Giant Hepatocytes Research Articles

Carcinogenic effect of human tumor-derived cell-free filtrates in nude mice.

Cancer remains a worldwide cause of morbidity and mortality. Investigational research efforts have included the administration of tumor-derived extracts to healthy animals. Having previously demonstrated that the administration of non-transmissible, human cancer-derived homogenates induced malignant tumors in mice, here, we examined the consequences of administering 50 or 100µg of protein of crude homogenates from mammary carcinoma, pancreatic adenocarcinoma, and melanoma samples in 6 inoculations per week during 2months. The concurrent control mice received homogenates of healthy donor-skin cosmetic surgery fragments. Mammary carcinoma homogenate administration did not provoke the deterioration or mortality of the animals. Multiple foci of lung adenocarcinomas with a broad expression of malignity histomarkers coexisting with small cell-like carcinomas were found. Disseminated cells, positive to classic epithelial markers, were detected in lymphoid nodes. The administration of pancreatic tumor and melanoma homogenates progressively deteriorated animal health. Pancreatic tumor induced poorly differentiated lung adenocarcinomas and pancreatic islet hyperplasia. Melanoma affected lungs with solid pseudopapillary adenocarcinomas. Giant atypical hepatocytes were also observed. The kidney exhibited dispersed foci of neoplastic cells within a desmoplastic matrix. Nuclear overlapping with hyperchromatic nuclei, mitotic figures, and prominent nuclear atypia was identified in epidermal cells. None of these changes were ever detected in the control mice. Furthermore, the incubation of zebrafish embryos with breast tumor homogenates induced the expression of c-Myc and HER-2 as tumor markers, contrasting to embryos exposed to healthy tissue-derived material. This study confirms and extends our hypothesis that tumor homogenates contain and may act as vectors for "malignancy drivers," which ultimately implement a carcinogenesis process in otherwise healthy mice.

Role of CD68+ and CD206+ cells in the progression of toxic liver fibrosis in rats

The aim of the work was to evaluate the role of stellate macrophages in a large number of points of toxic liver fibrosis in rats. Liver fibrosis and cirrhosis in male Wistar rats were induced with thioacetamide at a dose of 200 mg/kg animal weight for 17 weeks. Histological preparations of the liver were stained with hematoxylin and eosin according to the Mallory method. Immunohistochemical examination was performed on paraffin sections using monoclonal mouse antibodies CD68 and polyclonal rabbit antibodies CD206. The fibrosis degree was determined according to the Ishak semi-quantitative scale. Toxic liver fibrosis before the start of its transformation into cirrhosis (9 weeks) was accompanied by an increase in the number of CD68+ cells compared with the control. At all subsequent experiment stages, no differences were found in comparison to the control. In the liver of control rats, CD206+ cells were practically absent. Throughout the experiment, their number remained above the control point – 3 weeks. With the progression of liver cirrhosis, a decrease in the number of CD206+ cells was noted, but it did not reach a level of 3 weeks. Morphologically, two different groups of CD68+ cells were identified. One group of cells had a pterygoid shape and they were located mainly in the liver sinusoids. The second group of CD68+ cells had a round shape and different localization. They were detected around the vessels of portal zones, surrounded brown pigment accumulations in connective tissue septa, were observed near single lying groups or groups of giant hepatocytes and liver cells containing brown pigment in the cytoplasm, and were also noted in the foci of necrosis of hepatocytes. Cells, expressing the CD206 marker, are round in shape and are elongated and located in the liver sinusoids. Presumably, round-shaped CD68+ cells perform a phagocytic function, and pterygoid-shaped CD68+ cells transdifferentiate into CD206+ cells that have anti-inflammatory properties.

Association of giant cell hepatitis and autoimmune hemolytic anemia in infancy

Giant cell hepatitis associated with autoimmune hemolytic anemia (GCH-AIHA) is a rare disorder with unfavorable prognosis, affecting infants and young children. The mortality rate is high, complications of acute liver failure, sepsis, or liver transplantation can be responsible for fatal outcomes. An 18-month-old child who was diagnosed previously with autoimmune hemolytic anemia, developed acute hepatitis and acute liver failure concomitant to the relapse of the disease. GCH-AIHA is characterized by Coombs positive hemolytic anemia and progressive liver injury, histologically defined by widespread giant cell transformation. Liver biopsy was performed to establish the diagnosis, histological examination confirmed the presence of multinuclear, giant cell hepatocytes. Corticosteroid and azathioprine treatment were started. As a result of subsequent rituximab treatment and intravenous immunoglobulin therapy, acute liver failure and anemia gradually resolved. The exact background of the association of the two entities is still unknown, an autoimmune mechanism is suspected. Conventional immunosuppressive treatment with corticosteroid and azathioprine seems to be ineffective in most cases, therefore second- and third-line therapies are required. Since the introduction of the anti-CD20 rituximab therapy, the prognosis of GCH-AIHA has improved significantly. Orv Hetil. 2023; 164(36): 1432-1436.

S2513 Giant Cell Hepatitis Due to Drug-Induced Autoimmune Hepatitis from Dupilumab

INTRODUCTION: Giant cell hepatitis (GCH) is a pathologic diagnosis characterized by liver inflammation and large multinucleated hepatocytes. GCH is a common pathologic entity in infants but is exceedingly rare in adults. It is typically in response to drugs, autoimmune hepatitis (AIH), viruses and malignancy. We present a case of drug-induced autoimmune hepatitis causing giant cell transformation. CASE DESCRIPTION/METHODS: A 24-year-old male with eosinophilic asthma, chronic eosinophilia, primary sclerosing cholangitis (PSC) and Crohn’s disease presented with right upper quadrant pain, jaundice, anorexia, lymphadenopathy and weight loss. Labs on admission were AST 973 (u/L), ALT 801 (u/L), AP 225 (u/L), total bilirubin 16.6 (mg/dL), direct bilirubin 11.2 (mg/dL), INR 2.4, absolute eosinophil count 20.4 (k/uL). Extensive serologic work up of acute liver injury was unrevealing with the exception of a total IgG of 5291 (mg/dL). An MRI abdomen demonstrated hepatomegaly, non-specific hepatitis and findings consistent with his known PSC. Workup for infectious, autoimmune and malignant causes of hypereosinophilia was negative. Three months prior to admission, he was started on dupilumab for his eosinophilic asthma. A liver biopsy was pursued. H&E Staining (Figure 1) noted prominent giant cell hepatocellular transformation and hepatocyte ballooning degeneration. There were plasma cell, lymphocyte and eosinophil portal infiltrates present. Trichrome staining (Figure 2) showed fibrosis in a periportal and patchy sinusoidal pattern. The pathologic analysis was most consistent with giant cell hepatitis. His clinical and pathologic diagnosis was consistent with GCH due to drug-induced AIH from dupilumab. Management included discontinuation of dupilumab and IV methylprednisolone which was transitioned to a prolonged prednisone taper at discharge. After 6 months, his liver function tests have nearly normalized. DISCUSSION: GCH is a common pathologic entity in infants but is rare in adults. Fewer than 100 reported adult cases are present in the literature. AIH followed by drug-induced and viral hepatitis are most frequently causative of GCH. Our patient’s negative serologic workup, biopsy findings, and timing of dupilumab initiation to acute hepatitis makes drug-induced autoimmune hepatitis the most likely etiology. There have been no previous reports that dupilumab has been implicated in drug-induced liver injury, drug-induced AIH or has been responsible for the pathologic diagnosis of Giant Cell Hepatitis.Figure 1.: Liver biopsy (H&E stained slide, 200x): This portal tract demonstrates a mixed inflammatory infiltrate composed of lymphocytes, plasma cells, and eosinophils without vasculitis or ductulitis. The portal tract is surrounded by the prominent multinucleated, syncytial giant hepatocytes and ballooning degeneration.Figure 2.: Liver biopsy (Massons's Trichrome stain, 200x): The trichrome staining demonstrates increased periportal fibrosis and patchy perisinusoidal fibrosis.

S2405 Post-Infantile Giant Cell Hepatitis

INTRODUCTION: Post-infantile giant cell hepatitis (PIGCH) is a rare disorder among adults. Diagnosis is dependent on liver biopsy and its histologic hallmark is the presence of hepatocyte-derived multinucleated giant cells. This is thought to be due to increased hepatocyte regenerative activity that occurs as a response to noxious stimuli including viral infections, autoimmune disorders, leukemia and drug reactions. We report two cases of PIGCH including its management and outcome. CASE DESCRIPTION/METHODS: Case 1 is a 62-year-old African American male who presented with jaundice, dark urine and generalized malaise. Past medical history notable for alcohol use disorder in remission and chronic hepatitis C treated with antiviral therapy. Physical examination revealed jaundice. Bloodwork included ALT 2,300 U/L, AST 1,900 U/L, ALP 186 U/L, GGT 177 U/L, serum total bilirubin 29 mg/dL, direct bilirubin 20 mg/dL, AFP level 25 μg/L and INR 1.5. Infectious work up was negative and abdominal ultrasound was normal. Autoimmune markers ANA, SMA and AMA were positive. Liver biopsy showed severe syncytial giant cell hepatitis with 75% loss of hepatocytes. Patient was started on steroids with complete normalization of his transaminases on four month follow up. Case 2 is a 69-year-old Caucasian male with history of dyslipidemia, hypertension and chronic lymphocytic leukemia (CLL) on Ibrutinib, who presented with generalized malaise. He denied any alcohol, tobacco, or substance use. Physical examination revealed jaundice. Bloodwork included AST 2,385 U/L, ALT 5,609 U/L, ALP 286 U/L, total bilirubin 31.3 mg/dL, direct bilirubin 23.6 mg/dL and INR was 1.1. Infectious and autoimmune work up was negative. Abdominal ultrasound was normal. Liver biopsy showed syncytial giant cell hepatitis with CLL infiltrates on most portal tracks. Patient was started on steroids with temporary normalization of transaminases. Unfortunately, one week later, the patient died due to cancer-related complications. DISCUSSION: PIGCH has been commonly associated with autoimmune hepatitis but only a few case reports of CLL-associated PIGCH exist. Given its heterogeneous etiologies, PIGCH is difficult to prognosticate and manage. However, it should be considered in all patients with acute liver injury or chronic liver disease of unknown disease. Despite having a good response to immunosuppressive therapy, patients may still develop severe progressive disease requiring liver transplantation. Hence, prompt recognition and treatment is crucial.Figure 1.: The multinucleated giant cell hepatocytes (see arrows) are seen in H&E stained sections of biopsy. These are reactively altered hepatocytes (rather than multinucleated giant cell histiocytes). Immunoperoxidase stains show (see inset images) that within multinucleated hepatocytes, nuclei are strongly positive for Cyclin-D1 and cytoplasm is strongly positive for cytokeratin CK8/CK18 (Cam5.2).Figure 2.: In Case 2, the same stains were used as in Case 1 however the portal tract contains an infiltrate of neoplastic lymphoid cells (CLL).

Serum ferritin in neonatal cholestasis: A specific and active molecule or a non-specific bystander marker?

BackgroundSerum ferritin (SF) and consequently hepatic iron have long been considered important in liver fibrosis progression. They have been studied in different liver diseases with no previous reports in neonatal cholestasis (NC). This study aimed to measure SF in different etiologies of NC and investigate its relation to hepatic iron and fibrosis. MethodsSF was measured in 75 infants, including 50 with NC and 25 with sepsis. SF was compared between these two groups. Biochemical parameters, hepatic iron grades, and liver fibrosis and other histopathological characteristics and correlated with SF were assessed in NC group. Finally, a comparison between intrahepatic cholestasis and obstructive etiology was performed. ResultsSF was elevated in NC (1598 ± 2405 ng/mL) with no significant difference from those with sepsis (P = 0.445). NC and sepsis constituted augmenting factors leading to more elevation of SF (2589 ± 3511 ng/mL). SF was significantly correlated with hepatic iron grades (r = 0.536, P < 0.0001) and a cut-off value of 803.5 ng/mL can predict higher grades (≥ grade 3) of iron deposition with sensitivity of 100%, specificity of 70% and accuracy of 85%. Moreover, SF was significantly higher (P < 0.0001) in those with intrahepatic cholestasis (2602 ± 3154 ng/mL) and their prevalent pathological findings of giant cell transformation (P = 0.009) and hepatocyte swelling (P = 0.023) than those with obstructive etiology (672 ± 566 ng/mL) and their prevalent pathological findings of ductular proliferation (P = 0.003) and bile plugs (P = 0.002). SF was unrelated to the grade of liver fibrosis (P = 0.058). ConclusionsSF is non-specifically elevated in NC, with positive correlation to hepatic iron grades. SF ≥ 803.5 ng/mL can predict higher grades (≥ grade 3) of hepatic iron. However, an active role of increased SF and hepatic iron in disease progression remains questionable.

Leptospira induced abortion in goats in Southern Gujarat

Present report deals with the investigation of abortion in goats caused by Leptospira infection. The peritoneal fluid and blood samples were collected from aborted foetuses. On the basis of dark field microscopy, culture isolation and foetal pathology, the aetiological agent was confirmed to be Leptospira spp. Histopathologically, foetal liver and kidneys showed severe degenerative changes and infiltration of mononuclear inflammatory cells along with congestion and haemorrhages. In the liver, giant cell hepatocytes and dissociation of hepatic cords and in the kidneys, tubular ectasia and giant cells were also noted. The dam's sera were found negative for Brucella antibodies. Leptospira spp. was identified in sera samples of aborted foetuses by dark field microscopy and isolation of the organism.

An Elderly Man with Syncytial Giant Cell Hepatitis Successfully Treated by Immunosuppressants

Here, we report an elderly man with acute-on-chronic hepatitis accompanied by massive ascites. He showed elevated serum transaminase and anti-nuclear antibody (ANA) levels. Liver biopsy showed diffuse multinucleated giant hepatocytes with interface hepatitis, and he recovered with administration of azathioprine in addition to corticosteroids. Follow-up liver biopsy after recovery showed improvement of hepatic inflammation and reduction of giant hepatocyte formation. The patient is receiving low-dose corticosteroid maintenance therapy and he has remained healthy for 8 years to date. Active immunosuppressive treatment may be beneficial in patients with adult syncitial giant cell hepatitis (AGCH).

Relapsing features of bile salt export pump deficiency after liver transplantation in two patients with progressive familial intrahepatic cholestasis type 2

PFIC2 is caused by mutations in ABCB11 encoding BSEP. In most cases affected children need liver transplantation that is thought to be curative. We report on two patients who developed recurrent normal GGT cholestasis mimicking primary BSEP disease, after liver transplantation. PFIC2 diagnosis was made in infancy in both patients on absence of canalicular BSEP immunodetection and on ABCB11 mutation identification. Liver transplantation was performed at age 9 (patient 1) and 2.8 (patient 2) years without major complications. Cholestasis with normal GGT developed 17 and 4.8years after liver transplantation, in patient 1 and patient 2, respectively, during an immunosuppression reduction period. Liver biopsies showed canalicular cholestasis, giant hepatocytes, and slight lobular fibrosis, without evidence of rejection or biliary complications. An increase in immunosuppression resulted in cholestasis resolution in only one patient. Both patients developed atrial fibrillation, and one melanonychia. The newborn of patient 1 developed transient neonatal normal GGT cholestasis. Immunofluorescence staining of normal human liver sections with patient's sera, collected at the time of cholestasis, and using an anti-human IgG antibody to detect serum antibodies, showed reactivity to a canalicular epitope, likely to be BSEP. Indeed, Western blot analysis showed that patient 2 serum recognized rat Bsep. Allo-immune mediated BSEP dysfunction may occur after liver transplantation in PFIC2 patients leading to a PFIC2 like phenotype. Extrahepatic features and/or offspring transient neonatal cholestasis of possible immune mediated mechanisms, may be associated. Increasing the immunosuppressive regimen might be an effective therapy.

Atp8b1 and Abcb11 Analysis in 62 Children With Normal Gamma-Glutamyl Transferase Progressive Familial Intrahepatic Cholestasis (Pfic): Phenotypic Differences Between Pfic1 and Pfic2 and Natural History

Progressive familial intrahepatic cholestasis (PFIC) types 1 and 2 are characterized by normal serum gamma-glutamyl transferase (GGT) activity and are due to mutations in ATP8B1 (encoding FIC1) and ABCB11 (encoding bile salt export pump [BSEP]), respectively. Our goal was to evaluate the features that may distinguish PFIC1 from PFIC2 and ease their diagnosis. We retrospectively reviewed charts of 62 children with normal-GGT PFIC in whom a search for ATP8B1 and/or ABCB11 mutation, liver BSEP immunostaining, and/or bile analysis were performed. Based on genetic testing, 13 patients were PFIC1 and 39 PFIC2. The PFIC origin remained unknown in 10 cases. PFIC2 patients had a higher tendency to develop neonatal cholestasis. High serum alanine aminotransferase and alphafetoprotein levels, severe lobular lesions with giant hepatocytes, early liver failure, cholelithiasis, hepatocellular carcinoma, very low biliary bile acid concentration, and negative BSEP canalicular staining suggest PFIC2, whereas an absence of these signs and/or presence of extrahepatic manifestations suggest PFIC1. The PFIC1 and PFIC2 phenotypes were not clearly correlated with mutation types, but we found tendencies for a better prognosis and response to ursodeoxycholic acid (UDCA) or biliary diversion (BD) in a few children with missense mutations. Combination of UDCA, BD, and liver transplantation allowed 87% of normal-GGT PFIC patients to be alive at a median age of 10.5 years (1-36), half of them without liver transplantation. PFIC1 and PFIC2 differ clinically, biochemically, and histologically at presentation and/or during the disease course. A small proportion of normal-GGT PFIC is likely not due to ATP8B1 or ABCB11 mutations.

Variable Clinical Spectrum of the Most Common Inborn Error of Bile Acid Metabolism—3β‐hydroxy‐Δ5‐C27‐steroid Dehydrogenase Deficiency

We studied the clinical features of children with 3beta-hydroxy-Delta 5-C27-steroid dehydrogenase (3beta-HSDH) deficiency presenting to King's College and Great Ormond Street hospitals between 1989 and 2005. The diagnosis was made biochemically by detection of sulphated dihydroxycholenoic acids and trihydroxycholenoic acids in urine by fast atom bombardment mass spectrometry or electrospray ionisation tandem mass spectrophotometry and a plasma bile acid profile showing absent or low cholic and chenodeoxycholic acid levels and high concentrations of 3beta-7 alpha-dihydroxy-5-cholenoic acid and 3beta-7 alpha-12 alpha-trihydroxy-5-cholenoic acid. Eighteen children (12 male) with 3beta-HSDH deficiency were identified and diagnosed at a median age of 1.35 years (range 8 weeks-11 years). The presenting features included neonatal cholestasis (n = 11), rickets (n = 8, 1 of whom also had hypocalcaemic tetany, seizures, and normal liver biochemical markers), hepatomegaly (n = 7), pruritus (n = 3), and steatorrhoea and failure to thrive (n = 3). Ten children had low serum 25-OH vitamin D levels, of whom 8 also had low vitamin E and 6 had low vitamin A serum levels. Liver histology showed giant cell change and hepatocyte disarray in all with added features of cholestasis in 11, bridging fibrosis in 6, micronodular cirrhosis in 1, fatty change in 1, and active lobular and portal inflammation in 1. Five patients were treated with cholic acid and chenodeoxycholic acid (7 mg x kg(-1) x day(-1) of each), 7 with chenodeoxycholic acid only (7-18 mg x kg(-1) x day(-1)), and 1 with cholic acid (8 mg x kg(-1) x day(-1)) only. Repeated liver biopsies performed in 4 patients 6 months after starting replacement therapy showed improved histological changes. Three children died untreated before 5 years of age. After a median follow-up of 5.5 years (range 1-17 years) 12 out of 13 treated children have no clinical signs of liver disease or of fat-soluble vitamin deficiency. 3beta-HSDH deficiency is a rare inborn error of metabolism with diverse clinical features. Early replacement treatment leads to clinical and biochemical control and prevents chronic liver and bone disease, at least in the medium term.

Recent developments in liver pathology

Progress in liver histopathology continues to be made, as evidenced by recent publications in all areas of hepatobiliary disease. Multinucleated giant hepatocytes, known to be associated with autoimmune and drug hepatitis, now have been seen in chronic hepatitis C with or without HIV infection and in patients with infection by human herpesvirus-6A. The new term Mallory-Denk body (formerly the Mallory body) recognizes the substantial contributions to this field by Professor Helmut Denk of Austria. The problems of fatty liver and hepatic iron overload have been addressed in studies highlighting their complex pathogenesis. Genomic and immunohistochemical analysis of liver tumors provides important diagnostic information, particularly regarding the use of glypican-3 in the diagnosis of hepatocellular carcinoma.

A case of lamivudine-sensitive de novo acute hepatitis B induced by rituximab with the CHOP regimen for diffuse large B cell lymphoma

A case of de novo acute hepatitis B that showed symptoms of general malaise and anorexia during rituximab therapy with the CHOP regimen for diffuse large B cell lymphoma is reported. Lamivudine was strikingly effective, showing a rapid recovery from liver damage with jaundice. Hepatitis B virus (HBV) DNA in serum became and stayed undetectable even after the withdrawal of lamivudine, although HBsAg remained positive over 42 months from the onset. Liver biopsy showed a picture suggestive of acute viral hepatitis with multinucleated giant hepatocytes and CD38-positive plasma cell infiltration into liver parenchyma. Immunohistochemically, CD3-positive T-cells were predominant cells that infiltrated in liver parenchyma, whereas CD20-positive B cells were essentially null. Hence, it is suggested from these findings that B lymphocytes might be crucial for the continuous latency in HBV infection and may give rise to de novo acute hepatitis B if totally deleted. Moreover, the CHOP regimen might have some additive effects with the repeated on-off use of corticosteroids to the onset of the disease. In addition, significance of plasma cell infiltration in this setting is discussed.

Familial Perinatal Liver Disease and Fetal Thrombotic Vasculopathy

The association between placental fetal thrombotic vasculopathy (FTV) and perinatal liver disease was not recognized until 2002, when Dahms and colleagues reported a series of 3 patients in whom severe liver disease developed in the first 2 days of life. All had abnormal liver histology and showed a variety of abnormalities, including Budd-Chiari syndrome, changes mimicking extrahepatic obstruction, lobular fibrosis, cholestasis, and hepatocyte giant cell transformation. We report recurrent significant perinatal liver disease in a family, associated with proven FTV in at least 1 pregnancy. A 30-year-old gravida 4 female with a history of heterozygous methylenetetrahydrofolate A1298C mutation had a normal 1st pregnancy and then experienced an intrauterine fetal demise at 38 weeks of gestation. Placental examination revealed extensive occlusive and mural thrombi of chorionic vessels associated with a large focus of avascular villi. Histologic examination of the liver showed extensive giant cell transformation and hepatocyte dropout. No excess hemosiderin pigment was present in the liver, pancreas, or heart. A 3rd pregnancy produced a live-born term infant with transient neonatal cholestasis. The 4th pregnancy also produced a term neonate who presented with acute hepatic failure of unknown cause, ultimately requiring liver transplantation. Fetal thrombotic vasculopathy is an underrecognized association with perinatal liver disease that may be associated with abnormal liver perfusion and that may recur in families, especially when a genetic thrombophilia is present.

Giant Cell Hepatitis and Autoimmune Hemolytic Anemia Successfully Treated With Rituximab

Giant Cell Hepatitis and Autoimmune Hemolytic Anemia Successfully Treated With Rituximab

Syncytial giant cell hepatitis in human immunodeficiency virus–infected patients with chronic hepatitis C: 2 cases and review of the literature

Syncytial giant cell hepatitis (SGCH) among adult human immunodeficiency virus (HIV)-infected patients has been rarely described. Most cases have been reported in subjects coinfected with the hepatitis C virus (HCV), but its prevalence and outcome remain unknown. We performed a retrospective analysis of all cases of SGCH among 332 liver biopsies from HIV-infected patients seen at a tertiary center in Madrid, Spain, between 1984 and March 2004. Two hundred fifty specimens were obtained from HCV-coinfected patients. There were 2 cases of SGCH, leading to an observed overall prevalence of 0.6% (0.8% when considering only HCV-coinfected patients). In addition to histological changes secondary to chronic hepatitis C, the liver cords were replaced by syncytial giant cells with up to 30 nuclei. There was no histological evidence of measles (among paramyxoviruses) or herpes viruses group infections. In patient 1, there was a progressive clinical worsening after a 3-month course of prednisone, leading to liver failure and death. His postmortem liver biopsy showed more abundant giant hepatocytes accompanied with the development of a histologic pattern of severe fibrosing cholestatic hepatitis. The second patient received a prolonged course of pegylated interferon-alpha-2b and ribavirin with clearance of syncytial giant hepatocytes despite HCV-RNA persistence. SGCH is a rare histological finding among HIV-infected patients with chronic hepatitis C. Specific treatment with pegylated interferon and ribavirin can lead to histological resolution and biochemical improvement, even in the absence of HCV-RNA clearance.

Liver disease caused by failure to racemize trihydroxycholestanoic acid: Gene mutation and effect of bile acid therapy

Background & Aims: Inborn errors of bile acid metabolism may present as neonatal cholestasis and fat-soluble vitamin malabsorption or as late onset chronic liver disease. Our aim was to fully characterize a defect in bile acid synthesis in a 2-week-old African-American girl presenting with coagulopathy, vitamin D and E deficiencies, and mild cholestasis and in her sibling, whose liver had been used for orthotopic liver transplantation (OLT). Methods: Bile acids were measured by mass spectrometry in urine, bile, serum, and feces of the patient and in urine from the unrelated recipient. Results: Liver biopsy specimens showed neonatal hepatitis with giant cell transformation and hepatocyte necrosis; peroxisomes were reduced in number. High concentrations of (25R)3α,7α,12α-trihydroxy-5β-cholestanoic acid in the urine, bile, and serum established a pattern similar to that of Zellweger syndrome and identical to the Alligator mississippiensis. Serum phytanic acid was normal, whereas pristanic acid was markedly elevated. Biochemical, MRI, and neurologic findings were inconsistent with a generalized defect of peroxisomal function and were unique. Analysis of the urine from the recipient of the deceased sibling's liver confirmed the same bile acid synthetic defect. A deficiency in 2-methylacyl-CoA racemase, which is essential for conversion of (25R)THCA to its 25S-isomer, the substrate to initiate peroxisomal β-oxidation to primary bile acids, was confirmed by DNA analysis revealing a missense mutation (S52P) in the gene encoding this enzyme. Long-term treatment with cholic acid normalized liver enzymes and prevented progression of symptoms. Conclusions: This genetic defect further highlights bile acid synthetic defects as a cause of neonatal cholestasis.GASTROENTEROLOGY 2003;124:217-232

Post-Infantile Giant Cell Hepatitis Associated with Autoimmune Hepatitis and Polyarteritis Nodosa

We report the case of a patient with corticosteroid-responsive giant cell hepatitis associated with typical manifestations and changes of polyarteritis nodosa from the kidney and central nervous system. Initially, the patient presented with transient right hemiparesis, followed by spontaneous remission without any abnormalities on computed tomography scan, magnetic resonance imaging and cerebrospinal fluid examination. A few months later he was admitted to our clinic because of icterus, peripheral oedema and abdominal distension. He was found to have clinical signs of active cirrhosis. Serological tests for hepatitis B, C and HIV virus were negative. Serum ceruloplasmin, a 1 -AT and ferritin levels were within normal limits. Antinuclear antibodies were positive (1:160). Liver biopsy showed micronodular cirrhosis with many eosinophils in the portal tracts and giant hepatocytes with multiple nucleoli in the lobule. Fulfilling the diagnostic criteria for autoimmune hepatitis, he was started on treatment with prednisolone and azathioprine, resulting in both clinical and biochemical responses. Four years later he presented with severe pain at the right costovertebral angle. Ultrasonography revealed a haematoma at the right kidney, and selective angiography of the abdominal aorta, renal arteries and hepatic artery documented microaneurysms in both kidney and liver arteries. Because of severe haemorrhage, right nephrectomy was performed. Histology of kidney specimen showed characteristic lesions of polyarteritis nodosa. Several months later, while on treatment with prednisolone and cyclophosphamide, the patient experienced a fatal episode of brain haemorrhage. An association between autoimmune hepatitis, polyarteritis nodosa and postinfantile giant cell hepatitis has not been reported previously.

Carcinogenicity of bisphenol-A in Fischer rats and B6C3F1 mice.

Bisphenol-A (BP-A; 4,4'-isopropylidenediphenol) is a monomer of plastics commonly used in various consumer products, and is used as an intermediate in the manufacture of epoxy, polycarbonate, and polyester-styrene resins. A National Toxicology Program carcinogenesis bioassay of BP-A (>98% pure) was conducted by feeding diets containing 0, 1000, or 2000 ppm BP-A to groups of 50 male and 50 female Fischer (F)344 rats; 0, 1000, or 5000 ppm to groups of 50 male B6C3F1 mice; and 0, 5000, or 10,000 ppm to groups of 50 female B6C3F1 mice for 103 weeks. The mean body weights of the low- and high-dose rats and of female mice and high-dose male mice were lower than those of the controls throughout much of the study. Lower body weight gains in rats were likely caused by reduced food consumption. Survivals were comparable among groups. Regarding neoplasia, leukemias occurred at increased incidences in BP-A-dosed rats of both sexes: male, 13/50 controls vs 12/50 low-dose and 23/50 high-dose (P < 0.03); in females, the respective findings were 7/50, 13/50, and 12/50. Interstitial-cell tumors of the testes were increased in BP-A-dosed male rats: 35/49 controls vs 48/50 (P < 0.01) and 46/49 (P < 0.01); and an increasing trend was observed for mammary gland fibroadenomas in male rats (P < 0.05, 0/50 controls vs 0/50 and 4/50). In male mice, lymphomas/leukemias were increased: 2/49 controls vs 9/50 (P < 0.05) and 5/50. Multinucleated giant hepatocytes were observed in male mice (1/49 controls vs 41/49 and 41/50), whereas there was no increase of liver tumors. In their BP-A bioassay report, the National Toxicology Program concluded that there was no convincing evidence that BP-A was carcinogenic for rats or mice. However, the marginal increases in leukemias in male and female rats, along with increases in the combined incidence of lymphomas and leukemias in male mice, suggest that BP-A may be associated with increased cancers of the hematopoietic system. Increases in interstitial-cell tumors of the testes in rats were also evidence of carcinogenesis, as was the unusual occurrence of mammary gland fibroadenomas in male rats.

Syncytial giant-cell hepatitis due to autoimmune hepatitis type II (LKM 1+) presenting as subfulminant hepatitis

Giant cell hepatitis (GCH) in adults is a rare event. The diagnosis of GCH is based on findings of syncytial giant hepatocytes. It is commonly associated with either viral infection or autoimmune hepatitis type I. A patient with GCH due to autoimmune hepatitis type II (LKM 1+) is described, a combination that has not been previously reported. Corticosteroid therapy was effective in decreasing serum liver enzymes; however, the patient deteriorated rapidly and developed subfulminant hepatic failure. Although an emergency orthotopic liver transplantation was performed, the patient died because of reperfusion injury. Interestingly, only a few giant hepatocytes were noted in the explanted liver. This case stresses the association of GCH with autoimmune disorders, the possible immune mechanism involved in the formation of giant cell hepatocytes, and illustrates the rapidly progressive course and unfavorable prognosis that these patients can develop.