Hepatic Biopsy Research Articles

Diagnostic histochemistry in hepatic pathology.

Histochemistry has an important, continuing role in the current assessment of hepatic biopsies and resection specimens. The evaluation of connective tissue elements in the liver can be accomplished with such methods as the Masson trichrome, Snook reticulin, Vierhoff van Gieson, orcein, and Victoria blue stains. The results contribute to the diagnosis of acute and chronic hepatitis, submassive necrosis, venous outflow obstruction, steatohepatitis, and cirrhosis. Fat stains done on frozen sections of liver tissue are routinely performed in the evaluation of donor liver allograft biopsies. Iron stains such as Perls' method and the Prussian blue technique contribute to the recognition of hemochromatosis and hemosiderosis. The rhodanine, orcein, and Timm stains for copper are used in the characterization of chronic cholestatic liver disease and Wilson's disease. Labeling of carbohydrate-based moieties in various disorders is accomplished with the digested and undigested periodic acid-Schiff method, and Congo red or crystal violet stains can be employed to detect amyloid deposition. Lastly, evaluations of the thickness of the cell plates and continuity of the reticulin framework, as seen with the Snook reticulin stain, can contribute to the diagnostic separation of benign from malignant hepatocellular neoplasms.

Intraductal Papillary Neoplasm of the Bile Duct Progressing to Hepatic Mucinous Adenocarcinoma

Intraductal papillary neoplasm of the bile duct (IPNB) is a rare variant of bile duct cancer and represents about only 10% of all resectable cases. The most common abnormal preoperative findings are intraductal masses and bile duct dilation. The purpose of this case report is to distinguish IPNB from invasive carcinoma, discuss the case presentation, and assess the best treatment options. We present a case of a 58 yo female with history of hyperlipidemia that presented to gastroenterologist with right upper quadrant pain. She underwent cholecystectomy but continued to have persistent fatigue, weight loss, and then developed jaundice. Family history was significant for prostate cancer in father and hepatocellular carcinoma (HCC) in mother. Initial endoscopic retrograde cholangiopancreatograophy (ERCP) showed common bile duct (CBD) dilation; balloon sphincterotomy of distal CBD was then done. She then had endoscopic ultrasound (EUS) which showed no solid or cystic masses seen in the pancreas and dilated extra and intrahepatic biliary system. ERCP revealed frond-like tumor in hilar/left intrahepatic duct takeoff with mucin secretion concerning for biliary IPMN tumor vs cholangiocarcinoma. Patient had bile duct stent placement. Biopsy of duct lesion showed IPNB with intermediate to high-grade dysplasia with initially no signs of invasive carcinoma. She underwent left hepatectomy with Roux-en-Y hepaticojejunostomy and portal lymphadenectomy. Final pathology showed an invasive mucinous adenocarcinoma of the left hepatic duct T2b N0/8 lymph nodes and she was started on adjuvant chemotherapy. Early diagnosis of IPNB is crucial because it is regarded as a premalignant lesion towards invasive cholangiocarcinoma/adenocarcinoma and this determines a patient's prognosis and specific targeted therapy. Our patient had major hepatectomy and portal lymphadenectomy, as aggressive surgical resection is recommended as treatment of choice for IPNB due to relatively good prognosis after resection. IPNB is difficult to diagnose preoperatively and has a high risk of progression to invasive cholangiocarcinoma or adenocarcinoma. Diagnostic modalities must be utilized early as aggressive surgical resection early generally gives good prognosis. New treatment modalities, such as ERCP-guided radiofrequency ablation and self-expandable metal stents can be utilized in non-surgical cases to prevent further biliary obstruction and palliative treatment and should be further studied.1248_A.tif Figure 1: A) Intraductal papillary neoplasm of bile duct with high to intermediate grade dysplasia. B) Papillary architecture with nuclei loss of orientation and characteristic fibrovascular cores. Neutrophils presenting showing inflammation. C) Fibrovascular cores present with pseudostratified epithelium and crowded nuclei with hyperchromaticity1248_B.tif Figure 2: A) Left hepatic lobe biopsy showing fibrovascular cores and pseudostratified epithelium. B) Biopsy showing prominent nucleoli with loss of orientation in nuclei and high-intermediate grade dysplasia, especially in top right of image.1248_C.tif Figure 3: A) Intraductal papillary neoplasm (top right) and mucinous adenocarcinoma present. B) Grade 2 moderately differentiated carcinoma with >50% mucinous differentiation involved and cribriform architecture pattern present.

Gastric Ulcer and Perforation Due to Mucormycosis in an Immunocompetent Patient

Mucormycosis is a rare fungal disease with high mortality and morbidity in immunocompromised patients that typically involves the nasal sinuses, orbit and brain. In recent years increased gastrointestinal involvement of mucormycosis has been reported. Here we present a case of gastric ulcer and perforation due to gastrointestinal mucormycosis (GIM) in an immunocompetent individual. A 48-year-old healthy male was brought to the emergency department after a transpelvic gunshot wound. Patient was in hypotensive shock upon arrival and was immediately taken to the operative room (OR) for further evaluation. He sustained rectal and small bowel injury for which he underwent multiple bowel resections but his hospital course was complicated by multiple anastomotic perforations. Hepatic and mesenteric biopsies showed mucormycosis and he was started on liposomal amphotericin B. Subsequently, he developed coffee ground emesis and an EGD showed a large gastric ulcer in the proximal stomach. Biopsies taken from the ulcer showed fungal organism consistent with mucormycosis. Two days later, he developed massive hematemesis and frank blood was seen in his wound vacuum assisted closure and multiple surgical drains. He became hemodynamically unstable and was taken back to the OR for emergent laparotomy where he was noted to have a 8 x 4 cm area of perforated ulcer in the lesser curvature of the stomach. He succumbed to his injuries in the OR. GIM accounts for only 7% of all mucormycosis cases but is associated with a high mortality rate of 85%. Traditional risk factors include immunodeficiency states such as poorly controlled diabetes mellitus, bone marrow or solid organ transplantation, neutropenia, glucocorticoid use and HIV. The stomach is the most common site of GIM followed by the colon and ileum. The fungus has a tendency to invade blood vessels causing disseminated infection. Per our literature search, in the past 5 years, there appears to be an increase in reported cases of GIM after penetrating traumas such as gunshot wound and car accidents regardless the immunocompetent states of the patients. Polyene antifungal drugs such as liposomal amphotericin B is the recommended first-line therapy. Early diagnosis, timely initiation of antifungal treatment and surgical debridement of infected tissues are the keys to improve a patient's survival against this highly fatal opportunistic infection.1970_A Figure 1. EGD demonstrated a large ulcer in the proximal stomach with biopsy showing mucormycosis.1970_B Figure 2. Gastric ulcer, H+E stain, low-magnification, showing necrotic exudate containing fungal aseptate hyphae morphologically consistent with mucormycosis.1970_C Figure 3. Gastric ulcer, H+E stain, high-magnification, showing mucormycosis.

Extraordinary Hyperbilirubinemia in a Patient With Multiple Myeloma

Multiple myeloma (MM) is a hematologic malignancy that classically manifests with hypercalcemia, renal insufficiency, anemia, and bone disease. Liver dysfunction is a less known complication that usually occurs through liver infiltration by plasma cells, amyloid deposition, or iron deposition. We present a case of a 49 year old Female patient with MM and extreme hyperbilirubinemia. This was a 49 year old female who presented to the emergency room with profound fatigue, progressive jaundice, and pruritus. She had a history of relapsed refractory stage III MM that was being treated with bendamustine. The patient was transfusion dependent, requiring blood transfusions twice a week. Vital signs revealed tachycardia. Her physical exam was remarkable for dry mucous membranes, jaundice, scleral icterus, diffuse abdominal tenderness, and hepatosplenomegaly. Labs were significant for a Hgb of 10 g/dL, platelets of 40,000/mL, total bilirubin of 49.5 mg/dL, direct bilirubin of 30 mg/dL, AST of 18 U/L, ALT of 51 U/L, alkaline phosphatase of 80 U/L, albumin of 3.8 g/dL, INR of 1.3, ferritin of 15,000, and iron of 206. Further work-up, including a hepatitis panel, autoimmune workup, hemolytic workup, toxicology screen, US, MRCP, etc., did not yield a diagnosis.. Transjugular hepatic biopsy was performed to assess the etiology of the hyperbilirubinemia. It showed infiltration of plasma cells, extensive iron deposition in hepatocytes, and Kupffer cells with pericellular fibrosis in the areas infiltrated by plasma cells (figures 1, 2). The patient's liver dysfunction was attributed to secondary hemochromatosis and malignant infiltration of MM. The patient was treated with supportive care. Given her poor prognosis, goals of care were discussed, and she was eventually discharged with home hospice. It is important to recognize liver dysfunction in patients with Multiple Myeloma. Up to 40% of individuals with multiple myeloma have some plasma cell infiltration of the liver. Involvement of the liver in MM carries a poor prognosis. The literature search found that the total bilirubin usually ranges from 3.2 to 17.3 mg/dL in these cases. Our case demonstrated a staggering total bilirubin of 49.5mg/dL. This was multifactorial due to plasma cell infiltration of the liver and secondary hemochromatosis from numerous transfusions. It is important to keep in mind that Bendamustine has also been documented to cause an unconjugated hyperbilirubinemia secondary to hemolytic anemia.2257_A Figure 1. Medium power photomicrograph of a transjuglar liver biopsy with hemosiderin-laden hepatocytes and sinusoidal plasma cell infiltrate with associated fibrosis.2257_B Figure 2. Strong expression of kappa IgG by infiltrating cells.

Sevoflurane Protects Hepatocytes From Ischemic Injury by Reducing Reactive Oxygen Species Signaling of Hepatic Stellate Cells: Translational Findings Based on a Clinical Trial.

Randomized controlled trials (RCTs) data demonstrate that sevoflurane postconditioning improves clinical outcomes of liver resection with inflow occlusion, presumably due to hepatocyte protection from ischemic injury. However, mechanisms remain unclear. This study examines liver biopsy samples obtained in an RCT of sevoflurane postconditioning to test the hypothesis that sevoflurane attenuates hepatocyte apoptosis. Messenger ribonucleic acid (mRNA) of pro- and antiapoptotic regulators Bax and B-cell lymphoma 2 (Bcl2) was examined in hepatic biopsies obtained during the RCT. Hepatic stellate cells (HSCs) and hepatocytes were exposed to hypoxia/reoxygenation (H/R) in vitro to evaluate the effect of sevoflurane postconditioning on apoptosis. The role of HSC as a potential apoptosis trigger in hepatocytes through the production of reactive oxygen species induced by H/R was explored by transferring supernatants from H/R-exposed HSC to hepatocytes as target cells. In patients of the RCT, the Bax/Bcl2 mRNA ratio in liver tissue was markedly decreased in the sevoflurane arm (25% ± 21% reduction; P = .001). In vitro, H/R increased reactive oxygen species production in HSC by 33% ± 16% (P = .025), while it was abolished in the presence of sevoflurane (P < .001). In hepatocytes, caspase was minimally activated by H/R. However, incubation of hepatocytes with supernatants of HSC, previously exposed to H/R, increased caspase activity by 28% ± 13% (P < .001). When exposed to supernatants from HSC undergoing sevoflurane postconditioning, caspase activation in hepatocytes was reduced by 20% ± 9% (P < .001), similarly to the sevoflurane effect on the BAX/Bcl2 mRNA ratio in the liver samples. The study shows that sevoflurane postconditioning affects apoptosis of hepatocytes after ischemia-reperfusion injury in patients. It also demonstrates that HSC may be the effector cells of sevoflurane protection.

Herbal Drugs: Friend or Foe?

We herein report a rather peculiar case of acute liver injury. A 78-year-old woman developed asthenia and weakness. Her previous medical history was irrelevant, except for having received etoricoxib 60mg/24h for osteoarthritis 1 month before. Liver biochemistry indicated hepatic failure; all tests for viral, bacterial, or parasitic infections were negative, as were the autoimmunity tests. As the patient's status gradually declined, a transjugular hepatic biopsy was obtained and confirmed hepatocyte necrosis with severe inflammation and presence of numerous eosinophils. Suspecting a potential toxic cause of the disorder, the patient was requestioned and admitted curcuma consumption for a long time. She was asked to discontinue it and her status gradually improved, with normalization of all the analytical parameters. On the long-term follow-up, she remains well. We consider that this case of acute liver injury can be explained with the combination of the acute toxic effect of a drug, etoricoxib, and the herbal remedy curcuma. This case is illustrative of the risk of interactions between drugs and natural remedies, and to the best of our knowledge, it is the first case of severe hepatotoxicity related to etoricoxib, probably potentiated by long-term curcumin intake. Besides, it illustrates the fact that patients do not generally consider natural remedies as potential source of toxicity, and this can lead to a delay in diagnosis.

Recipient HO-1 inducibility is essential for posttransplant hepatic HO-1 expression and graft protection: From bench-to-bedside.

By documenting potent antioxidative and anti-inflammatory functions, preclinical studies encourage heme oxygenase-1 (HO-1)-inducing regimens in clinical orthotopic liver transplantation (OLT). We aimed to determine the importance of recipient-derived HO-1 in murine and human OLTs. Hepatic biopsies from 51 OLT patients were screened for HO-1 expression (Western blots) prior to put-in (basal) and post reperfusion (stressed) and correlated with the hepatocellular function. In parallel, livers from HO-1 proficient mice (WT; C57/BL6), subjected to ex vivo cold storage (18hour), were transplanted to syngeneic myeloid HO-1 deficient (mHO-1 KO) or FLOX (control) hosts, and sampled postreperfusion (6hour). In human OLT, posttransplant but not pretransplant HO-1 expression correlated negatively with ALT levels (P=.0178). High posttransplant but not pretransplant HO-1 expression trended with improved OLT survival. Compared with controls, livers transplanted into mHO-1 KO recipient mice had decreased HO-1 levels, exacerbated hepatic damage/frequency of TUNEL+ cells, increased mRNA levels coding for TNFα/CXCL1/CXCL2/CXCL10, higher frequency of Ly6G+/4HN+ neutrophils; and enhanced MPO activity. Peritoneal neutrophils from mHO-1 KO mice exhibited higher CellRox+ ratio and increased TNFα/CXCL1/CXCL2/CXCL10 expression. By demonstrating the importance of posttransplant recipient HO-1 phenotype in hepatic macrophage/neutrophil regulation and function, this translational study identifies recipient HO-1 inducibility as a novel biomarker of ischemic stress resistance in OLT.

Aging aggravates hepatic ischemia-reperfusion injury in mice by impairing mitophagy with the involvement of the EIF2α-parkin pathway.

Hepatic ischemia-reperfusion (I/R) injury fundamentally influences the performance of aged liver grafts. The significance of mitophagy in the age dependence of sensitivity to I/R injury remains poorly understood. Here, we show that aging aggravated hepatic I/R injury with decreased mitophagy in mice. The enhancement of mitophagy resulted in significant protection against hepatic I/R injury. Parkin, an E3 ubiquitin ligase, was found depleted by I/R in aged livers. In oxygen-glucose deprivation reperfusion (OGD-Rep.)-treated L02 cells, parkin silencing impaired mitophagy and aggravated cell damage through a relative large mitochondrial membrane potential transition. The phosphorylation of the endoplasmic reticulum stress response protein EIF2α, which was also reduced in the aged liver, induced parkin expression both in vivo and vitro. Forty-six hepatic biopsy specimens from liver graft were collected 2 hours after complete revascularization, followed by immunohistochemical analyses. Parkin expression was negatively correlated to donor age and the peak level of aspartate aminotransferase within first week after liver transplantation. Our translational study demonstrates that aging aggravated hepatic I/R injury by impairing the age-dependent mitophagy function via an insufficient parkin expression and identifies a new strategy to evaluate the capacity of an aged liver graft in the process of I/R through the parkin expression.

α-lipoic acid reduces postreperfusion syndrome in human liver transplantation - a pilot study.

A double-blind randomized controlled trial was performed to compare the safety and efficacy of α-lipoic acid (ALA) in liver transplantation (LT). The grafts were randomized to receive ALA or placebo before the cold ischemia time. Furthermore, patients transplanted with the ALA-perfused graft received 600 mg of intravenous ALA, while patients with the nonperfused graft received the placebo just before graft reperfusion. Hepatic biopsy was performed 2 h postreperfusion. Blood samples were collected before, during and 1 and 2 days after reperfusion. Quantitative polymerase chain reaction (qPCR) analysis was performed on biopsies to assess genes involved in the response to hypoxia, apoptosis, cell growth, survival and proliferation, cytokine production and tissue damage protection. Nine of 40 patients developed postreperfusion syndrome (PRS), but seven of them belonged to the control group. There was a decrease in PHD2 and an increase in alpha subunit of hypoxia-inducible factor-1 (HIF-1α) and baculoviral IAP repeat containing 2 (Birc2) transcript levels in the biopsies from the ALA-treated versus the control group of patients. Additionally, plasma levels of alarmins were lower in ALA-treated patients than control patients, which suggests that ALA-treated grafts are less inflammatory than untreated grafts. These results showed that ALA is safe for use in LT, induces gene changes that protect against hypoxia and oxidative stress and reduces the appearance of PRS.

Insuficiência cardíaca grave de etiologia amiloidótica

A amiloidose é uma doença sistêmica causada pela deposição extracelular de fibrilas insolúveis de proteínas de baixo peso molecular em diversos tecidos. Pode ser classificada nas formas: primária, secundária, hereditária e sistêmica senil. Relatamos o caso de um paciente masculino, 75 anos, que deu entrada em emergência cardiológica com quadro progressivo de edema em membros inferiores iniciado há quatro meses. Trinta dias antes do internamento passou a apresentar dispneia de médios para pequenos esforços, evoluindo para dispneia ao repouso e em decúbito (insuficiência cardíaca – classe funcional IV). Ao exame físico apresentou-se em estado geral regular, consciente, taquidispneico, afebril, hidratado, hipocorado (1+/4+), ictérico (2+/4+), acianótico e presença de estase jugular a 45°. O ritmo cardíaco era regular em dois tempos e bulhas, normofonéticas, com sopro sistólico em foco mitral (2+/6+) desdobramento fixo da segunda bulha; pressão arterial de 80x40 mmHg e frequência cardíaca de 84 bpm. O eletrocardiograma de admissão mostrou ritmo sinusal regular, bloqueio atrioventricular de 1º grau, baixa voltagem em derivações de plano frontal, zona eletricamente inativa em região ântero-septal e distúrbio de condução pelo ramo esquerdo do feixe de His. Radiografia de tórax com área cardíaca aumentada, padrão de congestão pulmonar e derrame pleural bilateral, mais acentuado à esquerda. Também foi realizado ecocardiograma transtorácico que evidenciou câmaras cardíacas aumentadas à direita, função sistólica de ventrículo direito levemente deprimida, insuficiência tricúspide moderada a importante, hipertensão pulmonar moderada, hipertrofia de ventrículo esquerdo, disfunção de ventrículo esquerdo e achado de ecogenicidade granular brilhante. Ultrassonografia de abdome mostrou fígado e baço com textura heterogênea, sugestivo de doença granulomatosa. Posteriormente foi realizada biópsia hepática que confirmou a hipótese de doença infiltrativa determinada pela amiloidose cardiovascular. Paciente evoluiu com rebaixamento de nível de consciência e insuficiência renal aguda, sendo realizada hemodiálise e transferência para Unidade Coronariana, onde apresentou parada cardiorrespiratória e evolução para óbito.

Imaging characteristics of Fasciola gigantica, a report of 29 cases

ObjectiveTo analyze imaging findings of Fasciola (F.) gigantica infection on computed tomography (CT), magnetic resonance imaging (MRI), and ultrasonography (US). MethodTwenty-nine patients with F. gigantica were admitted to the Affiliated Hospital of Dali University (n = 18) and Dali Prefecture People's Hospital (n = 11) from November 2011 to April 2012. All patients were examined by routine CT scan and US, and 24 of them were detected by MRI and MR cholangiopancreatography (MRCP). Serologic methods using enzyme-linked immunosorbent assay (ELISA) in 27 patients, stool examination in all patients, and hepatic tissue biopsy in 3 patients were performed. CT and US as follow-up examination was carried out in most patients for 3 years. ResultsMultiple and scattered hypodense lesions in liver were seen in all patients on CT. Four types of hepatic lesions were observed on MRI as follows: tunnel-like lesions, abscesses, enhancement lesions, and iso- or slightly hypointense areas on T1-weighted images or T2-weighted images. These hepatic lesions were hypoechoic on US. Pathological images showed coagulation necrosis of liver lesions. Multiple calcifications were disclosed in 19 patients at follow-up. ConclusionThe imaging findings of CT, MRI, and US are helpful for the diagnosis of acute and chronic stages of Fasciola gigantica in liver.

Abstract 5210: Liver prometastatic genes in patients with and without colorectal cancer

Abstract Metastasis-related hepatic genes were investigated in the tumor-unaffected hepatic tissue from patients with hepatic colorectal cancer (CRC) metastases. In addition, the contribution of CRC and patient's clinical parameters and comorbidities to hepatic expression of CRC prometastatic genes was also studied in new hepatic biopsies from metastasis-free CRC patients and from CRC-free patients used as controls. The expression level of 58% metastasis-associated hepatic genes significantly changed between patients with and without CRC. Principal component and Linear discriminant statistical analyses, and a hierarchical cluster analysis based on Pearson's correlation indices uncovered a subset of 37 CRC-dependent liver prometastatic genes able to segregate patients with and without CRC. Functionally, they belonged to immune regulation, inflammation, metabolic bioprotection, hepatokines and regeneration factors. More importantly, a multivariate canonical correlation analysis showed the additional contribution of patient's pathophysiology and comorbidities to hepatic gene expression and metastasis risk. The liver prometastatic gene expression pattern represented a patient-specific and heterogeneous hepatic reaction to CRC-specific factors, which developed prior to metastatic recurrence and varied according to location of such CRC in the left and right-sided colonic area and rectum. Citation Format: Fernando Vidal-Vanaclocha. Liver prometastatic genes in patients with and without colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5210.

Metastatic Breast Cancer Presenting as Painless Jaundice

Jaundice carries with it a wide-ranging differential diagnosis, including etiologies relating to infection, autoimmune, toxins, malignancy, and metabolic derangements. We present a case involving a female with history of breast cancer and relapse-free interval of 15 years who presented with an initial complaint of painless jaundice and was unfortunately diagnosed with metastatic disease involving the liver, bone, and lymph nodes. A 56-year-old female presented to the emergency department for evaluation of painless jaundice, first noticed by family members one day prior to arrival. The patient has a history of breast cancer at age 36, treated with chemotherapy, radiation, and right mastectomy. Physical exam revealed jaundice and scleral icterus and a firm, non-tender liver, palpable beyond the costal border with a negative Murphy's sign. Laboratory findings were consistent with a cholestatic process. A right upper quadrant abdominal ultrasound revealed a 4.1 x 3.6 cm poorly defined mass in the right lobe of the liver, common bile duct measuring 8.6 mm, and intrahepatic ductal dilatation, suggestive of distal common bile duct obstruction. A follow up MRCP showed extensive hepatic metastases with innumerable liver lesions of varying shape and size. The patient underwent an ERCP, where a pancreatic duct stent was deployed but the common bile duct could not be cannulated. The patient subsequently underwent a hepatic lesion biopsy and placement of an internal/external biliary drainage catheter by Interventional Radiology secondary to complete, abrupt obstruction of the distal common bile duct. Biopsy results were positive for primary mammary malignancy. A review of the literature revealed only a select number of cases where patients presented with painless jaundice deemed secondary to metastatic breast cancer. This is the first such case in which the patient already had a known diagnosis of breast cancer, irrespective of prior treatment. In patients with malignant obstruction, biliary stenting has been shown to improve jaundice and deliver improved quality of life. In conclusion, in patients with known malignancy, the development of jaundice may indicate hepatic or biliary metastasis with bile duct obstruction. While a multidisciplinary approach to treatment is necessary, biliary stenting to relieve obstruction is a viable option for palliation.1364_A.tif Figure 1: Papanicolaou stain, (A, 40x) showing numerous large atypical atypical cells with high nuclear to cytoplasmic ratios. H&E stain (B, 10x) of the core biopsy showing this infiltrate within the liver parenchyma. Additional immunohistochemical stains show these cells are positive for GATA3 (C, 10x), GDCDFP-15 (D, 10x), mammaglobin (E, 10x), and ER (F, 10x).1364_B.tif Figure 2: MRI of abdomen: axial image showing extensive hepatic metastases with innumerable liver lesions of varying shape and size.

Evaluation of β-carotene assimilation in leopard geckos (Eublepharis macularius).

Although leopard geckos (Eublepharis macularius) are commonly kept under human care, their vitamin requirements are largely unknown. Many invertebrate preys display a low vitamin A concentration; thus, gut-loading insects with vitamin A or carotenoids is a common practice. The objective of this prospective experimental study was to investigate whether dietary supplementation with β-carotene, including prey gut-loading, leads to sufficient vitamin A hepatic storage and prevents epithelial squamous metaplasia development in leopard geckos. Ten clinically healthy female leopard geckos were randomly divided in two groups with various supplementations: a group receiving vitamin A supplementation and a group receiving β-carotene. Insects were gut-loaded continuously with a supplement containing vitamin A or β-carotene, depending on the group. Oral supplementation with cod liver oil or carrot juice was administered weekly to each lizard from "vitamin A group" and "carotenoid group" respectively. After 10weeks of supplementation, surgical hepatic biopsies were obtained in three geckos of each group while the two remaining geckos were euthanized to undergo complete necropsy. Hepatic vitamin A concentration was determined for each lizard (n=10) by ultra-performance liquid chromatography. Histopathology revealed hepatocellular vacuolization and vitellogenic follicles in five females. Epithelial squamous metaplasia was not observed in any of the geckos. Hepatic vitamin A concentration was significantly higher in the carotenoid-supplemented group than in the vitamin A-supplemented group (p=0.03). Our results suggest that in leopard geckos, dietary supplementation with β-carotene allows sufficient vitamin A hepatic storage.

Síndrome febril sin foco en paciente con infección por el VIH

With antirretroviral therapy, the incidence of opportunistic infections has decreased; nevertheless, fever in HIV-infected patients is a common symptom. A complete study should be made (history and physical examination) and complementary tests can be very useful: blood cultures, imaging tests such as thoracoabdominal CT or PET-CT, and bone marrow, hepatic or lymph biopsies. Infections are the most frequent cause (80%) of fever of unknown origin, and tuberculosis is the most common. Other common causes are: Mycobacterium avium complex, Leishmania (especially in the Mediterranean area), toxoplasmosis, cytomegalovirus, Pneumocystis jiroveci, cryptococcus and histoplasmosis (in areas of high prevalence). Other possible causes of fever can be due to neoplasias such as lymphoma, immune reconstitution inflammatory syndrome and drug-associated fever.

Periductal Lymphocytic Infiltrate at Bilary Atresia Diagnosis Increases the Risk of Addition to the Transplant Waitlist

PurposeBiliary atresia (BA) is the main indication for pediatric liver transplantation. The aim of this study is to correlate aspects of histological examinations of diagnostic hepatic biopsies for BA with the patients' clinical progression and successful addition to the liver transplant waitlist. MethodsThis was a retrospective study of all 108 BA cases treated at the Federal University of São Paulo (1998–2015). Demographic and clinical data were correlated with histological findings. A logistic regression was used for outcome analysis, while the Kaplan-Meier method was applied for survival analysis. ResultsThere were 108 patients with BA, 68.5% of whom underwent Kasai surgery. Patients added to the transplant waitlist tended to undergo Kasai surgery at a later time (P = .035). Periductal lymphocytic infiltrate was correlated with the addition to the transplant waitlist, with an odds ratio of 3.92 (P = .033). Patients who developed ascites after surgery were more frequently added to the transplant waitlist (P = .05). ConclusionPatients added to the transplant waitlist underwent Kasai surgery later than other patients. Periductal lymphocytic infiltrate in the diagnostic hepatic biopsy and ascites after Kasai surgery were associated with an increased likelihood of addition to the transplant waitlist.

Serelaxin induces Notch1 signaling and alleviates hepatocellular damage in orthotopic liver transplantation.

Liver ischemia-reperfusion injury (IRI) represents a risk factor for early graft dysfunction and an obstacle to expanding donor pool in orthotopic liver transplantation (OLT). We have reported on the crucial role of macrophage Notch1 signaling in mouse warm hepatic IRI model. However, its clinical relevance or therapeutic potential remain unknown. Here, we used Serelaxin (SER), to verify Notch1 induction and putative hepatoprotective function in ischemia-reperfusion-stressed OLT. C57BL/6 mouse livers subjected to extended (18-hour) cold storage were transplanted to syngeneic recipients. SER treatment at reperfusion ameliorated IRI, improved post-OLT survival, decreased neutrophil/macrophage infiltration, and suppressed proinflammatory cytokine programs, while simultaneously increasing Notch intracellular domain (NICD) and hairy and enhancer of split 1 (Hes1) target genes. In bone marrow-derived macrophage cultures, SER suppressed proinflammatory while enhancing antiinflammatory gene expression concomitantly with increased NICD and Hes1. Hepatic biopsies from 21 adult primary liver transplant patients (2hours postreperfusion) were divided into low-NICD (n=11) and high-NICD (n=10) expression groups (western blots). Consistent with our murine findings, human livers characterized by high NICD were relatively IRI resistant, as shown by serum alanine aminotransferase (ALT) levels at day 1 post-OLT. Our study documents the efficacy of SER-Notch1 signaling in mouse OLT and highlights the protective function of Notch1 in liver transplant patients.

Aflatoxin B1 residues in human livers and their relationship with markers of hepatic carcinogenesis in São Paulo, Brazil.

In this study, hepatic biopsies from autopsy cases in São Paulo, Brazil, showing hepatocellular carcinoma (HCC, n = 8), cirrhosis associated with viral hepatitis (VC, n = 20), cirrhosis associated with alcoholism (AC, n = 20), and normal livers (NL or controls, n = 10) were subjected to determination of aflatoxin B1 (AFB1) and its main metabolites, and of markers of hepatic carcinogenesis Only non-metabolized AFB1 was detected in 13 samples (27.1%, N = 48) of liver disorders (HCC, VC and AC), at levels between 10.0 and 418.0 pg/g (mean: 76.6 ± 107.7 pg/g). Immuno-labeling of p53, cyclin D1, p21, β-catenin, and Prohibitin (PB) increased mainly in HCC patients, in relation to the controls. AFB1+ samples of HCC presented higher expressions of p53, cyclin D1, p21, and β-catenin compared with AFB1-livers. In contrast, p27, p16, and Rb immuno-labeling decreased in HCC, VC, and AC samples, compared with NL, with lowest values in AFB1+ samples for all liver disorders. Compared with NL, gene expression of cyclin D1 and PB in AFB1+ samples of HCC and AC were also higher, along with higher gene expression of p21 in VC and AC AFB1+ livers. Results indicated that patients with liver disorders were exposed to dietary aflatoxins, and that residual AFB1 in liver negatively affected the p53 and protein Rb pathways in HCC. Moreover, the presence of AFB1 in cirrhotic livers warrants concern about the potential contribution of dietary aflatoxin to disease progression during VC and AC.

Tumor syndrome, hepatic and hematological features revealing undiagnosed early rheumatoid arthritis

Background: Extra-articular manifestations in rheumatoid arthritis (RA) are rare and generally occur in an advanced stage of the disease. We report a case of an unusual onset of early RA. Case presentation: A 21 year old male complains of polyathritis involving small and large joints, associated with fever, asthenia, anorexia and weight loss. The temperature was up to 38.8°. There was a left cervical adenopathies, hepato-splenomegaly and there were synovitis in all joints sparing distal interphalangial joints. The erythrocyte sedimentation rate was accelerated; the C-reactive protein was up to 222 mg/l. The number of white blood cells were 9000/mm3 with monocytosis, lymphocytosis and thrombocytosis at 986000/mm3 . There was cholestasis with cytolysis. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (ACCP) were positive. The hands X-ray didn’t show any RA specific signs. The chest X-Ray showed a left pleurisy. The CT scan showed multiple axillar and mediastinal lymphadenopathies, hepato-splenomegaly with multiple coelio-mesenteric and retroperitoneal lymph nodes. The pleural biopsy as well as the biopsy of the adenopathy and the salivary glands didn’t show any specific abnormalities or signs of lymphoma. The hepatic biopsy revealed an inflammatory lymphohistiocytic infiltrate with rare foci of necrosis and a dilatation of the hepatic sinusoids. The diagnosis of RA was suspected and confirmed by the MRI of the hands. Conclusion: RA may have an unusual onset such as hematologic, hepatic, pleuropulmonary features or tumor syndrome, but it is rarely reported. The diagnosis in this case is difficult

КЛИНИЧЕСКАЯ МОРФОЛОГИЯ ПЕЧЕНИ: ЦИТОТОКСИЧЕСКИЕ ЛИМФОЦИТЫ

Background. The liver is the organ of the immune system, in which various populations of lymphocytes are representatives of congenital and acquired immunity: NK cells, NKT cells, LGL cells, CD8 + (CTL) cells that participate in cytotoxic reactions. The aim of the study is to present the structural and functional characteristics of the main populations of cytotoxic lymphocytes that take an active part in the development of inflammation in viral liver damage. Material and methods. Morphological evaluation of intravital hepatic biopsy specimens of patients with chronic viral hepatitis was performed by light and electron microscopy with the use of classical and original techniques for fixing and staining preparations. Results. A detailed description of the structure of the main populations of lymphocytes in the liver (NK cells, NKT cells, LGL cells, CD8 + cells) and their basic immunomorphological data and cytotoxic characteristics are presented. The main methods used in clinical practice for morphological evaluation of the activity of inflammation in the liver are described. Conclusions. The most studied participants in the development of cytotoxicity in chronic viral hepatitis are lymphocytes, which cause direct and indirect damage to hepatocytes: NK cells, NKT cells, LGL and CTL (CD8+ T cells) cells that differ by their phenotypic as well as structural and functional characteristics. The classical method of light microscopy of liver biopsy samples does not allow to differentiate populations of cytotoxic lymphocytes, in contrast to light microscopy of semi-thin sections and electron microscopy. An additional morphological indicator for the evaluation of activity and monitoring of inflammation in the liver can be a morphological (quantitative) characteristic of the cellular population of lymphocytes of the congenital and adaptive immunity.