CD14-positive hepatic monocytes/macrophages increase in hereditary hemochromatosis.

Background/aims: Iron overload in hereditary hemochromatosis (HH) may result in hepatic fibrosis and cirrhosis, primarily due to collagen production by hepatic stellate cells that become activated to myofibroblasts. Endotoxin-responsive monocytes/macrophages (CD14-positive) are potential sources of profibrogenic factors. The aims of this study were to determine (1) whether CD14-positive monocytes/macrophages are present in the livers of patients with HH and (2) the potential relationship between CD14-positive cells and hepatic fibrosis in HH.

Damage to the reticulotegmental nucleus of the pons in spinocerebellar ataxia type 1, 2, and 3.

Background: The reticulotegmental nucleus of the pons (RTTG) is among the precerebellar nuclei of the human brainstem. Although it represents an important component of the oculomotor circuits crucial for the accuracy of horizontal saccades and the generation of horizontal smooth pursuits, the RTTG has never been considered in CAG repeat or polyglutamine diseases.

Methods: Thick serial sections through the RTTG of 10 patients with spinocerebellar ataxias (SCAs) assigned to the CAG repeat or polyglutamine diseases (2 SCA-1 patients, 4 SCA-2 patients, and 4 SCA-3 patients) were stained for neuronal lipofuscin pigment and Nissl material.

Metabolic storage diseases: amyloidosis.

This article provides an overview of the current concepts in pathogenesis, epidemiology, clinical significance, and treatment options for amyloidosis. Emphasis is given to hepatic amyloidosis, which ranges from a clinically insignificant histologic curiosity to a harbinger of widespread disease accompanied by a poor prognosis. Clinical characteristics and clues to the diagnosis are discussed as well as the importance of histologic confirmation and the controversy surrounding liver biopsy.

Nonalcoholic steatohepatitis: histologic features and clinical correlations with 30 blinded biopsy specimens.

Thirty overweight patients with clinically characterized and biopsy proven nonalcoholic steatohepatitis (NASH) were enrolled in a 48-week treatment trial with rosiglitazone, a peroxisome proliferator-activator receptor (PPAR)-gamma agonist that enhances insulin sensitivity. Improvement in laboratory liver tests, insulin resistance and liver fat content were documented; blinded biopsy review demonstrated decreases in necroinflammatory activity or grade and in individual components of grade, and changes in the relationship of lobular and portal inflammation as well as in the nature of perisinusoidal fibrosis. The current study identified correlations of histological features of the protocol entry biopsy specimens with contemporaneous laboratory and imaging tests.

Degeneration of the central vestibular system in spinocerebellar ataxia type 3 (SCA3) patients and its possible clinical significance.

Although the vestibular complex represents an important component of the neural circuits crucial for the maintenance of truncal and postural stability, and it is integrated into specialized oculomotor circuits, knowledge regarding the extent of the involvement of its nuclei and associated fibre tracts in cases with spinocerebellar ataxia type 3 (SCA3) is incomplete. Accordingly, we performed a pathoanatomical analysis of the vestibular complex and its associated fibre tracts in four clinically diagnosed and genetically confirmed SCA3 patients with the aim of providing more exact information as to the involvement of the vestibular system in this disorder. By means of unconventionally thick serial sections through the vestibular nuclei stained for lipofuscin pigment and Nissl material, we could show that all five nuclei of this complex (interstitial, lateral, medial, spinal, and superior vestibular nuclei) are subject to neurodegenerative processes in SCA3, whereby examination of thick serial sections stained for myelin revealed that all associated fibre tracts (ascending tract of Deiters, juxtarestiform body, lateral and medial vestibulospinal tracts, medial longitudinal fascicle, vestibular portion of the eighth cranial nerve) underwent atrophy and demyelinization in all four of the patients studied.

Accumulation of aberrant ubiquitin induces aggregate formation and cell death in polyglutamine diseases.

Polyglutamine diseases are characterized by neuronal intranuclear inclusions (NIIs) of expanded polyglutamine proteins, indicating the failure of protein degradation. UBB(+1), an aberrant form of ubiquitin, is a substrate and inhibitor of the proteasome, and was previously reported to accumulate in Alzheimer disease and other tauopathies. Here, we show accumulation of UBB(+1) in the NIIs and the cytoplasm of neurons in Huntington disease and spinocerebellar ataxia type-3, indicating inhibition of the proteasome by polyglutamine proteins in human brain.

Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers.

The work of liver stem cell biologists, largely carried out in rodent models, has now started to manifest in human investigations and applications. We can now recognize complex regenerative processes in tissue specimens that had only been suspected for decades, but we also struggle to describe what we see in human tissues in a way that takes into account the findings from the animal investigations, using a language derived from species not, in fact, so much like our own. This international group of liver pathologists and hepatologists, most of whom are actively engaged in both clinical work and scientific research, seeks to arrive at a consensus on nomenclature for normal human livers and human reactive lesions that can facilitate more rapid advancement of our field.

Caspase-mediated proteolysis of the polyglutamine disease protein ataxin-3.

Spinocerebellar ataxia type-3, also known as Machado-Joseph Disease, is one of many inherited neurodegenerative disorders caused by polyglutamine-encoding CAG repeat expansions in otherwise unrelated disease genes. Polyglutamine disorders are characterized by disease protein misfolding and aggregation; often within the nuclei of affected neurons. Although the precise mechanism of polyglutamine-mediated cell death remains elusive, evidence suggests that proteolysis of polyglutamine disease proteins by caspases contributes to pathogenesis.

Histological changes after the use of mycophenolate mofetil in autoimmune hepatitis.

Corticosteroids and azathioprine are considered standard treatment for autoimmune hepatitis. There are, however, well-known systemic side effects that may preclude continuation with these immunosuppressive therapies, and small trials of the anti-metabolite mycophenolate mofetil have been reported. We report liver biopsy findings in a follow-up biopsy of a patient who had been switched from azathioprine to mycophenolate mofetil for treatment of presumed, steroid-responsive autoimmune hepatitis.

Nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is being increasingly recognized as a common liver disorder that represents the hepatic manifestation of the metabolic syndrome, a variably defined aggregate of disorders related to obesity, insulin resistance, type II diabetes, hypertension and hyperlipidemia. Nonalcoholic steatohepatitis (NASH) is the progressive form of liver injury that carries a risk for progressive fibrosis, cirrhosis, and end-stage liver disease. Hepatocellular carcinoma (HCC) is a documented complication in an as yet unknown percentage of cases of NASH cirrhosis.

Biliary-venous fistula complicating transjugular intrahepatic portosystemic shunt presenting with recurrent bacteremia, jaundice, anemia and fever.

A 50-year-old White man with noncirrhotic portal hypertension presented with bleeding from gastric varices. Bleeding was initially managed with band ligation and subsequent transjugular intrahepatic portosystemic shunt (TIPS). Over the next few months, the patient had recurrent episodes of anemia, jaundice, fever and polymicrobial bacteremia.

Gene expression profiling in ataxin-3 expressing cell lines reveals distinct effects of normal and mutant ataxin-3.

Spinocerebellar ataxia type 3 (SCA3) is a late-onset neurodegenerative disorder caused by the expansion of a polyglutamine tract within the gene product, ataxin-3. We have previously shown that mutant ataxin-3 causes upregulation of inflammatory genes in transgenic SCA3 cell lines and human SCA3 pontine neurons. We report here a complex pattern of transcriptional changes by microarray gene expression profiling and Northern blot analysis in a SCA3 cell model.

Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone.

Insulin resistance (IR) commonly is associated with nonalcoholic steatohepatitis (NASH). To establish whether IR causes NASH, this study was undertaken to determine if improving IR would improve the histologic features that define NASH. Thirty adults with prior biopsy evidence of NASH were enrolled to receive rosiglitazone, 4 mg twice daily for 48 weeks.

Effect of iron overload and dietary fat on indices of oxidative stress and hepatic fibrogenesis in rats.

Background/aims: Oxidative stress is presumed to play an important role in hepatic fibrogenesis. Diets high in polyunsaturated fatty acids (PUFA) enhance fibrosis and have been associated with increased oxidative damage in some models of liver injury. The aim of this study was to determine the effects of dietary fat of varying PUFA content on iron-induced oxidative stress and fibrosis.

Hepatic iron overload in blacks and whites: a comparative autopsy study.

Objective: Genetic susceptibility to iron loading is an important factor in the development of iron overload in Africans. This suggests that persons of African descent may be at risk to develop iron overload with its attendant complications, but relatively little is known about hepatic iron overload among blacks. The aim of this study was to compare the prevalence, histological features, and clinical correlates of hepatic iron overload in a group of autopsied black and white veterans.

Thalamic involvement in a spinocerebellar ataxia type 2 (SCA2) and a spinocerebellar ataxia type 3 (SCA3) patient, and its clinical relevance.

In spite of the considerable progress in clinical and molecular research, knowledge regarding brain damage in spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3) still is limited and the extent to which the thalamus is involved in both diseases is uncertain. Accordingly, we performed a pathoanatomical analysis on serial thick sections stained for lipofuscin granules and Nissl substance through the thalami of two genetically confirmed cases: one an SCA2 patient, the other an SCA3 patient. During this systematic study, we detected severe destruction of the reticular (RT), fasciculosus (FA), ventral anterior (VA), ventral lateral (VL), ventral posterior lateral (VPL), ventral posterior medial (VPM), cucullar (CU) and mediodorsal thalamic nuclei (MD), the lateral geniculate body (LGB) and inferior nucleus of the pulvinar (PU i) in the SCA2 case, and a severe neuronal loss in the RT, FA, VA and PU i of the SCA3 case.

Orlistat in the treatment of NASH: a case series.

Nonalcoholic steatohepatitis is now recognized as a common chronic liver disorder. Up to 16% of affected patients may progress to cirrhosis. The incidence and prevalence of this disease are noted to be increasing, in parallel with the nationwide increase in obesity and diabetes.

Interim results of a pilot study demonstrating the early effects of the PPAR-gamma ligand rosiglitazone on insulin sensitivity, aminotransferases, hepatic steatosis and body weight in patients with non-alcoholic steatohepatitis.

Background/aims: Hyperinsulinemia may cause hepatic steatosis and non-alcoholic steatohepatitis (NASH). The aims of this pilot study were to examine the safety of using the insulin-sensitizing peroxisomal proliferator activated receptor (PPAR) gamma ligand rosiglitazone in patients with NASH and determine whether improved insulin sensitivity correlates with improved fatty liver.

Methods: Thirty subjects with NASH and elevated alanine aminotransferase (ALT) levels received rosiglitazone, 4 mg twice daily for 48 weeks; the preliminary results presented here were obtained at 24 weeks.

The nucleus raphe interpositus in spinocerebellar ataxia type 3 (Machado-Joseph disease).

The nucleus raphe interpositus (RIP) plays an important role in the premotor network for saccades. Its omnipause neurons gate the activity of the burst neurons for vertical saccades lying within the rostral interstitial nucleus of the medial longitudinal fascicle and that for horizontal saccades residing in the caudal subnucleus of the pontine reticular formation. In the present study we investigated the RIP in five patients with clinically diagnosed and genetically confirmed spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease.

Guidelines for the pathoanatomical examination of the lower brain stem in ingestive and swallowing disorders and its application to a dysphagic spinocerebellar ataxia type 3 patient.

Despite the fact that considerable progress has been made in the last 20 years regarding the three-phase process of ingestion and the lower brain stem nuclei involved in it, no comprehensive descriptions of the ingestion-related lower brain stem nuclei are available for neuropathologists confronted with ingestive malfunctions. Here, we propose guidelines for the pathoanatomical investigation of these nuclei based on current knowledge with respect to ingestion and the nuclei responsible for this process. The application of these guidelines is described by drawing upon the example of the lower brain stem of a male patient with spinocerebellar ataxia type 3, also known as Machado-Joseph disease, who displayed malfunctions during the preparatory phase of ingestion, as well as lingual and pharyngeal phases of swallowing.

Concurrence of histologic features of steatohepatitis with other forms of chronic liver disease.

Steatohepatitis, of either alcoholic or nonalcoholic etiologies, is ultimately diagnosed by clinical-pathologic correlation and is characterized histologically by lesions that differ from the portal-based chronic inflammation and fibrosis of most other forms of chronic liver disease. With the increasing prevalence of steatohepatitis in our society, it is likely that some patients will have coexistent clinical and/or histopathologic findings of steatohepatitis concurrently with another form of liver disease. The aim of this study was to document clinical and histologic findings in biopsies in an academic referral center.

Budd-Chiari syndrome and hepatocellular carcinoma: a case report and review of the literature.

Acid suppression medications have become A 62-yr-old woman with a long-standing history of presumed cryptogenic cirrhosis was referred for evaluation of an elevated bilirubin level. Workup showed an elevated alpha-fetoprotein level, and a mass in the liver was detected by imaging studies; this was confirmed as hepatocellular carcinoma by biopsy. Her past medical history was significant for a portocaval shunt procedure 30 yr prior; a wedge biopsy obtained at that time had been interpreted as postnecrotic cirrhosis, but upon current review, lesions of acute and chronic venous outflow obstruction consistent with Budd-Chiari syndrome were noted.

Expression of P-glycoprotein and C-MOAT in human hepatocellular carcinoma: detection by immunostaining.

P-Glycoprotein and C-MOAT are important hepatic transport proteins which play a role in handling anticancer drugs. Hepatocellular carcinoma is a common hepatic malignancy that is relatively resistant to chemotherapeutic drugs. We therefore studied the expression of these two transport proteins in liver sections from hepatocellular carcinoma by immunohistochemistry and compared the reactivity to that in other liver conditions, including cirrhosis and dysplasia.

Episodic ataxia type 2. Three novel truncating mutations and one novel missense mutation in the CACNA1A gene.

We analysed the CACNA1A gene, located on chromosome 19p13, in three unrelated families and one sporadic case with episodic ataxia type 2 (EA-2). In two of the families and the sporadic patient, novel truncating mutations, which disrupt the reading frame and result in a premature stop of the CACNA1A protein, were identified in exons 14, 16 and 26. In the remaining family, a novel missense mutation (H253Y) was found.