Sarcopenia in the elderly: diagnosis, physiopathology and treatment

Sarcopenia, defined as a syndrome rather than as a pathology, is the loss of muscle mass and function associated with age. Sarcopenia is an enigma for medicine, and despite the numerous publications available in the literature and the number of papers currently being published, there is no agreement about its definition, and even less about its root causes. One salient aspect that proves the lack of consensus is the fact that different working groups are still debating about the right name for this syndrome (which is associated with the loss of muscle mass and strength in the elderly). In hospitalized patients, sarcopenia has been shown to raise the risk of complications such as infections, pressure ulcers, loss of autonomy, institutionalization and poor quality of life, as well as to increase mortality. The factors that contribute to the development of sarcopenia in the elderly are: the state of chronic inflammation, atrophy of motoneurons, reduced protein intake (secondary among others to the condition defined as geriatric anorexia), and immobility. There is ongoing debate about the causes of sarcopenia, but the aspect that generates most interest today is the quest to achieve repeatable and clinically useful diagnostic criteria for its diagnosis, prevention and treatment. The aim of this narrative review is to summarise the abundant information available in the literature and to draw useful conclusions.     

Hepatic fibrosis: role of matrix metalloproteases and TGFbeta

Liver fibrosis and cirrhosis involve multiple cellular and molecular events that lead to deposition of an excess of extracellular matrix proteins and increase the distortion of normal liver architecture. Etiologies include chronic viral hepatitis, alcohol abuse and drug toxicity. Degradation of these matrix proteins occurs predominantly as a result of a family of enzymes called metalloproteases (MMPs) that specifically degrade collagenous and non-collagenous substrates. Matrix degradation in the liver is due to the action of at least four of these enzymes: MMP-1, MMP-2, MMP-3 and MMP-9. In the fibrinolytic system, MMPs can be activated through proteolytic cleavage by the action of urokinase plasminogen activator; a second mechanism includes the same metalloproteases. This activity is regulated at many levels in the fibrinolytic system. The main regulator is the PAI-1. This molecule blocks the conversion of plasminogen into plasmin, and the MMP cannot be activated. At a second level, the inhibition is possible by binding to inhibitors called TIMP that can inhibit the proteolitic activity even when the MMPs had been previously activated by plasmin. During abnormal conditions, overexpression of these inhibitors is directed by the transforming growth factor-beta that in a fibrotic disease acts as an extremely important adverse factor.     

Hepatic stellate cells and liver fibrosis

Substantial evidence now exists to recognize hepatic stellate cells (HSCs) as the main matrix-producing cells in the process of liver fibrosis. Liver injury of any etiology will ultimately lead to activation of HSCs, which undergo transdifferentiation to fibrogenic myofibroblast-like cells. Quantitative analysis of HSC activation by immunohistochemistry has been shown to be useful in predicting the rate of progression of liver fibrosis in some clinical situations. In the activation process, transforming growth factor beta is thought to be the main mediator of fibrogenesis and platelet-derived growth factor is the major inducer of HSC proliferation. Different platelet-derived growth factor and transforming growth factor beta inhibitors have been shown to effectively prevent liver fibrosis in animal models and represent promising therapeutic agents for humans.     

Hepatic fibrosis in Kabuki syndrome

Kabuki (Niikawa-Kuroki) syndrome (KS) is characterized by a distinctive face, mental retardation, growth deficiency, skeletal anomalies, dermatoglyphic abnormalities, palatal anomalies, congenital heart defects, and urogenital malformations. Congenital hepatic abnormalities have been sporadically described in patients with KS from the literature, consisting of extrahepatic biliary atresia, neonatal sclerosing cholangitis, and severe neonatal jaundice. We report here on an additional patient with a congenital abnormality of the liver consisting of hepatic fibrosis. To our knowledge, idiopathic congenital hepatic fibrosis has not been reported in KS. Thus, our observation expands the spectrum of liver malformations found in KS with the inclusion of hepatic fibrosis and supports the evidence that hepatic abnormalities may not be uncommon in KS. Clinician should be advised to search for the specific facial anomalies of KS in patients with syndromic congenital hepatic diseases, and KS should be added to the list of previously recognized multiple congenital anomaly syndromes with hepatic involvement. Due to the frequent association with congenital heart malformations, KS should be considered in the evaluation of patients with neonatal liver disease and cardiac malformation. Due to the expression patterns of Notch genes, involvement of the Notch signaling pathway in the development of heart and liver anomalies in KS should be considered.     

Hepatic fibrosis and collapse: histological distinction by orcein staining

Collapse of liver parenchyma, as seen in acute hepatitis with bridging necrosis, can be distinguished from new fibre formation in chronic liver disease by orcein staining. This shows abundant elastic fibres in association with fibrosis, but not in areas of collapse.     

Hepatic fibrosis and its serum markers]

As serum markers for hepatitis fibrosis, prolyl hydroxylase (PH), type III procollagen peptide (PIIIP), type IV collagen, mesenchymal metalloproteinase (MMP), tissue inhibitor of metalloproteinase (TIMP) and laminin are reliable for clinical application. PH, PIIIP, MMP, TIMP and LM are regarded as the marker of ongoing hepatic fibrosis. Type IV collagen and LM are indicative for the extent of hepatic fibrosis.     

Hepatic structural correlates of liver fibrosis: a morphometric analysis

Liver fibrosis is an important feature of many liver diseases, and the assessment of fibrosis is essential for diagnosis and prognosis. Liver needle biopsy, however, tends to sample preferentially the soft parenchyma, which poorly reflects the true extent of fibrosis. Therefore, we have searched for capsule and parenchymal features that are correlated with the fibrosis. To test for these correlations, we used a morphometric analysis of a rat model of liver fibrosis. We demonstrated that, of the variables examined, capsule thickness was the best correlate of liver fibrosis. Our results also showed that there were parenchymal structures that underwent changes that were well-correlated with the development of fibrosis in the liver. These changes were identified as increases in hepatocyte nucleus, cytoplasm, and mitochondria. These facts suggest that, at least in a rat model of fibrosis, capsule thickness is a useful parameter by which to assess liver fibrosis and that specific and apparently adaptive parenchymal changes are well-correlated to fibrosis.     

Endocrine tumors: biology and physiopathology

Endocrine tumors are defined as neoplastic lesions resulting from the proliferation of cells engaged in an endocrine differentiation pathway, as shown by their expression of a set of specific markers, including true endocrine markers (such as chromogranine A) and neuro-endocrine markers, shared between neurons and endocrine cells (such as synaptophysin). The demonstration of the synthesis and secretion of one or several hormones is not necessary for the assessment of the endocrine nature of a tumor; only tumors associated with a clinical syndrome resulting from hormone overproduction can be said functioning endocrine tumors. Beyond their common features, endocrine tumors are characterized by a marked diversity, which results from the large functional, structural and embryological heterogeneity of normal endocrine cells. The natural history of endocrine tumors is also characterized by a marked heterogeneity in their evolution and rate of progression. While most endocrine tumors are locally and slowly evolving, some of them behave as truly malignant tumors, as shown by their capacity of metastatic dissemination and their fatal evolution. A better understanding of the cellular and molecular mechanisms involved in tumor progression and metastatic dissemination is necessary for the identification of new prognostic tools and novel therapeutic targets.     

Hepatic regeneration after hepatectomy in schistosomatic fibrosis

After partial hepatectomy (approximately 30%), the labelled hepatocyte index (LHI) of the normal mouse is increased and reaches its highest value 48 h after surgery. In mice with schistosomatic fibrosis (SF), the LHI was lower than in the controls at 24, 48 and 72 h after hepatectomy.     

Hepatic sinusoidal fibrosis in agnogenic myeloid metaplasia

Autopsy studies in two patients who had agnogenic myeloid metaplasia of long duration revealed significant extramedullary hematopoiesis in the liver associated with significant hepatic perisinusoidal/sinusoidal fibrosis. Fibrosis was nonzonal and irregularly distributed throughout the livers. Early changes were found in areas with normal parenchymal architecture and showed significant thickening of collagen fibers surrounding the liver cell plates. In areas with extensive fibrosis, coarse collagen fibers filled the sinusoidal space and resulted in the loss of hepatocytes, but nodular regeneration was absent. Hepatic perisinusoidal/sinusoidal fibrosis in livers with extensive extramedullary hematopoiesis may be more common than previously recognized.     

Paraneoplastic neurologic syndromes: pathogenesis and physiopathology

Since 1965 when the first paraneoplastic antineuronal antibody was reported by Wilkinson and Zeromski (55), the number of immunological responses detected in association with paraneoplastic syndromes of the nervous system has steadily increased. These responses are characterized by the presence of antineuronal antibodies in serum and CSF and/or infiltrates of T-cells in the tumor and nervous system. A few syndromes are mediated by antibodies; they include those resulting from dysfunction of the neuromuscular junction at the pre- or post-synaptic level (Lambert-Eaton myasthenic syndrome, myasthenia gravis) or ion channel dysfunction in the peripheral nervous system (i.e, Voltage-gated potassium channel and neuromyotonia). In most other paraneoplastic syndromes, including those involving the central nervous system, the pathogenic role of highly specific antineuronal antibodies (anti-Hu, anti-Yo, etc.) has not been established; nevertheless these antibodies should be regarded as useful markers of specific paraneoplastic syndromes and tumors. Moreover, there is increasing evidence that in some of these syndromes T-cell mediated mechanisms can cause the neurologic dysfunction and contribute to tumor rejection. Some paraneoplastic syndromes are caused by the tumor secretion of antibodies (macroglobulinemia and MAG antibodies), hormones, and cytokines. In other instances, the tumor may compete with the nervous system for an essential substrate (glucose, tryptophan) and result in neurologic dysfunction.     

Antiphospholipid antibodies: clinical significance and biological diagnosis

The term "antiphospholipids" (aPLs) refers to an heterogeneous family of antibodies diagnosed either by clotting tests: the lupus anticoagulants or by Elisa: anticardiolipin (aCL) and anti-beta2-glycoprotein I (anti-beta2GP1) especially. aPLS recognize phospholipids, alone or bound to plasma protein cofactor(s), or the cofactors themselves. aPLs have long been described in autoimmune diseases such as SLE, but may also be found in other clinical settings including infections, malignancies and drug administration. Their persistent presence can be associated with venous and/or arterial thrombotic complications and/or recurrent miscarriage, thus defining the "antiphospholipid syndrome" (APS). The heterogeneity of aPLs makes a comprehensive approach to laboratory investigation essential. Detection of lupus anticoagulants relies on increased clotting times in phospholipid-dependent tests. Their 4 step diagnosis includes: 1) screening (by at least two different tests); 2) demonstration of an inhibitory activity; 3) evidence of its phospholipid dependence; 4) exclusion of an associated coagulopathy. Among the aPLs detected by Elisa, IgG aCL are the most frequently investigated. However, other antibodies may represent useful biological tools. Among them, anti-beta2GP1 are thought to be more closely associated with a history of thrombosis than aCL and testing for anti-beta2 GP1 should now be systematically included in the biological diagnosis of APS. The Elisa used for aCL and anti-beta2GP1 are not fully standardized, and a number of methodological parameters may account for the interlaboratory discrepancies often observed. The clinical importance of other antibodies such as antiphosphatidylethanolamine, antiprothrombin or antiannexin V is being evaluated. An appropriate laboratory investigation of APS should, in all cases, combine the use of clotting and immunological assays, and assess the persistence of autoantibodies over time.     

Hepatic steatosis, fibrosis, and cancer in elderly cadavers

The incidence of hepatic steatosis, fibrosis, and cancer in the elderly population remains unknown. Human cadavers used in anatomy teaching, which come largely from older adults, may provide liver tissue for examining their pathologies. Livers were obtained from 68 cadavers (mean age 82.1 ± 10.4 years) with diverse causes of death in the Anatomy course at Mount Sinai School of Medicine. Paraffin sections were stained with hematoxylin and eosin and Sirius red and evaluated for steatosis, fibrosis, cancer, and lipofuscin. Tissue preservation was graded as good in 38.2% of the embalmed livers, fair in 36.7%, and poor in 25.0%. Steatosis was observed in 35.3% of the livers, central vein fibrosis in 49.2%, perisinusoidal fibrosis in 63.2%, portal tract (PT) fibrosis in 47.0%, septa formation in 44.1%, bridging fibrosis in 30.8%, and cirrhosis in 4.4%. One hepatocellular carcinoma (HCC) and six metastatic tumors were detected. Lobular inflammation occurred in 20.8% of the livers and PT inflammation in 38.8%. Nine livers showed minimal change. Lipofuscin was detected in 60.2% of the livers. Steatosis, fibrosis, and cancer are highly prevalent in elderly cadavers with diverse causes of death. The prevalence of steatosis and fibrosis is consistent with the data in patients with specific liver diseases. Steatosis alongside fibrosis can accelerate the progression of fibrosis to cirrhosis and ultimately HCC. Though not indicated as the primary cause of death, the liver injury may have compromised hepatic functions and enhanced disease susceptibility, thereby exacerbating the health conditions in this elderly population.     

肝组织中糜酶浓度在慢性肝炎肝纤维化中的意义

目的:为探讨肝组织中糜酶(Chymase)浓度在慢性病毒性肝炎肝纤维化中的意义。方法:采用酶联免疫吸附实验(ELISA)检测45例慢性肝炎肝组织中Chymase浓度,观察不同的纤维化分期(S1-S4),其肝组织中Chymase浓度;用免疫组织化学染色法观察Chymase单克隆抗体标记的肥大细胞分布情况。结果:慢性肝炎纤维化分期重的S3和S4患者,其肝组织中Chymase浓度(S3+S4=31.3±24.6ng/mg)明显高于纤维化轻的S1和S2患者(S1+S2=5.7±4.8ng/mg),P<0.01;免疫组化染色结果,Chymase标记的肥大细胞主要分布于纤维化旺盛的汇管区与类洞壁,其分布与纤维化部位相一致,且肝组织中Chymase浓度高的患者,其肝组织内Chymase标记的肥大细胞分布增多。结论:肝组织中Chymase浓度可能与慢性肝炎肝纤维化关系密切。     

Hepatic leiomyosarcoma: Ultrastructural study and review of the differential diagnosis

A primary leiomyosarcoma of the liver in a 12 year old female is reported. It is the eleventh such tumor to be recorded, the first to be documented in an adolescent and the first to be studied electron microscopically. By light microscopy the well differentiated portions of the tumor were characteristic of leiomyosarcoma. Ultrastucturally a minority of tumor cells contained myofilaments along with cytoplasmic dense bodies and marginal dense plaques, the most distinctive subcellular markers of smooth muscle cells. A brief review of the differential diagnosis is provided.     

Chronobiology and renal physiopathology

This review presents our recent knowledge in renal chronobiology, considering physiology, pathology, pharmacology and toxicology. In a first part, are described renal chronophysiological data, pointing out particularly urinary excretion rhythms, largely described for last century. Such physiological observations lead to conclude that renal structures and functions present large temporal variations. Endogenous and exogenous origins of these rhythms are widely discussed. Evidence of such circadian and circannual variations in these renal structures and functions permit to understand why different agents, pathogeneous, toxic or medicamentous, will present time-dependent effects at renal level. So, a second part presents some recent experimental and clinical data in chrononephrology, chronopharmacology and chrononephrotoxicity. Finally, the concept of renal chronesthesy is presented and discussed, in order to explain these temporal variations in renal target susceptibility to different substances acting at this level.