Renal impairment with sublethal tubular cell injury in a chronic liver disease mouse model

The pathogenesis of renal impairment in chronic liver diseases (CLDs) has been primarily studied in the advanced stages of hepatic injury. Meanwhile, the pathology of renal impairment in the early phase of CLDs is poorly understood, and animal models to elucidate its mechanisms are needed. Thus, we investigated whether an existing mouse model of CLD induced by 3, 5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC) shows renal impairment in the early phase. Renal injury markers, renal histology (including immunohistochemistry for tubular injury markers and transmission electron microscopy), autophagy, and oxidative stress were studied longitudinally in DDC- and standard diet-fed BALB/c mice. Slight but significant renal dysfunction was evident in DDC-fed mice from the early phase. Meanwhile, histological examinations of the kidneys with routine light microscopy did not show definitive morphological findings, and electron microscopic analyses were required to detect limited injuries such as loss of brush border microvilli and mitochondrial deformities. Limited injuries have been recently designated as sublethal tubular cell injury. As humans with renal impairment, either with or without CLD, often show almost normal tubules, sublethal injury has been of particular interest. In this study, the injuries were associated with mitochondrial aberrations and oxidative stress, a possible mechanism for sublethal injury. Intriguingly, two defense mechanisms were associated with this injury that prevent it from progressing to apparent cell death: autophagy and single-cell extrusion with regeneration. Furthermore, the renal impairment of this model progressed to chronic kidney disease with interstitial fibrosis after long-term DDC feeding. These findings indicated that DDC induces renal impairment with sublethal tubular cell injury from the early phase, leading to chronic kidney disease. Importantly, this CLD mouse model could be useful for studying the pathophysiological mechanisms of sublethal tubular cell injury

Mitochondrial fission in hepatocytes as a potential therapeutic target for nonalcoholic steatohepatitis

[Aim] The mitochondria are highly plastic and dynamic organelles; mitochondrial dysfunction has been reported to play causative roles in diabetes, cardiovascular diseases, and nonalcoholic fatty liver disease (NAFLD). However, the relationship between mitochondrial fission and NAFLD pathogenesis remains unknown. We aimed to investigate whether alterations in mitochondrial fission could play a role in the progression of NAFLD. [Methods] Mice were fed a standard diet or choline-deficient, L-amino acid-defined (CDAA) diet with vehicle or mitochondrial division inhibitor-1. [Results] Substantial enhancement of mitochondrial fission in hepatocytes was triggered by 4 weeks of feeding and was associated with changes reflecting the early stage of human nonalcoholic steatohepatitis (NASH), steatotic change with liver inflammation, and hepatocyte ballooning. Excessive mitochondrial fission inhibition in hepatocytes and lipid metabolism dysregulation in adipose tissue attenuated liver inflammation and fibrogenesis but not steatosis and the systemic pathological changes in the early and chronic fibrotic NASH stages (4- and 12-week CDAA feeding). These beneficial changes due to the suppression of mitochondrial fission against the liver and systemic injuries were associated with decreased autophagic responses and endoplasmic reticulum stress in hepatocytes. Injuries to other liver cells, such as endothelial cells, Kupffer cells, and hepatic stellate cells, were also attenuated by the inhibition of mitochondrial fission in hepatocytes. [Conclusions] Taken together, these findings suggest that excessive mitochondrial fission in hepatocytes could play a causative role in NAFLD progression by liver inflammation and fibrogenesis through altered cell cross-talk. This study provides a potential therapeutic target for NAFLD

The effectiveness and limitations of triphenyltetrazolium chloride to detect acute myocardial infarction at forensic autopsy.

Triphenyltetrazolium chloride (TTC) is one of the most conventional stains to detect infarcted area of the heart in animal experiments. However, its availability and limitations have not been thoroughly discussed in the forensic field. Here, authors stained human hearts with TTC soon after the harvest. Photographs of the samples were analyzed using image analysis software, which evaluated the occupying ratio of the stained area on the surface of each slice. The results showed that the stainability of TTC declines with the length of the postmortem interval (PMI). Specimens reacted well to TTC within 1.5 days after death and then decreased the stainability logarithmically with PMI (y = - 0.294 In (x) + 1.0441; x = PMI, y = TTC-stained areatotal myocardial area, R = 0.5673). Samples with old myocardial infarction produced clear TTC contrast; normal tissue is vivid red, and fibrotic myocardium is white discoloration. In acute myocardial infarction cases where death occurred within 9 hours after the attack, however, the detection of infarcted area was very difficult even when PMI was less than 1.5 days. In summary, the TTC method may be useful within 1.5 days after death, but short suffering period before death disturbs its staining efficiency

Ectopic cervical thymus associated with infant death: 2 case reports and literature review.

An ectopic cervical thymus is a rare congenital anomaly that can be located anywhere along the developmental pathway of thymic descent. Most lesions manifest as a cystic mass and have an indolent course. Two fatal cases associated with ectopic cervical thymus in the form of a solid mass are presented in conjunction with a review of the clinicopathological characteristics of the solid form. This report emphasizes the importance of considering a diagnosis of ectopic cervical thymus in infants with neck masses, with or without obstructive symptoms, to prevent possibly fatal outcomes

Bile canalicular abnormalities in the early phase of a mouse model of sclerosing cholangitis.

[Background]The bile canaliculus is the smallest and first biliary channel and is formed by two or three adjacent hepatocytes. Previous studies of chronic cholangiopathies such as primary sclerosing cholangitis have focused on the bile ductules. However, little is known about the pathological alterations in bile canaliculi in the early phase of cholangiopathies. [Aim]To characterize the bile canalicular morphology in the early phase of sclerosing cholangitis we used 3, 5-diethoxycarbonyl-1, 4-dihydrocollidine-induced mouse model of sclerosing cholangitis. [Methods]Mice were fed a diet with 3, 5-diethoxycarbonyl-1, 4-dihydrocollidine (0.1%). Serum biochemical, histological, immunohistochemical, and electron microscopic analyses were performed 1, 2, 4, and 7 days after feeding. [Results]All experimental groups showed significantly increased serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels. From day 1, bile canalicular abnormalities such as dilatation and meandering and loss of microvilli were observed. After bile canalicular abnormalities had appeared, substantial infiltration of inflammatory cells was observed amongst the necrotic cells and periductal region. After these inflammatory changes, cholangiocytes proliferated in the portal area and formed ductular reactions. Finally, periductal fibrosis appeared. [Conclusion]This study provides novel evidence of the occurrence of bile canalicular abnormalities during the early phase of sclerosing cholangitis

Fatal Dieulafoy lesion with IgG4-related disease: An autopsy case report

Dieulafoy lesions are rare vascular malformations of the gastrointestinal tract; however, they can lead to fatal vascular bleeding. Immunoglobulin G4-related disease (IgG4-RD) is a rare systemic fibroinflammatory disease involving multiple organs, including the vasculature. To date, no autopsy reports of Dieulafoy lesions with IgG4-RD have been described in the literature. A 48-year-old man was found dead in his home with hematochezia. Postmortem computed tomography revealed high-density gastric contents and an enlarged iso-density area in the pancreas, indicating gastric hemorrhage and mass-forming lesions. Macroscopic and histological examinations revealed an ulcer of the body of the stomach with a large amount of hemorrhage from the enlarged artery in the submucosal layer, confirming the rupture of the Dieulafoy lesion. Moreover, lymphocyte infiltrations with increased IgG4 positive cells were found in the pancreas, thyroid gland, and arteries in non-ulcer regions of the stomach, suggesting IgG4-RD. Serum biochemical analysis showed elevated levels of inflammatory mediators, such as IgE, soluble-interleukin-2 receptor, and C-reactive protein. These findings suggest that systemic inflammation caused by IgG4-RD could, at least in part, contribute to the development of Dieulafoy lesions and fatal rupture of the lesion. This case report highlights the importance of autopsy research focusing on Dieulafoy lesions and IgG4-RD to promote awareness and a better understanding of the relationships between these treatable diseases to establish earlier and effective interventional strategies for better patient outcomes

Pituitary abscess presenting a very rapid progression: report of a fatal case.

Pituitary abscess is a rare disease presenting with nonspecific clinical symptoms, and diagnosis is often difficult. This disease is potentially life-threatening, but most cases have a chronic and indolent course. We report a case of a 60-year-old man with a pituitary abscess associated with pituitary adenoma who died 5 days after the onset of clinical symptoms without a definitive diagnosis. Postmortem computed tomography and autopsy findings revealed a sellar mass with cystic change and extension toward the optic chiasm. Histopathology of the lesion demonstrated an abscess with suppurative meningitis and encephalitis. The disturbance of the cardiac autonomic nervous system because of hypothalamus involvement was suggested as the cause of rapid progression and death. This case provides useful information for clinicians to avoid a lethal outcome

Ectopic cervical thymus: A clinicopathological study of consecutive, unselected infant autopsies

[Objectives] An ectopic cervical thymus (ECT) is regarded as a rare congenital anomaly; therefore, the optimal diagnostic and therapeutic strategy remains a debatable matter. We designed a study to elucidate the clinicopathological characteristics of ECTs in consecutive, unselected infant autopsies, to help guide case management. [Methods]We searched for ECTs in all of the 21 consecutive, unselected infant autopsy cases performed at our institution over a period of 3 years, and all ECT consensus diagnoses were confirmed by histological examination. The following clinical characteristics were evaluated in cases with ECTs: age, gender, birth week and weight, clinical symptoms due to the ECT(s), position on discovery of death, cause of death, ECT contribution to the cause of death, and concomitant congenital disorders. The anatomical features evaluated included the location, number, size, color, shape, and margins of the ECTs, and the presence of a mediastinal thymus. Histological findings of the ECT(s) and the mediastinal thymus were compared within each individual. Fusion of the parathyroid and the ECT was also investigated histologically. Spearman's rank correlation coefficient (ρ) and the corresponding P value were calculated to determine if there was an association between ECT diameter and age. [Results]We detected 10 ECT lesions in seven cases (33%) among the 21 infant autopsy cases. The ECT cases involved five boys and two girls, with ages ranging from 1 day to 4 months. There were no reports of a positive family history of sudden death or antemortem clinical symptoms due to ECT in any of the cases. The ECTs were considered incidental regarding the cause of death, with the exception of one case that was extremely rare. Most ECTs were localized to the inferior thyroid, ranging from 0.4 to 1.9 cm in size. Size demonstrated a significant negative correlation with age (ρ = −0.75 and P = 0.034). [Conclusions]This study revealed that ECT is an essentially benign anomaly that occurs frequently during the development of the thymus, and may disappear over the first few years of life. These results suggest a conservative approach to the management of ECTs would be appropriate

Transmesenteric hernia due to double-loop formation in the small intestine: a fatal case involving a toddler.

We report a unique case of transmesenteric hernia resulting in death, which went undiagnosed during a recent hospital visit. The victim was a 2.5-year-old girl who - with the exception of chronic constipation - had no medical history. One night she complained of abdominal pains and was taken to a pediatric hospital where doctors performed an abdominal X-ray and echography. No significant findings suggesting bowel obstruction (e.g. air-fluid levels or dilation of the bowel) were obtained on examinations and bloody feces were not observed in this particular episode. As her abdominal pain gradually attenuated, the doctor allowed her to return home. A few hours later, she lost consciousness and expired despite resuscitation efforts attempted at an emergency hospital. A subsequent autopsy revealed that the small bowel had herniated through a defect in the mesentery resulting in two consecutive and inversely forming loops, in which each loop protruded on either side of the mesentery. This rare morphological anatomy seems to have progressed in a two-step process. The girl's mild abdominal pain was likely induced by herniation and formation of the first intestinal loop, followed by severe shock occurring when the subsequent intestinal segment invaginated into the same defect forming the second loop on the opposite side of the mesentery. This case illustrates the difficulty of diagnosing transmesenteric hernia due to the presentation of unspecific symptoms; especially in infants and toddlers. Furthermore, this report demonstrates the value of a complete autopsy in cases of sudden and unexpected deaths involving children

Pivotal role of liver sinusoidal endothelial cells in NAFLD/NASH progression.

Advance online publication 27 July 2015Liver sinusoidal endothelial cells (LSECs) are involved in the transport of nutrients, lipids, and lipoproteins, and LSEC injury occurs in various liver diseases including nonalcoholic fatty liver disease (NAFLD). However, the association between LSEC injury and NAFLD progression remains elusive. Accordingly, in this study, we aimed to elucidate the precise role of LSEC in the pathophysiology of NAFLD using two different mouse models, namely the choline-deficient, L-amino acid-defined and high-fat diet models. Administration of these diets resulted in liver metabolic dysregulation mimicking human NAFLD, such as steatosis, ballooning, lobular inflammation, and fibrosis, as well as central obesity, insulin resistance, and hyperlipidemia. LSEC injury appeared during the simple steatosis phase, and preceded the appearance of activated Kupffer cells and hepatic stellate cells (HSCs). These results indicate that LSEC injury may have a 'gatekeeper' role in the progression from simple steatosis to the early nonalcoholic steatohepatitis (NASH) stage, and LSEC injury may be necessary for the activation of Kupffer cells and HSCs, which in turn results in the development and perpetuation of chronic liver injuries. Taken together, our data provide new insights into the role of LSEC injury in NAFLD/NASH pathogenesis