitis and primary biliary cirrhosis are generally easy to discriminate on the basis of clinical, laboratory, and histological findings. The presence of anti-mitocondrial antibodies seropositivity and cholestatic clinical, laboratory, and/or histological features in patients with autoimmune hepatitis indicates the overlap syndrome of autoimmune hepatitis and primary biliary cirrhosis. Fulminant hepatic failure is an unusual initial form of presentation of autoimmune hepatitis and primary biliary cirrhosis overlap syndrome. We report the case of a 50-year-old woman with autoimmune hepatitis and primary biliary cirrhosis overlap syndrome who presented with fulminant hepatic failure. Fulminant hepatic failure has a high mortality rate and may require liver transplant. Our patient revealed a good response to corticosteroid and ursodeoxycholic acid therapy. It is important to identify and distinguish autoimmune hepatitis and variant syndromes from other forms of liver disease because of response to corticosteroid therapy.