Does Autophagy have a Role in the Pathogenesis of Pediatric Hepatic Steatosis?

Hepatic steatosis has become the most common cause of chronic liver disease among children worldwide.  Lipophagy has been considered as a pathway affecting steatosis development and progression. OBJECTIVE: this study aimed to evaluate the immunohistochemical expression of Beclin1 and LC3A in pediatric hepatic tissues with steatosis and to correlate their expression with clinicopathological parameters. METHODS: this study included 81 Egyptian pediatric patients with hepatic steatosis and 21 pediatric cases without hepatic steatosis. All specimens were stained by Beclin1 and LC3A antibodies. According to final diagnosis obtained from Pediatric Hepatology department, patients were divided into two groups: chronic liver disease (CLD) group that included 45 cases and inborn error of metabolism (IEM) group that included 36 cases. RESULTS: higher beclin1 expression was significantly correlated with higher stages of fibrosis and distorted liver architecture in CLD group, (P=0.043) for both. The control group showed higher positivity, percentage, as well as the median values of the H score of LC3A expression than did the CLD group or the IEM group (P=0.055, 0.001, and 0.008, respectively). Higher positivity of LC3A was significantly associated with higher stages of fibrosis and distorted liver architecture in the studied IEM group (P=0.021) for both. CONCLUSIONS: Varying intensity grades of LC3A and Beclin 1 immunohistochemical expression demonstrate the variation of autophagy at different phases of pediatric hepatic steatosis and varied disease etiology.

STIM1/SOX2 proteins are co-expressed in the tumor and microenvironmental stromal cells of pancreatic ductal adenocarcinoma and ampullary carcinoma.

Pancreatic ductal adenocarcinoma (PDAC) and ampullary carcinoma (AAC) are lethal malignancies with modest benefits from surgery. SOX2 and STIM1 have been linked to anticancer activity in several human malignancies. This study included 94 tumor cases: 48 primary PDAC, 25 metastatic PDAC, and 21 primary AAC with corresponding non-tumor tissue. All cases were immunohistochemically stained for STIM1 and SOX2 and results were correlated with clinicopathologic data, patient survival, and BCL2 immunostaining results. Results revealed that STIM1 and SOX2 epithelial/stromal expressions were significantly higher in PDAC and AAC in comparison to the control groups. STIM1 and SOX2 expressions were positively correlated in the primary and metastatic PDAC (P = 0.016 and, P = 0.001, respectively). However, their expressions were not significantly associated with BCL2 expression. SOX2 epithelial/stromal expressions were positively correlated with the large tumor size in the primary AAC group (P = 0.052, P = 0.044, respectively). STIM1 stromal and SOX2 epithelial over-expressions had a bad prognostic impact on the overall survival of AAC (P = 0.002 and P = 0.001, respectively). Therefore, STIM1 and SOX2 co-expression in tumor cells and intra-tumoral stroma could contribute to the development of PDAC and AAC. STIM1/SOX2 expression is linked to a bad prognosis in AAC.

EpCAM, Ki67, and ESM1 Predict Hepatocellular Carcinoma Recurrence After Liver Transplantation.

Liver transplantation (LT) is a good therapeutic decision, cures hepatocellular carcinoma (HCC) and promotes survival of cases with unrespectable HCC based on the Milan criteria. HCC still recur after LT. Identifying high risk tissue markers that predict recurrence becomes important for LT decision-making. Little is known regarding use of tissue expression of epithelial cell adhesion molecule (EpCAM) to predict HCC recurrence. This study investigates the role of EpCAM, Ki67, and endothelial-cell-specific molecule-1 (ESM1) as immunohistochemical markers to predict HCC recurrence after LT. It included 52 explanted HCC tissues from Egyptian patients who had undergone LT for HCC according to Milan criteria. Immunohistochemical staining was done on paraffin-embedded formalin-fixed tissue sections. HCC recurrence occurred in 13.5% cases. Positive EpCAM expression in HCC, was significantly associated with HCC recurrence, ( P =0.011), achieving 71.43% sensitivity, 84.44% specificity and 78.8% accuracy in predicting recurrence. High Ki67 percentage was significantly associated with HCC recurrence, ( P =0.005), achieving 57.14% sensitivity, 86.67% specificity and 82.69% accuracy in predicting HCC recurrence. ESM1 showed significant association with HCC recurrence ( P =0.041), with 71.43% sensitivity, 71.11% specificity and 71.15% accuracy in predicting HCC recurrence. EpCAM score and Ki67 percentage showed positive correlation. In conclusion, it is suggested that large tumor size (≥3 cm), advanced pathologic staging and Ki67 could be stratified as high risk predictors of HCC recurrence after LT. Although higher classes of Child-Turcotte-Pugh classification, high serum alpha-fetoprotein, microvascular invasion, positive EpCAM and ESM1 are stratified as lower risk predictors of HCC recurrence after LT.

Lymphoepithelioma-like Hepatocellular Carcinoma: a Case Report and Review of Literature.

We report a case of hepatic lymphoepithelioma-like carcinoma-hepatocellular carcinoma subtype (LEL-HCC) in a 41-year-old man with chronic hepatitis C virus (HCV) infection. The patient presented with abdominal pain and further assessment revealed a hypoechoic mass on ultrasonography. Serum alpha-fetoprotein (AFP) was 13·6 ng/dl. The patient was diagnosed as hepatocellular carcinoma based on the established triphasic computed tomography (TCT) diagnostic criteria and he underwent a surgical resection of the mass. Microscopic examination showed sheets and cords of malignant epithelial cells intermixed with heavy lymphoid infiltrate, with more than 100 tumor-infiltrating lymphocytes (TILs) per 10 high-power-field (HPF). Based on immunohistochemical studies, the malignant cells were positive for Hep Par 1 and glypican 3, focally positive for cytokeratin 7 (CK7), and negative for cytokeratin 20 (CK20). TILs were diffusely positive for cluster of differentiation 3 CD3 with an approximately equal CD4/CD8 ratio. The patient was recurrence free at 25 months after surgery, as evident by CT and serum alpha-fetoprotein level. LEL-HCC is a rare variant of HCC with a relatively better prognosis. Exploring the potential for immune modulator-based therapy in this subset of tumors is highly recommended.

Role of liver biopsy in management of liver diseases without hepatic nodules following end of the interferon era: experience of a tertiary referral center.

Liver biopsy (LB) is the cornerstone in the management of patients with liver diseases. However, a lot of queries had emerged about its role following the end of the interferon era. The aim of this study was to re-evaluate the current role of LB in the diagnosis of liver diseases. All patients who had underwent LB at the Department of Hepatology, National Liver Institute, from January 2015 through December 2018 were recruited. Indications for LB, pathology reports and medical records of all cases were retrieved, reviewed and statistically analyzed. A total of 275 liver biopsies were collected, 191 males and 84 females with mean age 41.22 ± 13.36 years. Etiological diagnosis made by histopathological evaluation was 48 drug-induced liver injury (DILI), 42 nonalcoholic fatty liver disease (NAFLD), 34 chronic hepatitis B, or C with cholestasis, 29 autoimmune hepatitis, 34 primary sclerosing cholangitis, 13 primary biliary cholangitis, 7 autoimmune overlap syndrome, 13 active bilharziasis and 10 Wilson's disease. Minor number of cases was diagnosed by different other etiologies. Initial diagnosis was made by liver biopsy and confirmed by clinical response and laboratory findings. Liver biopsy is still considered as the gold standard diagnostic measure of different liver diseases representing an integral component of management decisions in hepatology.

The clinicopathological and prognostic factors of hepatocellular carcinoma: a 10-year tertiary center experience in Egypt.

BACKGROUND: Hepatocellular carcinoma (HCC) remains a major health problem despite the emergence of several preventive and therapeutic modalities. HCC has heterogeneous and wide morpho-molecular patterns, resulting in unique clinical and prognostic criteria. Therefore, we aimed to study the clinical and pathological criteria of HCC to update the morpho-molecular classifications and provide a guide to the diagnosis of this disease. METHODS: Five hundred thirty pathologically analyzed HCC cases were included in this study. The clinical and survival data of these cases were collected. RESULTS: Hepatitis C virus is still the dominant cause of HCC in Egypt. Post-direct-acting antiviral agent HCC showed an aggressive course compared to interferon-related HCC. Old age, male gender, elevated alpha-fetoprotein level, tumor size, and background liver were important prognostic parameters. Special HCC variants have characteristic clinical, laboratory, radiological, prognostic, and survival data. Tumor-infiltrating lymphocytes rather than neutrophil-rich HCC have an excellent prognosis. CONCLUSIONS: HCC is a heterogenous tumor with diverse clinical, pathological, and prognostic parameters. Incorporating the clinicopathological profile per specific subtype is essential in the treatment decision of patients with HCC. TRIAL REGISTRATION: This was a retrospective study that included 530 HCC cases eligible for analysis. The cases were obtained from the archives of the Pathology Department, during the period between January 2010 and December 2019. Clinical and survival data were collected from the patients' medical records after approval by the institutional review board (IRB No. 246/2021) of Liver National Institute, Menoufia University. The research followed the guidelines outlined in the Declaration of Helsinki and registered on ClinicalTrials.gov (NCT05047146).

Epithelial-Mesenchymal Transition Markers in HCVAssociated Hepatocellular Carcinoma: A Multivariate Follow Up Study.

OBJECTIVE: Validated markers to predict recurrence after surgical resection of hepatocellular carcinoma (HCC) are needed. Little data is available regarding epithelial-mesenchymal transition (EMT) markers in HCC. The objective of this study was to investigate the expression of EMT markers and their correlation with clinicopathological variables and survival in hepatitis C virus (HCV)-associated HCC. METHODS: This longitudinal study included 109 cases of HCV-associated HCC treated with surgical resection. Nine different EMT markers (vimentin, E-cadherin, N-cadherin, Stat3, Snail1, Slug, Twist1, Zeb1 and integrin α5) were evaluated on liver tissue from HCC cases. Twenty fresh HCC samples from the studied cases were used for gene expression of EMT markers by quantitative real time polymerase chain reaction (PCR). RESULTS: EMT markers expression was 71%, 25%, 26%, 27%, 9%, 4%, 72%, 47%, 87% for vimentin, E-cadherin, N-cadherin, Stat3 snail1, slug, twist1, Zeb1 and integrin α5 respectively.  EMT mRNA in HCC tissues correlated with protein expression by 50-70%.  Vimentin was independent predictor of large tumor size (P=0.001), high risk of recurrence (HRR) (P=0.006) and shorter disease free survival (P=0.03) in multivariate analysis.  Reduced E-cadherin was a predictor of HRR (P=0.002). CONCLUSION: Vimentin and E-cadherin were the most powerful prognostic EMT markers in HCV-associated HCC in prediction of recurrence.

Kupffer Cell Hyaline Globules in Children With Autoimmune Hepatitis.

BACKGROUND: Hyaline globules (HGs) in the cytoplasm of Kupffer cells (KCs) have been appraised for being a typical feature of autoimmune hepatitis (AIH). This study aimed to determine how useful Kupffer cell hyaline globules (KCHGs) are in diagnosing AIH vs. other causes of pediatric chronic liver diseases (PCLDs). MATERIALS AND METHODS: This retrospective study recruited 124 children; 58 with AIH, 50 with chronic hepatitis C virus (HCV) infection, and 16 with Wilson's disease (WD). Two pathologists retrieved paraffin blocks of liver biopsies and prepared new cut sections for Periodic acid-Schiff-Diastase (PAS-D) stain. They independently examined liver biopsies before starting treatment. Two pediatricians reviewed medical records for demographic, clinical, laboratory, and serological findings. RESULTS: Females represented 48.6% of the studied children with a median age of 5.8 (4.9) years. Pathologists identified KCHGs in 67.24%, 12.5%, and 6.0% of AIH, WD, and HCV affected children respectively, P < 0.001. A significantly higher proportion of seropositive than seronegative AIH patients had KCHGs (77.5% vs. 50.0%), (P < 0.05). In multivariate analysis, KCHGs and prolonged prothrombin time were the only significant predictors that differentiate between AIH and the other studied PCLDs. The odds ratio of having AIH increased 68 times if KCHGs were seen. Among children with AIH, the presence of KCHGs was associated with higher median levels of direct bilirubin 2.2 (1.3) vs. 1.2 (2.2), and immunoglobulin G 3.2 (1.9) vs. 2.0 (1.7), (P < 0.05), but not to histopathological findings or hepatic fibrosis and activity. CONCLUSIONS: KCHGs are key indicators that can differentiate between AIH and other PCLDs, and between seropositive and seronegative AIH.

Trichrome-positive intrahepatic cytoplasmic globules are potential histopathological clue for COVID-19-induced hepatitis: a case report.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection mainly affects respiratory system. Later, liver affection has also been reported in the form of marked elevated liver enzymes. However, the association of coronavirus disease-19 (COVID-19) and autoimmune diseases is not clear. CASE PRESENTATION: A female patient with a known history of autoimmune hemolytic anemia (AIHH) for which she was treated with prednisolone was admitted for uncontrolled anemia followed by fever and elevated liver enzymes. All the laboratory and radiological investigations were not typical for COVID-19 or any other etiology. Liver biopsy revealed numerous pale eosinophilic trichrome-positive intracytoplasmic globules. The pathology raised the suspicion for SARS-CoV-2-associated hepatitis, which was confirmed by a positive IgG titer. The patient showed a dramatic improvement on the maintenance dose of prednisolone. CONCLUSIONS: AIHA patients co-infected with SARS-CoV-2 may be at risk of uncontrolled disease and should continue their treatment regimen. Histopathology has a role in the diagnosis of liver affection due to SARS-CoV-2 infection.

Altered Protein and Gene Expression of Beclin-1 Correlates with Poor Prognosis of Hcv-Associated Hepatocellular Carcinoma in Egyptian Patients.

Autophagy modulation has recently been addressed as a novel target for overcoming therapeutic resistance in hepatocellular carcinoma (HCC) to currently available anti-HCC therapy. The aim of this study was to investigate the protein and gene expression of Beclin-1 and its correlation with prognosis in HCV-associated HCC in Egyptian patients. This prospective study included 50 patients with HCV-associated-HCC, treated with surgical resection. Immunohistochemistry of antibody and quantitative real-time PCR of Beclin-1 gene were assessed in liver tissues of HCC. A normal-like expression pattern of Beclin-1 was found in 100% of adjacent liver tissues, while in HCC three various patterns were recognized: negative expression [18 (36%)], over expression [16 (32%)] and normal pattern [16 (32%)] (p=0.001). Beclin-1 mRNA in HCC tissues correlated with protein expression with correlation coefficient of 0.774 (p <0.001). Patients with negative expression of Beclin-1 had a significantly poor overall survival rates compared with patients with normal-like expression pattern (p <0.007), which was confirmed by multivariate analysis (p=0.01). Over-expression of Beclin-1 was significantly associated with vascular invasion (p <0.003). However, high tumor histological grade, focal lesion multiplicity, presence of involved margin or cirrhosis were insignificantly related to Becin-1. Beclin-1 altered expression has an important role in development and prognosis of HCC.

Post direct acting anti-viral agents associated primary hepatic Castleman's disease: A case report.

Castleman's disease (CD) is a primary lymphoproliferative disorder of the lymph nodes with rare extra-nodal primary affection. PRESENTATION OF CASE: Here we present a case of primary hepatic CD associated with hepatocellular carcinoma (HCC). DISCUSSION: Sixty-two years old, male received direct-acting antiviral agents (DAAs) for HCV infection. Follow up revealed sustained virologic response; however, three hepatic focal lesions were accidently discovered. Triphasic CT confirmed the HCC nature of two masses while the other mass remained undiagnosed. Surgical intervention was the treatment of choice, and pathological examination showed a fairly circumscribed mass formed of angiolymphoid hyperplasia displayed atrophic germinal center, expanded mantle zone, and variable hyalinization. The radiological evaluation of lymph nodes was unremarkable. The patient is 40 months alive after resection, with no further management advised. CONCLUSION: The immune-modulatory effect of DAAs may induce hepatic CD development in a cirrhotic patient, necessitating further studies. A new radiologic finding was observed in the present case in the form of vessels traversing through the lesion with no attenuation or occlusion. Pathology remains the gold standard in the diagnosis of CD.

Presentations, Causes and Outcomes of Drug-Induced Liver Injury in Egypt.

Drug-induced liver injury (DILI) is a frequent cause of liver injury and acute liver failure. We aimed to review all hospitalized DILI cases in a tertiary Egyptian center from January 2015 through January 2016. Cases with elevated alanine aminotransferase more than 3-fold and/or alkaline phosphatase more than 2-fold the upper limit of normal value were prospectively recruited and followed for one year. Drug history, liver biopsy whenever feasible and application of Roussel Uclaf Causality Assessment Method (RUCAM) were the diagnostic prerequisites after exclusion of other etiologies of acute liver injury. In order of frequency, the incriminated drugs were: Diclofenac (31 cases, 41.3%), amoxicillin-clavulanate (14 cases, 18.7%), halothane toxicity (8 cases, 10.7%), ibuprofen (4 cases, 5.3%), Khat (3 cases, 4%), tramadol (3 cases, 4%), Sofosbuvir with ribavirin (2 cases, 2.7%), and acetylsalicylic acid (2 cases, 2.7%) with one offending drug in 93.3% of cases. Forty-four cases (58.7%) were males; while 56 cases (74.7%) had HCV related chronic liver disease. Thirty-two cases (42.7%) presented with pattern of hepatocellular injury, while 23 cases (30.7%) were with cholestasis, and 20 cases (20.7%) with a mixed hepatocellular/cholestatic injury. One case received a transplant (0.75%), 7 cases died (9.3%), 23 cases (30.6%) developed liver decompensation (hepatic encephalopathy and ascites), and 44 cases completely resolved (58.7%). In conclusion, Diclofenac is the commonest offender in DILI occurrence in an Egyptian cohort. Age and prothrombin concentration were the only predictors of unfavorable outcomes of DILI.

FIB-5 versus FIB-4 index for assessment of hepatic fibrosis in chronic hepatitis B affected patients.

AIM OF THE STUDY: Chronic hepatitis B virus (HBV) infection is one of the major health problems worldwide. Use of non-invasive tests for assessment of hepatic fibrosis such as the FIB-4 index could be used to avoid liver biopsy. Another promising noninvasive test, FIB-5, could also be used to detect significant hepatic fibrosis. The aim of the study was to compare the use of FIB-5 and FIB-4 as noninvasive markers to assess chronic HBV-related hepatic fibrosis. MATERIAL AND METHODS: This study was done on 176 chronic HBV patients who underwent liver biopsy. Grading and staging of liver fibrosis was done according to the METAVIR scoring system. FIB-5 and FIB-4 scores were calculated for all patients. RESULTS: As regards FIB-4 for differentiation between non-significant fibrosis (group I) and significant fibrosis (group II), at a cutoff level of 1.28 with positive predictive value (PPV) 41.4% and specificity 48% while at a cutoff level of 7.08 with PPV 98.8% and specificity 98% for FIB-5. CONCLUSIONS: As regards both scores, the FIB-5 score was more specific than FIB-4 for diagnosing significant from nonsignificant hepatic fibrosis in patients with chronic HBV infection.

Hepatic expression of programmed death-1 (PD-1) and its ligand, PD-L1, in children with autoimmune hepatitis: relation to treatment response.

AIM OF THE STUDY: Autoimmune hepatitis (AIH) is characterized histologically by aggressive inflammation with interface hepatitis and prominent lymphoplasmacytic infiltration. Programmed death-1 (PD-1) is expressed on activated lymphocytes. Engagement of PD-1 by its ligand PD-L1 leads to cell apoptosis and death. We aimed to evaluate the immunohistochemical expression of PD-1 and PD-L1 in children with AIH, and its relation to treatment outcome. MATERIAL AND METHODS: Pre-treatment liver biopsies of 31 children with AIH were compared to 30 children with chronic hepatitis C virus (HCV) infection as a control group. PD-1 was evaluated in lymphocytes, while PD-L1 was evaluated in lymphocytes, hepatocytes, biliary epithelial cells, sinusoidal endothelial cells and Kupffer cells. All AIH patients received the standard treatment. RESULTS: The mean PD-1 was significantly higher in AIH than HCV patients (29.19 ±18.5% vs. 15.2 ±10.1%; p = 0.002) while there was no statistically significant difference as regards PD-L1 on lymphocytes (p = 0.853). Neither PD-1 nor PD-L1 correlated with either liver fibrosis or the inflammatory activity (p > 0.05 for all). PD-1/PD-L1 ratio was significantly higher in AIH compared to HCV patients and in non-responder AIH patients compared to responders (46.9 vs. 6.58). PD-1 expression was comparable in both responders and non-responders (p = 0.813), while PD-L1 was significantly upregulated in responders (4.17 ±3.15% vs. 0.63 ±1.3%; p = 0.046). PD-L1 expression on hepatocytes, biliary epithelial cells, sinusoidal endothelial cells and Kupffer cells was comparable in AIH and HCV groups. CONCLUSIONS: PD-1/PD-L1 ratio, which reflects immune aggression, was significantly higher in AIH compared to HCV patients and in non-responder AIH patients compared to responders.

Reduced Immunohistochemical Expression of Hnf1ß and FoxA2 in Liver Tissue Can Discriminate Between Biliary Atresia and Other Causes of Neonatal Cholestasis.

Biliary atresia (BA) is a necroinflammatory occlusive cholangiopathy that affects infants. Genetic and environmental factors has been proposed for its occurrence. The objectives of this study was to investigate the protein expression of 2 important genes regulating ductal plate remodeling, hepatocyte nuclear factor 1-beta (Hnf1ß) and the fork head box protein A2 (FoxA2) in liver tissue from patients with BA and to compare their expression with other causes of neonatal cholestasis (NC). This retrospective study included 60 pediatric patients, 30 with BA and 30 with NC. Immunohistochemistry of Hnf1ß and FoxA2 was performed on liver tissues from studied patients as well as 20 healthy subjects. Statistical analysis between immunohistochemistry results and other parameters was performed. Liver tissue from patients with BA revealed reduced Hnf1ß and FoxA2 immunoexpression. A strong significant statistical difference between BA and NC group (P<0.0001) with regard to Hnf1ß and FoxA2 immunoexpression was evident. Moreover, Hnf1ß was significantly correlated with FoxA2 immunoexpression, stage of fibrosis, bile ductular proliferation, and bile plugs in bile ductules. Hnf1ß immunoreaction in BA cases showed 76.7% sensitivity, 90% specificity, 88.5% positive predictive value, 79.4% negative predictive value, and 83.4% accuracy. FoxA2 expression in BA cases revealed 70.0% sensitivity, 80.0% specificity, 77.8% positive predictive value, 72.7% negative predictive value, 75.0% accuracy. Hnf1ß and FoxA2 immunoexpression could differentiate between BA from other cause of NC.

The Role of Monocyte/Macrophage and CXCR3 in Differentiation between Recurrent Hepatitis C and Acute Cellular Rejection Postliver Transplantation.

OBJECTIVE: Liver transplantation (LT) is the recommended treatment for patients with advanced liver disease and cirrhosis in all guidelines, mostly as a complication of HCV. The distinction between reinfection of the graft with HCV and acute cellular rejection (ACR) is essential because they are managed differently. Hepatic macrophages, which can either arise from circulating blood-derived monocytes (BDM) or from resident tissue Kupffer cells, are central in the pathogenesis of chronic liver injury. The aim of this work was to evaluate whether the origin of macrophages and the immune mediator CXCR3 could help in differentiating between acute recurrent HCV and ACR after liver transplantation. METHODS: Twenty-nine cases of recurrent hepatitis C and 26 cases of ACR were included in this study. The expression of CD 68 (macrophage marker), CD11b (BDM marker), and CxCR3 in the postliver transplant biopsy using immunohistochemistry was determined. RESULTS: CD11b expression highlighting macrophages of BDM origin was in favor of recurrent hepatitis C (P < 0.001) than in ACR (P = 0.44), while CXCR3 expression by hepatocytes was in favor of ACR (P = 0.001). CONCLUSION: Macrophage infiltrating liver tissue post LT can distinguish between ACR by upregulation of CXCR3 and recurrent hepatitis C by predominant CD11b.

Expression of intrahepatic CD3, CD4, and CD8 T cells in biliary atresia.

AIM OF THE STUDY: Assessment of the expression of cluster of differentiation (CD)3, CD4, and CD8 T cells in biliary atresia (BA) cases in comparison to neonatal cholestasis other than BA. MATERIAL AND METHODS: This study included 79 patients: 34 patients with BA (BA group) and 35 patients with neonatal cholestasis due to causes other than BA (cholestasis group), and 10 normal liver donor as a control group. Immunohistochemical staining or CD3, CD4, and CD8 T cells in liver tissues for the 3 groups were evaluated. RESULTS: Presence of clay stool, high gamma-glutamyl transferase levels, thrombocytosis, and non-contractibility of the gallbladder was the main clinical, laboratory, and radiological findings, distinguishing BA from other disorders causing neonatal cholestasis. Portal ductular proliferation, bile plugs in portal ductules, and advanced grades of fibrosis were more predominant in liver biopsy specimens of BA patients. The CD3+, CD4+, and CD8+ expression in patients with BA were significantly higher than in both cholestasis and control groups, while it was comparable in the cholestasis and control groups, with cutoff values of 25, 12, and 2.5 cells/portal tract, respectively, differentiating between BA and cholestatic patients. CONCLUSIONS: Immune-mediated destruction of bile ducts is incriminated in the pathogenesis of BA. Lymphocytic infiltrate in portal tract is primarily composed of CD3, CD4, and CD8 T cells. Immunostaining of liver tissue for CD3, CD4, and CD8 T cells can help in ensuring diagnosis of BA.

Relationship between hepatic progenitor cells and stellate cells in chronic hepatitis C genotype 4.

Hepatitis C virus (HCV) infection represents a major health problem in many areas of the world, especially Egypt. Hepatic progenitor cells (HPCs) and hepatic stellate cells (HSCs) have been implicated in fibrosis progression in chronic HCV. The aim of this study was to investigate the role of HPCs and HSCs in chronic HCV infection and the relationship between both cell types. This retrospective study was conducted on 100 chronic HCV patients. Immunohistochemistry was performed on liver tissue sections for cytokeratin 19 (progenitor cell markers), smooth muscle actin (stellate cell markers), matrix metalloproteinase-9 (MMP-9), and transforming growth factor beta (TGF-ß). The necroinflammatory activity was significantly related to the number of isolated HPCs and TGF-ß expression (p = 0.003 and p = 0.001 respectively). Advanced stages of fibrosis showed significantly increase number of HPCs (p = 0.001), higher ratio of HSCs (p = 0.004), more expression of TGF-ß (p = 0.001) and MMP-9 (p = 0.001). There was a significant direct correlation between immunoexpression of HPCs and HSCs for isolated cells (r = 0.569, p = 0.001) and ductular reaction (r = 0.519, p = 0.001). Hepatic progenitor cells and stellate cells play a significant role in the development and progression of fibrosis in chronic HCV. More interestingly, the significant direct correlation between HPCs and HSCs suggests a synergistic interrelation.

Khat-induced liver injuries: A report of two cases.

Khat is consumed for recreational purposes in many countries, including Yemen, where >50% of adults chew khat leaves regularly. A wide spectrum of khat-induced liver injuries has been reported in the literature. Herein, we report two patients with khat-induced liver injury. Both patients clinically presented with acute hepatitis, one of whom showed radiological evidence of hepatic outflow obstruction. Based on the histological tests, both patients had acute hepatitis, which indicated drug-induced liver injury (DILI) on a background of chronic hepatitis and portal fibrosis; of the two, one presented with symptoms of immune-mediated liver injury.

Hepatic immunohistochemistry of bile transporters in progressive familial intrahepatic cholestasis.

UNLABELLED:  Background. Diagnosis of progressive familial intrahepatic cholestasis (PFIC) is a challenging matter that involves the summation of clinical, laboratory, radiological, and liver histological parameters; in addition to specific investigations to exclude other causes of neonatal cholestasis. The aim of this study was to evaluate liver tissue immunohistochemistry of bile salt export pump (BSEP) and multidrug resistance 3 (MDR3) proteins in differentiating PFIC from other causes of neonatal cholestasis, particularly, when genotyping is unavailable. MATERIAL AND METHODS: The study included 25 patients diagnosed phenotypically as PFIC including 2 with PFIC1, 17 with PFIC2 and 6 with PFIC3. A second group of 25 cholestatic newborns with confirmed etiologies other than PFIC, termed as non-PFIC, included as controls. Liver biopsies from all patients were obtained and immunostained for BSEP and MDR3. RESULTS: Negative immunoreaction of BSEP and MDR3 was found in the majority of PFIC group (76 and 64% respectively). Nonetheless, the negative immunoreaction was demonstrated in a considerable number of the non-PFIC group. BSEP immunoreaction was negative in the majority (82.4%) of PFIC2 but in none of the two patients with PFIC1. In addition, negative MDR3 immunoreaction was more frequently associated with PFIC3 compared to non-PFIC group. CONCLUSION: MDR3 and BSEP immunostaining would be a helpful tool in supporting the phenotypic diagnosis of PFIC subtypes and in differentiating PFIC from other causes of neonatal cholestasis.