TGF-ß signaling is activated in patients with chronic HBV infection and repressed by SMAD7 overexpression after successful antiviral treatment.

OBJECTIVES: Although animal studies demonstrated that Smad7 induction ameliorates TGF-ß/SMAD-mediated fibrogenesis, its role in human hepatic diseases is rather obscure. Our study explored the activation status of TGF-ß/activin pathway in patients with chronic liver diseases, and how it is affected by successful antiviral treatment in chronic HBV hepatitis (CHB). METHODS: Thirty-seven CHB patients (19 with active disease, 14 completely remitted on long-term antiviral treatment and 4 with relapse after treatment withdrawal), 18 patients with chronic HCV hepatitis, 12 with non-alcoholic fatty liver disease (NAFLD), and 3 controls were enrolled in the study. Liver mRNA levels of CTGF, all TGF-ß/activin isoforms, their receptors and intracellular mediators (SMADs) were evaluated using qRT-PCR and were correlated with the grade of liver inflammation and fibrosis staging. The expression and localization of pSMAD2 and pSMAD3 were assessed by immunohistochemistry. RESULTS: TGF-ß signalling is activated in CHB patients with active disease, while SMAD7 is up-regulated during the resolution of inflammation after successful treatment. SMAD7 overexpression was also observed in NAFLD patients exhibiting no or minimal fibrosis, despite the activation of TGF-ß/activin signaling. CONCLUSIONS: SMAD7 overexpression might represent a mechanism limiting TGF-ß-mediated fibrogenesis in human hepatic diseases; therefore, SMAD7 induction likely represents a candidate for novel therapeutic approaches.

A novel noninvasive index for nonalcoholic steatohepatitis: a pilot study.

OBJECTIVE: The potential development of a noninvasive marker predicting nonalcoholic steatohepatitis (NASH). METHODS: Thirty patients with biopsy-proven nonalcoholic fatty liver disease were evaluated by numerous anthropometric, clinical and biochemical parameters. RESULTS: Serum glutamic oxaloacetic transaminase (SGOT; p = 0.027), log (erythrocyte sedimentation rate) (ESR; p = 0.034) and homocysteine (p = 0.041) were associated with NASH independently from gender, age and body mass index. When combined, the regression model provided R(2) = 0.563 (p = 0.001) and area under the ROC curve = 0.873 ± 0.066 (p < 0.001). CONCLUSION: This noninvasive marker, named HSENSI (acronym of homocysteine, SGOT, ESR, Nonalcoholic Steatohepatitis Index), consists of three low cost, easily measurable parameters and may accurately predict NASH.

Adipocytokines and cytokeratin-18 in patients with nonalcoholic fatty liver disease: Introduction of CHA index.

BACKGROUND AND RATIONALE: Insulin resistance (IR), adipocytokines, oxidative stress and hepatic apoptosis play a pathogenetic role in nonalcoholic fatty liver disease (NAFLD). AIMS: The evaluation of specific adipocytokines and markers of IR, oxidative stress and apoptosis in NAFLD patients; the introduction of a combined non-invasive index for nonalcoholic steatohepatitis (NASH). MATERIAL AND METHODS: Thirty patients with biopsy-proven NAFLD (15 with simple nonalcoholic fatty liver [NAFL], 15 with NASH) and 24 controls were recruited. Blood samples for total and high molecular weight (HMW) adiponectin, visfatin and tumor necrosis factor (TNF)-α, the apoptotic by-product cytokeratin (CK)-18, the reactive oxygen metabolites (ROMs) and standard biochemical tests were measured. Homeostatic model of assessment - insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were calculated. MAIN RESULTS: Total and HMW adiponectin were significantly lower and TNF-α higher in either NAFL or NASH group compared to control group; CK-18 was significantly higher in NASH compared to either NAFL or control group. CHAI (an acronym of CK-18, HOMA-IR, AST Index) was calculated as the product of parameters being significantly different between NAFL and NASH groups. CHAI was significantly higher in NASH (24.2 [15.1-214.0]) compared to either NAFL (15.7 [6.8-22.7]) or control (5.1 [2.4-7.6]) group (p < 0.001) and significantly higher as the severity of steatosis, fibrosis, ballooning, lobular and portal inflammation advanced. CONCLUSION: CHAI was escalating from controls to NAFL and NASH and was higher by increasing the severity of all the main histological lesions. However, a validation study is needed before introducing CHAI in clinical practice.

Serum homocysteine levels in patients with nonalcoholic fatty liver disease.

Background and rational for the study. Nonalcoholic fatty liver disease (NAFLD) is regarded as the hepatic component of insulin resistance (IR) syndrome, but data on serum homocysteine (HCY) are limited. The aim of the study was the evaluation of serum HCY levels in patients with NAFLD. Material and methods. Thirty-one patients (54 ± 11 years, 8 males) with biopsy-proven NAFLD, 15 with simple nonalcoholic fatty liver (NAFL) and 16 with nonalcoholic steatohepatitis (NASH), and 22 healthy controls (52 ± 9 years, 5 males) matched for gender, age and body mass index (BMI), were recruited. Blood samples for HCY, folate, vitamin B12, insulin and standard biochemical tests were obtained after overnight fasting. Homeostatic model of assessment-insulin resistance (HOMA-IR) was calculated. Results. There was no difference in mean serum HCY levels between controls and NAFLD patients (12.6 ± 4.6 vs. 13.5 ± 2.6 mmol/L, respectively; p = 0.432). Serum folate and vitamin B12 were also similar between the study groups. Mean age, BMI, serum folate and vitamin B12 did not differ between NAFL and NASH patients. However, when compared with NAFL patients, NASH patients had lower mean serum HCY levels (12.3 ± 2.5 vs. 14.7 ± 2.1 mmol/L; p = 0.006). HCY was lower by increasing the grading of fibrosis (p = 0.005), portal inflammation (p = 0.029) and steatosis location (p = 0.021). In logistic regression analysis, HCY independently predicted NASH (p = 0.045) after adjustment for gender, age, BMI, AST, glucose and HOMA-IR. Conclusion. Our data suggest that serum HCY levels are lower in NASH compared with NAFL patients and can independently predict NASH. Serum HCY might represent another non-invasive marker for the assessment of NAFLD.

Serum vitamin B12 and folate levels in patients with non-alcoholic fatty liver disease.

The aim of the study was the evaluation of serum vitamin B12 and folate levels in patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD) and their association with the disease severity. Thirty patients with biopsy-proven NAFLD and 24 healthy controls matched for gender, age, body mass index and waist circumference were recruited. Blood samples for vitamin B12, folate, insulin and standard biochemical tests were obtained after overnight fasting. Homeostatic model of assessment-insulin resistance was calculated. There was no difference in serum vitamin B12 and folate levels between groups. Neither vitamin B12 nor folate levels were significantly different within any histological category, including steatosis grade, fibrosis stage, lobular inflammation, portal inflammation and ballooning. In conclusion, similar vitamin B12 and folate levels were observed in non-alcoholic steatohepatitis and non-alcoholic fatty liver patients, and controls. Furthermore, vitamin B12 and folate levels were not associated with either insulin resistance or the severity of liver disease.

Foxp3 expression in liver correlates with the degree but not the cause of inflammation.

Patients with chronic viral hepatitis display increased expression of Foxp3 in liver, suggesting that Tregs expansion contributes to persistent infection. The purpose of this study was to elucidate whether the expression of Foxp3 relates not to the viral infection but to the resulting liver inflammation. Liver biopsies obtained from 69 individuals (26 chronic HBV hepatitis, 14 chronic HCV hepatitis, 11 nonalcoholic fatty liver disease, 8 autoimmune diseases, 2 methotrexate-related toxicity, and 8 controls) were examined, by qRT-PCR, for the mRNA expression of Foxp3, IL-10, TGF-ß1, Fas, FasL, TRAIL, caspase-3, TNF-α, IFN-γ, and IL-1ß. Significant increase of Foxp3 was observed in all disease groups compared to controls, which was positively correlated with the intensity of inflammation. The expression of the apoptosis mediators Fas, FasL, and TRAIL, but not of IL-10 and TGF-ß1, was also significantly elevated. Our findings indicate that, independently of the initial inducer, liver inflammation is correlated with elevated expression of apoptosis mediators and is followed by local Treg accumulation. Further research towards the elucidation of the underlying casual relationships is required, in order to clarify whether our results signify the existence of a uniform Treg-mediated regulatory mechanism of apoptosis-induced inflammation.

HCC influence on patient survival after liver transplantation for HDV cirrhosis.

BACKGROUND/AIMS: The effect of hepatocellular cancer (HCC) in patients transplanted for hepatitis B and D virus (HB/DV) cirrhosis is not well studied. Our aim was to study the long-term survival outcomes of patients who underwent liver transplantation for HB/DV cirrhosis with and without HCC. METHODOLOGY: A total of 231 primary, adult, single- organ liver transplants were performed from 1990 to 2007. HB/DV was the cause of cirrhosis in 36 patients. Nine patients died during the first 3 postoperative months from surgical complications. The study group comprised the remaining 27 patients. The median follow-up was 1515 days. RESULTS: The mean patient survival was 3760 days (95% CI: 3013-4507). Six patients were diagnosed with HCC. The mean patient survival was 3011 days (95% CI: 2344-3679) and 4036 days (95% CI: 3002-5070) for recipients without and with HCC, respectively. For the same groups, the incidence of microbial infections was 61.9% and 33.3%, respectively (p=0.219). HCC has not recurred in any of the six patients. CONCLUSIONS: The mean long-term survival after liver transplantation for HB/DV and HCC surpassed 11 years. The superior survival of HCC patients is difficult to explain. The increased number (almost double) of microbial infections in the non- HCC population might be held accountable.

Adefovir plus lamivudine are more effective than adefovir alone in lamivudine-resistant HBeAg- chronic hepatitis B patients: a 4-year study.

BACKGROUND AND AIM: Adefovir dipivoxil (ADV) is effective in lamivudine (LAM)-resistant hepatitis B e antigen-negative (HBeAg(-)) chronic hepatitis B (CHB). However, it is unclear whether LAM treatment should be continued in these patients. We aimed to compare the long-term efficacy of adding ADV to ongoing LAM treatment versus switching to ADV monotherapy in LAM-resistant HBeAg(-) CHB. METHODS: Sixty LAM-resistant patients with HBeAg(-) CHB were randomly assigned (3:1) to combination therapy (10 mg ADV once daily plus ongoing LAM at 100 mg once daily [n = 45]) or 10 mg ADV monotherapy once daily (n = 15). Virological and biochemical responses were defined as hepatitis B virus (HBV)-DNA <400 copies/mL and as normalization of alanine aminotransferase levels, respectively. RESULTS: The median follow-up time was 53 months (range 20-60 months). A virological response was observed in 38/45 (84.4%) and 11/15 (73.3%) patients in the ADV/LAM and ADV monotherapy groups, respectively (P = 0.56). Biochemical response rates were higher in the ADV/LAM group than in the ADV monotherapy group (90.9% vs 57.1%, respectively; P = 0.01). In the ADV/LAM group, serum HBV-DNA remained undetectable in all patients who achieved a virological response (n = 38). In the ADV monotherapy group, virological breakthrough occurred in four of the 11 patients who achieved a virological response (36.4%; P < 0.001 vs the ADV/LAM group, log-rank test). In addition, two patients in each group who did not achieve a virological response eventually developed ADV resistance. CONCLUSIONS: Adding ADV to LAM is more effective than switching to ADV monotherapy in LAM-resistant patients with HBeAg(-) CHB.

Elevated markers of thrombin generation and fibrinolysis in patients with active and quiescent ulcerative colitis.

BACKGROUND: Prothrombotic abnormalities within the coagulation system, the presence of microvascular thrombi in intestinal mucosa, and the increased risk of thromboembolic complications in patients with Inflammatory bowel disease, suggest that a hypercoagulable state may be an important contributing factor in disease pathogenesis. The activation of the coagulation system in a cohort of ulcerative colitis patients was investigated. MATERIAL/METHODS: Markers of coagulation activation in blood (thrombin-antithrombin complex, TAT; prothrombin fragments 1 and 2, F1+2; and D-dimers) and markers of inflammation (erythrocyte sedimentation rate, ESR; C-reactive protein, CRP; and fibrinogen) were measured in 38 patients with active and 13 patients with long-standing quiescent ulcerative colitis. Disease activity was assessed by clinical, endoscopic, and histological criteria. The markers of coagulation activation were also measured in 28 healthy volunteers. RESULTS: There were no differences in TAT, F1+2, and D-dimer plasma levels between active and inactive ulcerative colitis. D-dimer and F1+2 levels were significantly higher in the active ulcerative colitis patients than in the healthy controls. Plasma levels of TAT, F1+2, and D-dimers did not differ between inactive ulcerative colitis patients and healthy controls. However, both active and inactive ulcerative colitis patients had significantly higher proportions of elevated (above-normal) values of coagulation markers than the healthy controls. Correlation analyses revealed strong correlation between ESR, fibrinogen, and D-dimers, which also correlated with the severity and extent of ulcerative colitis. CONCLUSIONS: A chronic low-grade activation of coagulation exists in ulcerative colitis, regardless of disease activity, and it might be implicated in disease pathogenesis.

Metastatic renal cell carcinoma to the earlobe 27 years after nephrectomy.

We present a case of a nodule on the earlobe of an elderly patient, without any known clinical history. Microscopic examination revealed a tumor with morphology reminiscent of metastatic clear cell renal cell carcinoma. The results of an extensive immunohistochemical (IHC) examination confirmed our initial diagnosis and further investigation of the patient's medical history revealed that a unilateral nephrectomy had been performed 27 years prior to the current tumor. We are reporting this case to emphasize the long interval between the primary tumor and its metastasis in an extremely unusual site, with a brief discussion on the ability of this particular neoplasm for extremely late metastasis to any site on the human body. Also, we are highlighting the extensive step-by-step IHC examination to confirm the diagnosis in routine pathology.

Von Recklinghausen's disease associated with malignant peripheral nerve sheath thmor presenting with constipation and urinary retention: a case report and review of the literature.

A malignant peripheral nerve sheath tumor (MPNST) is a rare neoplasm arising from peripheral nerve sheaths. We herein report the first case of MPNST originating from the left gluteal muscle region, diffusely extending into the adjacent small pelvis and perineum. The patient was a 25-year-old man who presented with symptoms of progressive constipation and urinary retention associated with weight loss. The patient had a family history of neurofibromatosis type 1. Physical examination showed numerous cafe-au-lait spots and sessile cutaneous neurofibromas. A computed tomography scan revealed a giant tumor which displaced the bladder and segments of the intestine. The histopathological diagnosis was MPNST. The mass was considered inoperable and palliative colostomy was performed. The patient declined chemotherapy and radiation therapy and died 2 months later.

Herb-induced hepatitis by Teucrium polium L.: report of two cases and review of the literature.

Herbal medicinal products are being increasingly used throughout the world. Herbal 'remedies' are, however, not risk free and many cases of hepatotoxicity have been reported. Teucrium polium grows mostly in the Mediterranean basin and is popular, because of hypoglycemic and hypolipidemic properties. We report two cases of T. polium-induced hepatitis in Greek female patients, who used the plant's extract to control the cholesterol levels. Both patients presented with very high aminotransferases after consuming herbal tea for 2 or 3 months. One patient also developed jaundice. Histologic examination of liver biopsies showed hepatitis with moderate or severe necroinflammatory activity. Discontinuation of the herbal remedy resulted in normalization of the liver enzymes in both patients. Our findings, and those of other authors, suggest that T. polium may not be safer than T. chamaedrys and T. capitatum, which have also been reported to occasionally cause hepatotoxicity.

Inflammatory pseudotumor of the liver successfully treated with nonsteroidal anti-inflammatory drugs: a challenge diagnosis for one not so rare entity.

Inflammatory pseudotumor of the liver is a rare, benign lesion characterized by a well-circumscribed mass of chronic inflammatory cell infiltration and proliferating fibrous tissue. Its etiology remains unclear, although inflammatory processes have been proposed. It is often misdiagnosed as a malignant tumor, and the management has been traditionally surgical. We report the case of a 16-year-old boy who was referred from another hospital with a fever of >38 degrees C with rigor and right upper quadrant pain which he had suffered from for 5 days. The ultrasonographic computed tomography and MRI findings were not diagnostic, and we performed a needle biopsy from the lesion that was consistent with inflammatory pseudotumor (of liver, mixed fibrous tissue and chronic inflammatory cell infiltration). The patient was treated with nonsteroidal anti-inflammatory drugs and had an uneventful clinical course. During follow-up, the lesion subsequently shrank to completely vanish 1 year later.

Grading of invasive breast carcinoma through Grassmannian VLAD encoding.

In this paper we address the problem of automated grading of invasive breast carcinoma through the encoding of histological images as VLAD (Vector of Locally Aggregated Descriptors) representations on the Grassmann manifold. The proposed method considers each image as a set of multidimensional spatially-evolving signals that can be efficiently modeled through a higher-order linear dynamical systems analysis. Subsequently, each H&E (Hematoxylin and Eosin) stained breast cancer histological image is represented as a cloud of points on the Grassmann manifold, while a vector representation approach is applied aiming to aggregate the Grassmannian points based on a locality criterion on the manifold. To evaluate the efficiency of the proposed methodology, two datasets with different characteristics were used. More specifically, we created a new medium-sized dataset consisting of 300 annotated images (collected from 21 patients) of grades 1, 2 and 3, while we also provide experimental results using a large dataset, namely BreaKHis, containing 7,909 breast cancer histological images, collected from 82 patients, of both benign and malignant cases. Experimental results have shown that the proposed method outperforms a number of state of the art approaches providing average classification rates of 95.8% and 91.38% with our dataset and the BreaKHis dataset, respectively.

Ductal plate malformation and congenital hepatic fibrosis Clinical and histological findings in four patients.

Congenital hepatic fibrosis belongs to the fibrocystic diseases of the liver and represents ductal plate malformation of interlobular bile ducts, along with a destructive cholangiopathy associated with fibrosis. Four patients with congenital hepatic fibrosis are described. Their median age at presentation was 25 years; none of them had a family history of liver or renal disease. Variceal bleeding was the initial manifestation in three patients. All of them required frequent endoscopic variceal ligation sessions and distal splenorenal shunting was also performed in two, almost obviating the need for further variceal ligation. Variceal bleeding did not recur during follow-up. One of these three patients rarely exhibited acute cholangitis; administration of ursodeoxycholic acid resulted in complete remission. In contrast, the fourth patient showed frequent severe episodes of acute cholangitis but normal cholangiographic findings. He underwent liver transplantation but died 2 months later. Laboratory findings disclosed pancytopenia in all patients whereas hepatic synthetic capacity was well preserved. Renal function was unaffected despite the presence of polycystic kidneys in two patients. In summary, congenital hepatic fibrosis can also be diagnosed in older ages, might have strikingly different manifestations and is associated with prominent portal hypertension necessitating aggressive management in order to prevent variceal bleeding.

Pegylated IFN-alpha 2b added to ongoing lamivudine therapy in patients with lamivudine-resistant chronic hepatitis B.

AIM: To investigate the role of pegylated-interferon (IFN) alpha-2b in the management of patients with lamivudine-resistant chronic hepatitis B. METHODS: Twenty consecutive anti-HBe positive patients were treated with pegylated IFN alpha-2b (100 mug sc once weekly) for 12 mo. There was no interruption in lamivudine therapy. Hematology, liver biochemistry, serum HBV DNA levels were detected by PCR, and vital signs were also assessed. Liver histology was assessed in some patients at entry and at wk 52 for comparison. RESULTS: Nine patients (45%) had a partial virological end-treatment response; seven patients (35%) showed complete virological end-treatment response. Eight patients (40%) showed biochemical end-treatment response. There was a trend for higher virological response rates in patients who had previously responded to IFN and relapsed compared to IFN non-responders (four out of seven patients vs none out of six patients, respectively; P=0.1). Patients without virological end-treatment response showed significant worsening of fibrosis [median score 2 (range, 1 to 3) vs median score 3 (range, 1 to 4)], in the first and second biopsy respectively (P=0.014), whereas necroinflammatory activity was not significantly affected. Patients with complete or partial virological end-treatment response did not show any significant changes in histological findings, possibly due to the small number of patients with paired biopsies (n=5). Nevertheless, after 12 mo of follow-up, only one patient (5%) showed sustained virological response and only 2 patients (10%) showed sustained biochemical response. Two patients (10%) discontinued pegylated IFN both after 6 mo of treatment due to flu-like symptoms. CONCLUSION: Pegylated IFNalpha-2b, when added to ongoing lamivudine therapy in patients with lamivudine-resistant chronic hepatitis B, induces sustained responses only in a small minority of cases.

A case of successful management with splenectomy of intractable ascites due to congenital dyserythropoietic anemia type II-induced cirrhosis.

The congenital dyserythropoietic anemias comprise a group of rare hereditary disorders of erythropoiesis, characterized by ineffective erythropoiesis as the predominant mechanism of anemia and by characteristic morphological aberrations of the majority of erythroblasts in the bone marrow. Congenital dyserythropoietic anemia type II is the most frequent type. All types of congenital dyserythropoietic anemias distinctly share a high incidence of iron loading. Iron accumulation occurs even in untransfused patients and can result in heart failure and liver cirrhosis. We have reported about a patient who presented with liver cirrhosis and intractable ascites caused by congenital dyserythropoietic anemia type II. Her clinical course was further complicated by the development of autoimmune hemolytic anemia. Splenectomy was eventually performed which achieved complete resolution of ascites, increase of hemoglobin concentration and abrogation of transfusion requirements.

Prevalence and severity of liver disease in patients with b thalassemia major. A single-institution fifteen-year experience.

During the last years, liver disease has emerged as a major cause of mortality in patients with b thalassemia major (TM). In spite of its clinical relevance, TM-associated liver damage has been insufficiently characterized. We therefore retrospectively analyzed all TM patients of our Department who underwent liver biopsy since 1990.

Advanced intrahepatic cholangiocarcinoma in hepatitis C virus-related decompensated cirrhosis: case report and review of the literature.

A 75-year-old man with no known previous liver disease was admitted to our institution because of right pleural effusion, backache, and pain in the upper right quadrant. Physical and laboratory work-up revealed decompensated liver cirrhosis. Spiral computed tomography (CT) showed a 6-cm tumour in the right liver lobe. Serum levels of aminotransferases, prothrombin time, total bilirubin, alphafetoprotein and carcinoembryonic antigen were within normal limits. However, the patient had elevated cholestatic enzymes, diffuse hypergammaglobulinaemia, a six-fold increase in carbohydrate antigen 19-9 (CA 19-9), cryoglobulinaemia, and reactivity against hepatitis C virus (anti-HCV). Although hepatocellular carcinoma is the most common cancer in a cirrhotic patient with chronic viral hepatitis, the investigation revealed the presence of intrahepatic cholangiocarcinoma (ICC). This is a less frequently occurring primary liver tumour, the aetiology and pathogenesis of which remain unclear in the majority of cases. The coexistence of HCV liver disease and ICC might be an incidental finding, but recently some reports have shown a relatively high incidence of this tumour in patients with HCV-related cirrhosis. The current aspects regarding ICC prevalence in HCV patients, the possible aetiopathogenetic links between this tumour and HCV, and the importance for ICC detection and characterization using the enhancement patterns with quadruple-phase spiral CT scan are also discussed.

Primary biliary cirrhosis presented as peripheral eosinophilia in asymptomatic women with or without elevated alkaline phosphatase.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by the destruction of biliary epithelial cells, presumably by autoimmune mechanism(s). Although lymphocytes play a pivotal role in the pathogenesis of PBC, the possible involvement of eosinophils has also been suggested. Recent studies have shown that eosinophilia possibly occurs in the peripheral blood of PBC patients. We present four cases of asymptomatic middle-aged women with moderate-to-high eosinophilia observed during random investigation. Alkaline phosphatase (ALP) was increased in two of them. As a result of clinical and laboratory evaluations the early stages of PBC were diagnosed in all the patients, as attested by the detection of high titres of anti-mitochondrial antibodies and the characteristic lesions on liver biopsies. Liver function tests and eosinophils returned within normal limits after 2 months of treatment with ursodeoxycholic acid, suggesting that its potential immunomodulatory actions may extend to eosinophils. Our report further supports the possibility that eosinophilia may occur in PBC, especially in its early stages. From the clinical point of view, we believe that PBC should be considered in the differential diagnosis of eosinophilia with an otherwise unknown origin. In particular, PBC should be suspected in a patient when other causes of eosinophilia have been excluded, irrespective of the presence or absence of symptoms, or the presence or absence of elevated ALP. In such cases further evaluation for anti-mitochondrial antibodies should be done. These observations might assist the development of future therapeutic concepts in the management of PBC, at least for patients in early stages of the disease.