Melatonin protects against common deletion of mitochondrial DNA-augmented mitochondrial oxidative stress and apoptosis

Defected mitochondrial respiratory chain (RC), in addition to causing a severe ATP deficiency, often augments reactive oxygen species (ROS) generation in mitochondria (mROS) which enhances pathological conditions and diseases. Previously, we demonstrated a potent endogenously RC defect-augmented mROS associated dose-dependently with a commonly seen large-scale deletion of 4977 base pairs of mitochondrial DNA (mtDNA), i.e. the common deletion (CD). As current treatments for CD-associated diseases are rather supplementary and ineffective, we investigated whether melatonin, a potential mitochondrial protector, provides beneficial protection for CD-augmented mitochondrial oxidative stress and apoptosis particularly upon the induction of a secondary oxidative stress. Detailed mechanistic investigations were performed by using laser scanning dual fluorescence imaging microscopy to provide precise spatial and temporal resolution of mitochondrial events at single cell level. We demonstrate, for the first time, that melatonin significantly prevents CD-augmented mROS formation under basal conditions as well as at early time-points upon secondary oxidative stress induced by H2O2 exposure. Thus, melatonin prevents mROS-mediated depolarization of mitochondrial membrane potential (DeltaPsim) and subsequent opening of the mitochondrial permeability transition pore (MPTP) and cytochrome c release. Moreover, melatonin prevents depletion of cardiolipin which appears to be crucial for postponing later MPTP opening, disruption of the mitochondrial membrane and apoptosis. Finally, the protection provided by melatonin is superior to those caused by the suppression of mitochondrial Ca2+ regulators including the mitochondrial Na+-Ca2) exchanger, the MPTP, and the mitochondrial Ca2+ uniporter and by antioxidants including vitamin E and mitochondria-targeted coenzyme Q, MitoQ. As RC defect-augmented endogenous mitochondrial oxidative stress is centrally involved in a variety of pathological conditions and diseases, melatonin thus may serve as a therapeutic drug to benefit many clinical conditions that involve malfunction of the mitochondria.     

Different pathophysiological mechanisms of intramitochondrial iron accumulation in acquired and congenital sideroblastic anemia caused by mitochondrial DNA deletion

Sideroblastic anemias (SA) are characterized by iron accumulation in the mitochondria of erythroblasts. Although we have evidence of mitochondrial gene alterations in sporadic congenital cases, the origin of acquired forms [refractory anemia with ring sideroblasts (RARS)], is still largely unknown. Here, we report the analysis of respiratory chain function in a patient with a large mitochondrial deletion and in patients with RARS. A young boy with SA showed symptoms typical of a mitochondrial disease with metabolic acidosis, muscle weakness and cerebral involvement. His bone marrow DNA was analyzed for the presence of mitochondrial deletions. We found a new mitochondrial (mt)DNA deletion spanning 3,614 bp and including all the mt genes encoding complex IV, plus ATPase 6 and 8, and several transfer (t)RNAs. All tissues analyzed (liver, skeletal muscle, brain, pancreas) showed a heteroplasmic distribution of this mutant DNA. Bone marrow homogenates were obtained from five patients with RARS and from three patients with normal bone marrow and respiratory chain function assayed by spectrophotometric analysis. Cytochrome c oxidase (CCO) activity was greatly reduced in the patient's bone marrow. In contrast, CCO activity and global respiratory chain function were conserved in patients with RARS. We conclude that deficient CCO activity secondary to mtDNA deletions is related to intramitochondrial iron accumulation, as in our patient or in those with Pearson's syndrome, whereas other mechanisms, e.g. nuclear DNA mutations, have to be proposed to be involved in the acquired forms of SA.     

Increased lipid peroxidation and mitochondrial dysfunction in aceruloplasminemia brains

Aceruloplasminemia is characterized by iron accumulation in the brain as well as in visceral organs, due to the absence of ceruloplasmin ferroxidase activity. The neurological symptoms, which include involuntary movements, ataxia, and dementia, reflect the sites of iron deposition. The unique involvement of the central nervous system distinguishes aceruloplasminemia from other inherited and acquired iron storage disorders. Excess iron functions as a potent catalyst of biologic oxidation. An increased iron concentration was associated with increased lipid peroxidation in the brains of three aceruloplasminemia patients. Positron emission tomography showed brain glucose and oxygen hypometabolism. Enzyme activities in the mitochondrial respiratory chain of the basal ganglia were reduced to about 50 and 43%, respectively, for complexes I and IV. Those of the cerebral and cerebellar cortices also were decreased approximately 62 and 65%. These findings suggest that iron-mediated free radicals may contribute to neuronal cell damage through increased lipid peroxidation and the impairment of mitochondrial energy metabolism in aceruloplasminemia brains.     

Inheritance of mitochondrial DNA in humans: implications for rare and common diseases

The first draft human mitochondrial DNA (mtDNA) sequence was published in 1981, paving the way for two decades of discovery linking mtDNA variation with human disease. Severe pathogenic mutations cause sporadic and inherited rare disorders that often involve the nervous system. However, some mutations cause mild organ‐specific phenotypes that have a reduced clinical penetrance, and polymorphic variation of mtDNA is associated with an altered risk of developing several late‐onset common human diseases including Parkinson’s disease. mtDNA mutations also accumulate during human life and are enriched in affected organs in a number of age‐related diseases. Thus, mtDNA contributes to a wide range of human pathologies. For many decades, it has generally been accepted that mtDNA is inherited exclusively down the maternal line in humans. Although recent evidence has challenged this dogma, whole‐genome sequencing has identified nuclear‐encoded mitochondrial sequences (NUMTs) that can give the false impression of paternally inherited mtDNA. This provides a more likely explanation for recent reports of ‘bi‐parental inheritance’, where the paternal alleles are actually transmitted through the nuclear genome. The presence of both mutated and wild‐type variant alleles within the same individual (heteroplasmy) and rapid shifts in allele frequency can lead to offspring with variable severity of disease. In addition, there is emerging evidence that selection can act for and against specific mtDNA variants within the developing germ line, and possibly within developing tissues. Thus, understanding how mtDNA is inherited has far‐reaching implications across medicine. There is emerging evidence that this highly dynamic system is amenable to therapeutic manipulation, raising the possibility that we can harness new understanding to prevent and treat rare and common human diseases where mtDNA mutations play a key role.     

线粒体动力学、线粒体自噬和心血管疾病

线粒体是一种动态的细胞器,通过响应各种代谢和环境的信号, 分裂和融合改变其形态和结构,从而维持细胞的正常功能。它们短暂而快速的形态变化对于细胞周期、免疫、凋亡和线粒体自噬的质量控制等许多复杂的细胞过程至关重要。线粒体自噬与线粒体质量控制密切相关,通过将受损的功能障碍的线粒体转运到溶酶体进行降解,促进心肌细胞受损线粒体的更新,并有效地抑制功能障碍线粒体的积累。由于心脏作为一个复杂而高耗能的器官,心肌细胞严重地依赖线粒体氧化代谢过程作为其能量和营养供应的来源。许多研究表明,线粒体融合、分裂和线粒体自噬的诸多影响和调控功能的因子都与各种心血管疾病有关,维持线粒体的功能和其完整性对正常心肌细胞的运行是至关重要的。在这篇的综述中,我们将重点概述一下线粒体的融合、分裂和线粒体自噬的诸多调控因子与心血管疾病的最新研究进展。     

Non-alcoholic fatty liver disease: The diagnosis and management

Non-alcoholic fatty liver disease(NAFLD) is now the most frequent chronic liver disease that occurs across all age groups and is recognized to occur in 14%-30% of the general population, representing a serious and growing clinical problem due to the growing prevalence of obesity and overweight. Histologically, it resembles alcoholic liver injury but occurs in patients who deny significant alcohol consumption. NAFLD encompasses a spectrum of conditions, ranging from benign hepatocellular steatosisto inflammatory nonalcoholic steatohepatitis, fibrosis, and cirrhosis. The majority of hepatocellular lipids are stored as triglycerides, but other lipid metabolites, such as free fatty acids, cholesterol, and phospholipids, may also be present and play a role in disease progression. NAFLD is associated with obesity and insulin resistance and is considered the hepatic manifestation of the metabolic syndrome, a combination of medical conditions including type 2 diabetes mellitus, hypertension, hyperlipidemia, and visceral adiposity. Confirmation of the diagnosis of NAFLD can usually be achieved by imaging studies; however, staging the disease requires a liver biopsy. Current treatment relies on weight loss and exercise, although various insulin-sensitizing agents, antioxidants and medications appear promising. The aim of this review is to highlight the current information regarding epidemiology, diagnosis, and management of NAFLD as well as new information about pathogenesis, diagnosis and management of this disease.     

调心方对Aβ所致Alzheimer痴呆大鼠线粒体呼吸功能的影响

目的　观察调心方对 Aβ所致痴呆大鼠空间学习记忆能力和脑线粒体呼吸功能的影响。方法　大鼠左侧脑室注射 Aβ1 - 4 0活性片段造成大鼠 Aβ沉积型 Alzheimer病 (AD)模型 ,Morris水迷宫法观察大鼠空间学习记忆能力 ;Clark氧电极法测定各组大鼠皮层细胞线粒体呼吸功能和呼吸链氧化酶的活性以及调心方的作用。结果　与正常对照组比较 ,模型鼠空间学习记忆能力、皮层细胞线粒体呼吸功能和呼吸链中氧化酶活性均显著降低 ,调心方对上述指标有不同程度的改善作用。结论　调心方具有改善 AD大鼠空间学习记忆能力、脑线粒体呼吸功能及呼吸链中氧化酶活性的作用     

The aggravation of mitochondrial dysfunction in nonalcoholic fatty liver disease accompanied with type 2 diabetes mellitus

Abstract

Objective. Nonalcoholic fatty liver disease (NAFLD) is a mitochondrial disease associated with the metabolic syndrome, but few data are available on the mitochondrial dysfunction of NAFLD after the development of type 2 diabetes mellitus (T2DM). We aimed to identify the changes of mitochondrial function in rat livers when T2DM develops after NAFLD. Material and methods. Rat models of nonalcoholic fatty liver (NAFL) and T2DM were established using high-fat diet and streptozocin. Mitochondria were isolated from the livers. The levels of reactive oxygen species (ROS) and mRNA and protein levels of mitochondrial complex IV (COX IV) and carnitine palmitoyltransferase-1 (CPT-1) were assessed in rat livers. The mitochondrial membrane potential (MP), and the enzyme activities of COX IV and CPT-1 were measured in isolated mitochondria. Results. There were increased ROS, decreased mitochondrial MP, and reduced COX IV and CPT-1 activity in the NAFL and T2DM groups compared with controls (p < 0.05). Compared with NAFL, the T2DM group had higher ROS levels and lower enzyme activity (p < 0.05), but showed no difference in mitochondrial MP. Although COX IV and CPT-1 expression levels in liver decreased in NAFL and T2DM, there was no significant difference between two groups. Conclusion. This study first identified progressively impaired mitochondrial respiratory chain and β-oxidation in NAFLD when T2DM develops, inducing overproduction of ROS, and finally triggering a vicious circle that leads to the aggravation of mitochondrial dysfunction in NAFLD after development of T2DM.     

Approach to the patient with early Parkinson disease: diagnosis and management

This article presents an evidence‐based approach to the patient with newly diagnosed Parkinson disease (PD). It includes a discussion of the current understanding of the aetio‐pathogenesis of PD and of clinical features, both motor and non‐motor, that assist the clinician in making this diagnosis. An approach to the management of early stage PD is discussed, including emerging evidence of the benefits of physical exercise in this condition, and issues to consider in the selection of dopaminergic medication. The newly diagnosed patient with PD is often keen to know what the future holds for them, as they face this progressive neurodegenerative condition. While currently available medical therapies are symptomatic, rather than disease‐modifying, in nature, it is hoped that improved understanding of the aetio‐pathogenesis of PD will pave the way for future disease‐modifying therapies.     

Intestinal pseudo-obstruction and urinary retention: cardinal features of a mitochondrial DNA-related disease

The syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a multisystemic disorder associated in most of the patients with an A to G transition at nucleotide position 3243 in the transfer RNA (tRNA)Leu(UUR) (A3243G) of the mitochondrial DNA. This syndrome is characterized by the preponderant involvement of skeletal muscle and central nervous system, but urinary or gastrointestinal symptoms are seldom documented. Here we report an unusual case of a 52-year-old woman with a clinical phenotype characterized by encephalopathy, left hemiparesis, urinary retention and gastrointestinal pseudo-obstruction. She had the classical A3243G mitochondrial DNA point mutation of MELAS syndrome. We also present a clinically heterogeneous multigenerational pedigree with several affected members in the maternal lineage.     

Refractory anaemia and mitochondrial cytopathy in childhood

SUMMARY. We report two cases of childhood myelodysplasia (MDS) related to a mitochondrial (mt) cytopathy that illustrate the difficulty in recognizing such disorders in patients with solely haematological signs. Both patients have refractory anaemia with ring sideroblasts and vacuolization of haemopoietic precursors. These cytological features are similar to those observed in Pearson's disease, recently identified as a mitochondrial disease, and are strongly suggestive of a mitochondrial enzyme defect. The diagnosis of mitochondrial cytopathy was established on Southern blotting of mt DNA, showing a mt DNA deletion, or on the impairment of the respiratory chain enzyme activities. The absence of cytogenic abnormalities, and the polyclonal pattern of peripheral neutrophil and lymphocyte fractions, suggest that, in mt cytopathies, MDS cannot be considered as a truly malignant disorder.     

Neoplastic pericardial disease: Old and current strategies for diagnosis and management

The prevalence of neoplastic pericardial diseases has changed over time and varies according to diagnostic methods. The diagnostic factor is usually the detection of neoplastic cells within the pericardial fluid or in specimens of pericardium, but the diagnosis may be difficult. Accurate sampling and cytopreparatory techniques, together with ancillary studies, including immunohistochemical tests and neoplastic marker dosage, are essential to obtain a reliable diagnosis. The goals of treatment may be simply to relieve symptoms (cardiac tamponade or dyspnea), to prevent recurrent effusion for a long-term symptomatic benefit, or to treat the local neoplastic disease with the aim of prolonging survival. Immediate relief of symptoms may be obtained with percutaneous drainage or with a surgical approach. For long term prevention of recurrences, various approaches have been proposed: extended drainage, pericardial window (surgical or percutaneous balloon pericardiostomy), sclerosing local therapy, local and/or systemic chemotherapy or radiation therapy (RT) (external or with intrapericardial radionuclides). The outcomes of various therapeutic approaches vary for different tumor types. Lymphoma and leukemias can be successfully treated with systemic chemotherapy; for solid tumors, percutaneous drainage and the use of systemic and/or local sclerosing and antineoplastic therapy seems to offer the best chance of success. The use of "pure" sclerosing agents has been replaced by agents with both sclerosing and antineoplastic activity (bleomycin or thiotepa), which seems to be quite effective in breast cancer, at least when associated with systemic chemotherapy. Local chemotherapy with platinum, mitoxantrone and other agents may lead to good local control of the disease, but the addition of systemic chemotherapy is probably relevant in order to prolong survival. The surgical approach (creation of a pericardial window, even with the mini-invasive method of balloon pericardiostomy) and RT may be useful in recurring effusions or in cases that are refractory to other therapeutic approaches.     

Polycystic liver disease: Classification,diagnosis, treatment process,and clinical management

Polycystic liver disease(PLD) is a rare hereditary disease that independently exists in isolated PLD, or as an accompanying symptom of autosomal dominant polycystic kidney disease and autosomal recessive polycystic kidney disease with complicated mechanisms. PLD currently lacks a unified diagnostic standard. The diagnosis of PLD is usually made when the number of hepatic cysts is more than 20. Gigot classification and Schnelldorfer classification are now commonly used to define severity in PLD. Most PLD patients have no clinical symptoms, and minority with severe complications need treatments. Somatostatin analogues,mammalian target of rapamycin inhibitor, ursodeoxycholic acid and vasopressin-2 receptor antagonist are the potentially effective medical therapies, while cyst aspiration and sclerosis, transcatheter arterial embolization, fenestration, hepatic resection and liver transplantation are the options of invasion therapies.However, the effectiveness of these therapies except liver transplantation are still uncertain. Furthermore, there is no unified strategy to treat PLD between medical centers at present. In order to better understand recent study progresses on PLD for clinical practice and obtain potential directions for future researches, this review mainly focuses on the recent progress in PLD classification, clinical manifestation, diagnosis and treatment. For information, we also provided medical treatment processes of PLD in our medical center.     

Kennedy's disease: genetic diagnosis of an inherited form of motor neuron disease

:Kennedy's disease (X-linked spinal and bulbar muscular atrophy) is an inherited form of motor neuron disease that may be diagnosed genetically using the polymerase chain reaction (PCR). This form of motor neuron disease principally affects the proximal limb girdle muscles as well as those involved with deglutition and phonation. Onset is usually late, in the fourth to fifth decades of life, and progression is slow. Moderate gynecomastia and testicular atrophy are usually present, suggesting a defect in androgen receptor function. Being inherited in an X-linked recessive manner, only males are affected, with females as the unaffected carriers.
The genetic abnormality that causes Kennedy's disease is an enlargement of the androgen receptor (AR) gene, which is located on the proximal long arm of the X chromosome. In patients with this disease, a region in the gene containing repeated CAG triplet nucleotides is approximately twice the size of that found in normal people. Using PCR to amplify this region of the AR gene, this study confirms this genetic mutation in 12 males from eight different families. All these families live on the east coast of Australia. This mutation was not found in five patients with other forms of motor neuron disease. Twelve heterozygote females, the daughters of affected males and carrier females, have also been identified. In addition, there are 14 asymptomatic and as yet untested sons of carriers, ranging in age from less than one year to over 40 years of age. Each has a 50% chance of inheriting the abnormal gene from his mother and thus developing Kennedy's disease.
This study shows that Kennedy's disease may be diagnosed genetically using whole blood, and discusses the ethics of prenatal and presymptomatic testing, particularly in males under 16. (Aust NZ J Med 1993; 23: 187–192.)     

Accelerated expansion of pathogenic mitochondrial DNA heteroplasmies in Huntington’s disease

Mitochondrial dysfunction is found in the brain and peripheral tissues of patients diagnosed with Huntington’s disease (HD), an irreversible neurodegenerative disease of which aging is a major risk factor. Mitochondrial function is encoded by not only nuclear DNA but also DNA within mitochondria (mtDNA). Expansion of mtDNA heteroplasmies (coexistence of mutated and wild-type mtDNA) can contribute to age-related decline of mitochondrial function but has not been systematically investigated in HD. Here, by using a sensitive mtDNA-targeted sequencing method, we studied mtDNA heteroplasmies in lymphoblasts and longitudinal blood samples of HD patients. We found a significant increase in the fraction of mtDNA heteroplasmies with predicted pathogenicity in lymphoblasts from 1,549 HD patients relative to lymphoblasts from 182 healthy individuals. The increased fraction of pathogenic mtDNA heteroplasmies in HD lymphoblasts also correlated with advancing HD stages and worsened disease severity measured by HD motor function, cognitive function, and functional capacity. Of note, elongated CAG repeats in HTT promoted age-dependent expansion of pathogenic mtDNA heteroplasmies in HD lymphoblasts. We then confirmed in longitudinal blood samples of 169 HD patients that expansion of pathogenic mtDNA heteroplasmies was correlated with decline in functional capacity and exacerbation of HD motor and cognitive functions during a median follow-up of 6 y. The results of our study indicate accelerated decline of mtDNA quality in HD, and highlight monitoring mtDNA heteroplasmies longitudinally as a way to investigate the progressive decline of mitochondrial function in aging and age-related diseases.

Huntington’s disease (HD) is a monogenic disorder caused by the expansion of cytosine–adenine–guanine trinucleotide (CAG) repeats in the HTT gene at chromosome 4p16.3 (1). Although HTT is expressed in various tissues, the brain, particularly the striatum, is vulnerable to mutant huntingtin (mHTT)-associated toxicity (2). The average age at onset of the characteristic motor symptoms of HD is between 40 and 50 y old, followed by a progressive decline of motor, cognitive, and psychiatric functions for an average of 20 y prior to death (3).The biological processes that determine the onset and progression of HD are still elusive. Recent studies suggest that mitochondrial dysfunction may be involved in HD pathogenesis (4, 5). Mitochondria are subcellular organelles of eukaryotes, which play vital roles in maintaining energetic and metabolic homeostasis (6, 7). Evidence for mitochondrial dysfunction in HD was first reported in the postmortem brain of HD patients, which show low mitochondrial oxidative phosphorylation (OXPHOS) protein activity and energy deficits (8–10). Mitochondrial dysfunction was further found in peripheral tissues and cell lines of HD patients, such as blood, lymphoblasts, skeletal muscle, and skin fibroblasts (11–17).Several molecular mechanisms have been proposed to connect mHTT to mitochondrial dysfunction. Studies in HD knockin mice indicate that toxic fragments derived from mHTT can suppress mitochondrial biogenesis and energy metabolism (18). mHTT has also been found to physically interact with mitochondria, reducing mitochondrial membrane potential (13, 19). Furthermore, mHTT may stimulate mitochondrial network fragmentation (20–22), and it has recently been found to impair mitophagy (23–28), an evolutionarily conserved quality control system in eukaryotes to selectively remove dysfunctional mitochondria (29). Perturbation of mitochondrial tubular networks, morphology, and mitophagy are pathological features common to various neurodegenerative diseases (30, 31).Mitochondrial function is determined not only by the nuclear genome but also by the mitochondrial genome (mtDNA). Human mtDNA is a 16.6-kb circular DNA located within mitochondria. It encodes 13 evolutionarily conserved proteins in four of the five OXPHOS protein complexes (32). The accumulation of mtDNA mutations in somatic tissues has been suggested as a possible driver of age-related mitochondrial dysfunction (33). Transgenic mice with an increased level of mtDNA mutations manifest progeroid phenotypes and early neurodegeneration that resemble human aging (34, 35). Clonal expansion of preexisting mtDNA mutations in somatic tissues has also been shown to contribute to accelerated mitochondrial aging and OXPHOS defects in human diseases (36, 37).Because there are multiple copies of mtDNA in a single cell, mutations can arise and coexist with wild-type mtDNA in a state called heteroplasmy, which has been linked to a variety of mitochondrial disorders in humans (32, 38). Our previous study on lymphoblasts from the 1,000 Genomes project indicates that about 90% of individuals in the general population carry at least one heteroplasmy in mtDNA, and purifying selection keeps most pathogenic heteroplasmies at a low fraction (39). Thus, when such a selective constraint on mitochondria is weakened under certain conditions (40), such as the presence of mHTT (20–28), these low-fraction pathogenic heteroplasmies may increase in their fractions in cells, culminating in dysfunctional mitochondria and related energy deficits (32).In the current study, we hypothesized that HD progression is partially driven by the deterioration of mtDNA quality. Since HTT is universally expressed, and mitochondrial dysfunction has been repeatedly observed in peripheral tissues (11–16), we surmised that HD-associated mtDNA changes can be detected in peripheral tissues and cell lines of HD patients, such as blood-derived lymphoblasts, which are readily available in large patient cohorts and thus can provide increased power for identifying mtDNA changes in HD. To test this hypothesis, we employed a sensitive mtDNA targeted sequencing approach, STAMP (sequencing by targeted amplification of multiplex probes) (41), to assess mtDNA heteroplasmies in lymphoblast and longitudinal blood samples from HD patients and healthy control individuals in the European Huntington’s Disease Network’s REGISTRY study (hereafter referred to as REGISTRY) (42). We achieved ultradeep sequencing coverage on mtDNA in these samples and revealed an accelerated expansion of pathogenic mitochondrial DNA heteroplasmies in HD, illustrating a molecular feature underlying HD biology.     

阿尔茨海默病康复管理中国专家共识(2019)

随着社会老龄化,阿尔茨海默病(AD)发病率逐渐增高。康复作为一种非药物治疗方法,旨在改善认知和运动功能障碍,减轻痴呆患者的行为和心理症状,提高患者的生活质量。为此,我们组织相关专家编写本共识,以积极推进AD的规范化康复治疗。     

Roles of gender, obesity, and lifestyle-related diseases in alcoholic liver disease: Obesity does not influence the severity of alcoholic liver disease

Aim: To elucidate gender differences and the influence of obesity and/or metabolic syndrome‐related fatty liver on alcoholic liver disease (ALD), we analyzed characteristic features of ALD. Methods: We investigated 266 ALD patients (224 males and 42 females) without hepatocellular carcinoma stratified by gender and the presence of cirrhosis. Male and female patients matched for age and total ethanol intake were also analyzed. A diagnosis of ALD was based on alcohol intake (>70 g daily for more than 5 years), clinical features, and exclusion of other liver diseases. The prevalence of obesity, lifestyle‐related diseases, and psychological disorders were assessed. Results: The prevalence of psychological disorders showed a significant gender difference among all ALD patients (12% in males versus 43% in females, P < 0.001), as well as in patients matched for age and total ethanol intake. There were 156 cirrhotic patients. Absence of dyslipidemia, presence of diabetes, and high total ethanol intake were selected as independent predictors of cirrhosis in males by multivariate analysis after excluding laboratory data of liver function tests. The prevalence of obesity was significantly lower in cirrhotic male patients than in non‐cirrhotic male patients (34% vs. 20%, P = 0.023). Among females, there were no significant predictors of cirrhosis on multivariate analysis after eliminating liver function tests. The prevalence of obesity and diabetes was similar in non‐cirrhotic and cirrhotic female patients. The prevalence of psychological disorders was 47% in cirrhotic females with ALD. Conclusions: Obesity was not common in cirrhotic ALD. Psychological disorders seem to be important for female ALD.