Liver and Bone

Abstract  To investigate the pathogenesis of hepatic osteodystrophy (HOD) in parenchymal liver disease, we developed a laboratory model in animals using carbon tetrachloride (CCl₄) and thioacetamide. Biochemical and histological parameters in the model were measured. In rats with both chronic non-cirrhotic liver injury and CCl₄-induced cirrhosis, tibial bone volume was significantly lower than in controls. In CCl₄-treated cirrhotic rats, the osteoid volume decreased while the urinary calcium/creatinine ratio increased. In all CCl₄-treated rats, bone volume was significantly correlated with both the serum albumin concentration and the number of goblet cells reflecting intestinal villous atrophy. The serum concentration of vitamin D metabolites was not correlated with bone volume. Whole body retention of ⁴⁷Ca was significantly lower in CCl₄-treated cirrhotic rats than in controls. Furthermore, the bone volume in thioacetamide-treated cirrhotic rats was significantly lower than in controls. These data demonstrate that chronic parenchymal liver injury itself causes osteoporosis (i.e. HOD) due to a combination of low bone formation rates and high resorption rates, that HOD begins at the stage of chronic non-cirrhotic liver injury, that bone volume in HOD parallels liver damage and that the principal pathogenesis of HOD seems to be intestinal Ca malabsorption due to lower serum albumin and villous atrophy, while serum levels of vitamin D metabolites have little influence on the pathogenesis of HOD.     

Trial of docosahexaenoic acid supplementation on a Japanese patient with a peroxisome biogenesis defect

A female Japanese patient diagnosed with peroxisome biogenesis defect (PBD), who had hypotonia and craniofacial dysmorphism, was given supplementation of docosahexaenoic acid (DHA). Accumulation of very long chain fatty acids was revealed, and a diagnosis of PBD was made at 2 months of age because of the absence of peroxisomes, a defect in peroxisomal β-oxidation enzymes and a decreased level of DHA in the erythrocytes. Supplementation of DHA was introduced at 3 months of age. For the first several months, psychomotor development was fairly good. The patient could laugh, brush off a blanket and play with toys at 6 months of age. However, neurological regression and convulsions occurred after 7 months of age. After recurrent respiratory infections and disturbance of the circadian rhythm, the patient died of liver failure and disseminated intravascular coagulopathy at 20 months of age. DHA may have a favorable effect on the early development of patients with PBD, but neurological deterioration cannot be prevented. Patients with a milder phenotype would be better candidates for DHA supplementation.     

A point mutation (Arg271→Cys) of a homozygote for dysfunctional prothrombin, prothrombin Obihiro, which has a region of high sequence variability

Summary. The molecular defect of a congenitally dysfunctional form of prothrombin, prothrombin Obihiro, was identified in a patient with a severe bleeding tendency. He showed reduced fibrinogen clotting activity, despite a normal prothrombin antigen level. Nucleotide sequencing of amplified DNA revealed a C→T change at nucleotide 7311 of exon VIII of the prothrombin gene. This resulted in the substitution of Arg271 by Cys at the factor Xa cleavage site which precludes normal activation of prothrombin Obihiro by factor Xa and the generation of thrombin. The proband was homozygous for this mutation. In addition, seven new nucleotide changes were identified in the prothrombin gene of this patient by comparison with the published gene sequence. Three polymorphisms at nucleotides 4291, 4298 and 7223 were exclusively identified in the prothrombin gene from Japanese. Particularly in the region containing exon VI and introns E and F (nucleotides 4048-4303), the prothrombin gene proved to be of high-sequence variability.     

Gastric microcirculatory disturbance and behaviour of leucocytes after thermal injury: Intravital observation of arteriovenous shunting channels in the gastric submucosal layer

In order to investigate the pathogenesis of acute gastric mucosal lesion after thermal injury, microcirculatory disturbance was assessed and observation of the behaviour of leucocytes was performed. Gastric blood flow decreased at 15 min post-thermal injury, and partially improved at 2 h; however, it decreased again at 5 h post-thermal injury. Mucosal microcirculatory disturbance was observed by using vascular labelling with monastral blue B. Deposits of monastral blue B were observed centring mainly on collecting venules but were also observed in the capillaries. Submucosal microcirculatory disturbance was observed through an intravital microscope. The irregularity of the wall and segmental constriction in the venules and presence of an arteriovenous shunting channel was observed in the submucosal layer at 5 h post-thermal injury. The percentage of rolling or sticking leucocytes that passed the confluence of a prevenule and a venule were significantly increased at 5 h after thermal injury. The present study revealed depression of gastric blood flow, mucosal and submucosal microcirculatory disturbance, and a significant increase of rolling and sticking leucocytes in the peripheral part of venules after thermal injury. Leucocyte-endothelial interactions may occur under such conditions and this interaction may play an important role in inducing the microcirculatory disturbance that results in an acute gastric mucosal lesion after thermal injury. The present study also demonstrated the possibility of intravital study of gastric submucosal arteriovenous shunting channels.     

Estimation of damaged tubular epithelium in renal allografts by determination of vimentin expression

BACKGROUND: Various invasive and non-invasive methods have been investigated for their prognostic value in predicting the outcome of renal allografts. In the present study, vimentin expression in tubular epithelial cells (TEC) was determined by the immunohistochemical examination of biopsy specimens and the prognostic value of this method was assessed. METHODS: Ninety-two renal transplant recipients were recruited for the present study. Protocol biopsy of the renal graft was performed 1, 3 and 5 years after transplantation in each case. All biopsy specimens were treated with conventional stains and immunostained with an antivimentin antibody. The correlation between vimentin expression and glomerular filtration rate (GFR) and the association between vimentin expression and histopathological findings were determined. RESULTS: Vimentin was localized in TEC adjacent to interstitial lesions with lymphocyte infiltration and also in TEC with tubulitis or in atrophic tubules. Vimentin positivity significantly correlated with GFR and both vimentin positivity and GFR were significantly associated with the extent of chronic allograft nephropathy, but not with acute rejection. Additionally, vimentin expression and GFR 3 and 5 years after transplantation were higher in cases where graft loss occurred between 5 and 7 years after transplantation compared with graft survival cases. CONCLUSIONS: These results suggest that immunohistochemistry using antivimentin antibodies on protocol biopsy specimens is useful for the detection of injured TEC and as a predictor of allograft outcome.     

Diagnosis of Early Gastric Cancer Seen as Less Malignant Endoscopically

Jn order to make the endoscopic diagnosis of early gastric cancermore accurate, we determined the endoscopic and clinicopathologicalcharacteristics of the 129 cases of early gastric cancer withless malignant appearance among the 978 cases of the diseasewith a solitary lesion detected at the National Cancer CenterHospital during the period between 1962 and 1981. Accordingto findings required to make a differential diagnosis, the endoscopicappearance of the 978 cases were divided into the followingfour groups: 170 cases of polypoid, 587 of ulcerative, 119 ofgastritis-like and 102 of advanced cancer-like. Among the fourgroups, the frequency of cases with less malignant appearancewas quite high in the gastritis-like group. The lesion in thisgroup was defined as the cancerous lesion which shows only superficialmucosal abnormality, not associated with any polypoid or ulcerativecomponents. Chronologically, it has been rapidly increasingin recent years. These two paradoxical phenomena in the gastritis-likegroup, that is, "high frequency of less malignant appearance"and "increase in number of cases" not only indicate the inadequacyof the conventional criteria for the recent cases but also showthat the gastritis-like malignancy is detectable. New additionalendoscopic criteria for the gastritis-like malignancy, for example,irregular margin of the shallow mucosal depression, disproportionof the mucosal granularity, irregularity on the erythematouschange and discoloration are essential in order to detect muchmore cases with less malignant appearance.     

Impaired monocyte differentiation in children with acute lymphoblastic leukaemia: its evaluation by peroxidase activity and ultrastructure

The ability of monocyte differentiation in childhood acute lymphoblastic leukaemia (ALL) was evaluated on the basis of the ultrastructure and peroxidase (PO) activity which could show the differentiation of cultured monocytes. In the control, PO activity limited to the granules decreased time-dependently during culture for 4 d, and was closely associated with the morphological development to macrophages. In childhood ALL, monocytes showed poor changes in both PO activity and morphological features during culture for 4 d compared to the control. Therefore, we conclude that monocyte to macrophage differentiation is impaired in childhood ALL.