Cause Of Cryptogenic Cirrhosis Research Articles

Unexplained Findings of Kayser-Fleischer-Like Rings in a Patient with Cryptogenic Cirrhosis

Cryptogenic cirrhosis (CC) is defined as cirrhosis occurring in an individual without an identifiable cause of liver disease, such as excessive alcohol consumption, viral hepatitis infection, hemochromatosis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, chronic intake of medications that could induce cirrhosis, alpha-1-antitrypsin deficiency, Wilson's disease, or any other rare cause of cirrhosis according to the clinical context. Cryptogenic cirrhosis is a common cause of liver-related morbidity and mortality in the United States. Nonalcoholic fatty liver disease is now recognized as the most common cause of cryptogenic cirrhosis. A biopsy specimen is also important for detecting histological advanced disease, which may be clinically silent and undetected by liver-related tests or diagnostic imaging. We are presenting an unusual case of a patient with cryptogenic cirrhosis found to have Kayser-Fleischer-like rings without evidence of Wilson's disease.

Frequency of Two Common HFE Gene Mutations (C282Y and H63D) in a Group of Iranian Patients With Cryptogenic Cirrhosis

: Background: The human HFE gene (a key component of iron homeostasis in humans) is involved in hereditary hemochromatosis, a common autosomal recessive genetic disorder that is characterized by excessive intestinal iron absorption and progressive iron overload.Objectives: In this study, we assessed the frequency of two common forms of hemochromatosis HFE gene mutation (C282Y and H63D) in patients suffering from cryptogenic cirrhosis.Patients and Methods: One hundred and fifty individuals were included in this study, in which 100 were patients with cryptogenic cirrhosis and 50 were from the normal population. All individuals were examined for common HFE gene mutations by amplification of nucleotide 845 C282Y and 187 H63D alleles and product analysis using the polymerase chain reaction method and restriction enzyme digestion.Results: No case of either a homozygous or heterozygous C282Y mutation was found. For the H63D mutation, no homozygosity was detected but heterozygosity was detected in 22% of patients and in 28% of the normal population.Conclusions: Hereditary hemochromatosis is not a major cause of cryptogenic cirrhosis in the Iranian population. Implication for health policy/practice/research/medical education:Hemochromatosis is a common disease in in western countries but by reading this article hepatologists will realize that this disease play a minor role in cirrhosis in Iran. Please cite this paper as:Jowkar Z ,Geramizadeh B, Shariat M. Frequency of Two Common HFE Gene Mutations (C282Y and H63D) in a Group of Iranian Patients With Cryptogenic Cirrhosis. Hepat Mon.2011;11(11): 887-889. DOI: 10.5812/kowsar.1735143x.781

Frequency of Two Common HFE Gene Mutations (C282Y and H63D) in a group of Iranian Patients with Cryptogenic Cirrhosis

The human HFE gene (a key component of iron homeostasis in humans) is involved in hereditary hemochromatosis, a common autosomal recessive genetic disorder that is characterized by excessive intestinal iron absorption and progressive iron overload. In this study, we assessed the frequency of two common forms of hemochromatosis HFE gene mutation (C282Y and H63D) in patients suffering from cryptogenic cirrhosis. One hundred and fifty individuals were included in this study, in which 100 were patients with cryptogenic cirrhosis and 50 were from the normal population. All individuals were examined for common HFE gene mutations by amplification of nucleotide 845 C282Y and 187 H63D alleles and product analysis using the polymerase chain reaction method and restriction enzyme digestion. No case of either a homozygous or heterozygous C282Y mutation was found. For the H63D mutation, no homozygosity was detected but heterozygosity was detected in 22% of patients and in 28% of the normal population. Hereditary hemochromatosis is not a major cause of cryptogenic cirrhosis in the Iranian population.

Association of nonalcoholic fatty liver disease with metabolic syndrome in Indian population

BackgroundNonalcoholic fatty liver disease (NAFLD), a common cause of cryptogenic cirrhosis is often associated with metabolic syndrome (MS) in the West. However, its association with MS in the Indian population is not well studied. AimsTo evaluate the association NAFLD with MS using the modified ATP-III criteria. Patients and methodsSeventy-six (62 men, mean age 40.05±11.4 years, range 18–66) apparently healthy subjects with fatty liver and histological evidence of NAFLD; with (64.5%) or without raised ALT, and 100 healthy controls were included in the study. The anthropometric measurements, metabolic parameters, tests of liver function and liver histology were studied. ResultsTwenty-one percent of the patients compared to 8% controls (p<0.01) had associated MS; according to ATP-III criteria while 42 and 12% were affected when the modified ATP-III criteria were used. About 35% of non-diabetic patients were insulin resistant with homeostatic model assessment-insulin resistance (HOMA-IR) cut-off set at 3. In patients, compared to controls, the mean BMI (25.2 vs. 22.7, p<0.01) and waist circumferences (92.9cm vs. 80.8cm, p<0.01) were higher. Seventy-nine percent of the patients and 44% of the controls were over weight. Stage 1 fibrosis was seen in 30 (39.5%), stage 2 in 10 (13.2%), stage 3 in 6 (7.9%) and stage 4 in 13 (17%) patients. ConclusionsInsulin resistance and obesity are associated in a proportion of Indian patients with NAFLD. However, the association with MS as defined by ATP-III in Indian patients is not strong compared to the West. It is likely that pathogenetic mechanisms unrelated to MS underlie development of NAFLD in a proportion of Indian patients.

The role of adiponectin in the pathogenesis and treatment of non‐alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is recognized as the most common type of chronic liver disease in Western countries and the leading cause of cryptogenic cirrhosis. Insulin resistance (IR) is a key factor in the pathogenesis of NAFLD, the latter being considered as the hepatic component of IR or metabolic syndrome (MetS). Although the pathogenesis of NAFLD is not fully elucidated, a complex interaction between adipokines and cytokines produced by adipocytes and/or inflammatory cells infiltrating adipose tissue appears to play a crucial role in MetS and NAFLD. Adiponectin is the most abundant and adipose-specific adipokine. In the liver, adiponectin acts through the activation of 5-AMP-activated protein kinase and peroxisome proliferator-activated receptor-alpha pathways and inhibition of toll-like receptor-4 mediated signalling. There is an evidence that adiponectin decreases hepatic and systematic IR and attenuates liver inflammation and fibrosis. Adiponectin generally predicts steatosis grade and severity of NAFLD, but it remains to be addressed to what extent this is a direct effect or related to the presence of more severe IR. Although there is no proven pharmacotherapy for the treatment of NAFLD, recent therapeutic strategies have focused on the indirect upregulation of adiponectin through the administration of various therapeutic agents and/or lifestyle modifications. Weight loss, through diet, lifestyle changes and/or medications including orlistat, sibutramine, rimonabant or bariatric surgery, increase adiponectin and may improve liver histology. Insulin sensitizers, including pioglitazone and rosiglitazone, and lipid-lowering agents, including statins and fibrates, also upregulate adiponectin and ameliorate liver histology. The wider use of new treatment approaches appears to signal the dawn of a new era in the management of NAFLD. In this adiponectin-focused review, the pathogenetic role and the potential therapeutic benefits of adiponectin in NAFLD are systematically analysed.

Liver transplantation of patients with cryptogenic cirrhosis: Clinical characteristics and outcome

Objectives. Non-alcoholic fatty liver disease (NAFLD), autoimmune hepatitis (AIH) and unapparent alcohol abuse may be underlying causes of cryptogenic cirrhosis, but the frequencies of these underlying factors differ between studies. Also, previous studies have shown various outcomes after orthotopic liver transplantation (OLT) for cryptogenic cirrhosis. The aims of this study were (1) to evaluate the presence of NAFLD in patients with cryptogenic cirrhosis evaluated for OLT and (2) to compare the severity of liver disease and patient survival in OLT candidates with cryptogenic cirrhosis and those with cirrhosis of another known origin. Material and methods. Four-hundred and seventy adult patients with end-stage liver cirrhosis evaluated for OLT between 1990 and 2004 were included, of whom 39 had cryptogenic cirrhosis. Clinical, histological and laboratory data that had been prospectively collected were re-evaluated. Results. Seventeen (44%) of the cryptogenic patients had NAFLD in a previous liver biopsy and/or clinical features of the metabolic syndrome. Two patients had occult alcohol over-consumption and one patient had burnt-out AIH. Cryptogenic patients had significantly higher frequencies of diabetes, ascites, and hyponatraemia and weight loss. Patient survival was similar between cryptogenic patients and cirrhotics with a known aetiology. Conclusions. Re-evaluation of patient data discovered probable underlying aetiologies in 51% of patients with cryptogenic cirrhosis evaluated for OLT, of which NAFLD was the most common (44%). Although cryptogenic patients had a more advanced liver disease when evaluated for OLT, patient survival was similar. Recent weight loss was significantly more common in cryptogenic patients, possibly being a sign of liver decompensation and signalling a need for OLT evaluation.

Nonalcoholic fatty liver disease: from clinical recognition to treatment

Nonalcoholic fatty liver disease (NAFLD) is probably the most common spectrum of metabolic liver disease in the world, encompassing simple steatosis to steatohepatitis, advanced fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD affects a significant part of the general population worldwide. The existing correlation between obesity and NAFLD in combination with the increase in the frequency of obesity in the developed world implies that the incidence and severity of NAFLD will increase in the near future. Newer data support the idea that NAFLD constitutes the more important cause of cryptogenic cirrhosis of the liver and a ground for the development of hepatocellular carcinoma. Liver biopsy remains the most specific and sensitive method to differentiate NAFLD, providing important information on the long-term prognosis of the patients. The ‘two hit’ hypothesis constitutes the currently prevailing theory for the development of NAFLD and nonalcoholic steatohepatitis. The first ‘hit’ is purported to be the increase of free fatty acids in hepatocytes, which results in a decrease of β-oxidation. The second step includes all mechanisms contributing to the development of necroinflammation and fibrosis. Currently, an effective treatment for patients with NAFLD does not exist. Improvement in liver histology remains the primary goal of any therapeutic approach in patients with NAFLD. Viewing NAFLD in the frame of the metabolic syndrome opens the possibility that both the onset of the disease and disease progression could be prevented by changes in lifestyle. Physical exercise and a low calorie diet in combination with the gradual loss of body weight represent the cornerstone for the management of NAFLD patients.

The effect of QuYuHuaTanTongLuo Decoction on the non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is the most common cause of cryptogenic cirrhosis, is becoming more prevalent in China. However, there is as yet no clearly established therapy for reversing fatty liver. Our aim is to explore the effect of traditional Chinese herbs QuYuHuaTanTongLuo Decoction (QYHTTLD) on non-alcoholic steatohepatitis. Sixty-nine non-alcoholic steatohepatitis patients were randomly divided into two groups. One group of 35 patients were treated by QYHTTLD, another group of 34 patients were treated by Ursodeoxycholic acid (UDCA). The TNF-alpha, IL-8, MDA level, SOD activity and liver function, as well as B ultrasonic image were detected before and after being treated. The results showed: after 6 months treatment, MBI of the treatment group was obviously decreased (p<0.05). The levels of TC, TG and LDL-C were significantly decreased whereas the level of HDL-C increased (p<0.01, p<0.05, p<0.05, and p<0.05, respectively) in the treatment group, the levels of TC, TG, LDL-C and HDL-C had no significant difference in the control group (p>0.05). The levels of TNF-alpha, IL-8 and MDA were significantly decreased whereas SOD activity was significantly increased (p<0.01, p<0.05, p<0.01, and p<0.01, respectively) in the treatment group, the level of MDA was significantly decreased in the control group (p<0.05). B ultrasonic images were ameliorated in different degree (p<0.01 and p<0.01, respectively). Both QYHTTLD and UDCA had the effect in improving the scores of symptoms and signs of patients, however, the difference value of the scores in treatment group were significantly higher than that in control group after being treated for 6 months (p<0.05). QYHTTLD is effective for treating non-alcoholic steatohepatitis, and its effect seems to relate with the ways of QYHTTL down-regulating inflammation cytokine IL-8 level and relieving lipid peroxidation of liver.

Effect of High Fat Diet on the Volume of Liver and Quantitative Feature of Kupffer Cells in the Female Rat: A Stereological and Ultrastructural Study

The role of Kupffer cells (KCs) in nonalcoholic steatohepatitis (NASH) which is regarded as a major cause of cryptogenic cirrhosis of the liver was investigated using stereological methods and electron microscopy in the rat model. To our knowledge, there is no stereological study on the volume of liver, total number, numerical density, and nuclear height of KCs of liver in the female rat fed with a high fat diet (HFD) in the literature. 16 female Sprague Dawley rats were randomized into HFD and control group, with HFD and standard diet for 12 weeks, respectively. In this study, two basic research methods were used to analyze the samples. One was histopathological observation at both light and electron microscopic level. The other was stereological methods that consist of Cavalieri principle for liver volume estimation and physical disector method for estimation of numerical density and total number of KCs in the liver. Liver volume, both mean numerical density and total number of KCs, were statistically increased in HFD rats. Ultrastructurally, a significant decrease in the mean nuclear height of KCs in HFD rats was also found. In the control group, no abnormal change was observed, but in the HFD group, some changes such as diffuse steatosis, mononuclear cell infiltration, necrosis, fibrosis, accumulation of fat droplets and intra-cytoplasmic vacuoles, and swollen mitochondria with irregular membranes were observed in the hepatocytes. The number and activity of KCs are increased significantly in NASH induced by HFD, and KCs might be involved in the pathogenesis of steatohepatitis as previously attributed as a major cause of cryptogenic cirrhosis of the liver.

Autoimmune Hepatitis: A Risk Factor for Cryptogenic Cirrhosis

Purpose: The etiology of cryptogenic cirrhosis (CC) is poorly understood. It is recognized that a significant number of patients with CC may result from nonalcoholic fatty liver disease (NAFLD) yet its cause in the others remains unknown. Occult autoimmune hepatitis or toxic liver injuries have been the other proposed causes of CC. The aim of the present study was to identify the clinical, biochemical, immunologic and histologic parameters of autoimmune hepatitis (AIH) in patients with CC to ascertain whether AIH is a causative risk factor for the disease. Methods: Thirty five consecutive patients who had liver transplant for CC were studied. Clinical, biochemical, immunologic and histologic parameters were analyzed and the International Autoimmune Hepatitis (IAH) score calculated. Explant histology was reevaluated by a hepatopathologist for the inflammation, lymphoid aggregate, plasma cells, interface hepatitis, steatosis, perivenular and sinusoidal changes, glycogenated nuclei, Mallory hyaline, bile duct changes, hepatocyte necrosis and fibrosis. Results: The mean age of patients was 53.7 ± 13 years, BMI was 29.6 ± 6.8 Kg M2 (range 21–42) and 57% were females. Diabetes was present in 42%; obesity in 63%, and 37% had concurrent illness. The liver chemistry revealed mild to moderate increase in aminotransferases (AST 85.5 ± 105, ALT 67 ± 70, AST/ALT 1.4 ± 0.6) and Alk Phos (187.7 ± 97.7). The ANA was positive in 17% and anti-smooth muscle antibody in 31%. Mean IAH score was 7.0 ± 3.0 and a score of 10 or greater was seen in 14%. However, in 60% of the patients with the high IAH score, the histologic features of residual NAFLD were also present. Liver histology showed cirrhosis in all. No interface hepatitis or plasma cell infiltrates were seen. Varying grades of centrivenular sclerosis (27 biopsies) and sinusoidal fibrosis (18 biopsies) indicative of residual NAFLD were seen in addition to Mallory hyaline seen in 23%. Conclusion: Occult or burnt-out AIH diagnosed by clinical, biochemical and immunologic criteria may be a risk factor leading to CC in a subset of patients. In some patients, dual injury from NAFLD and chronic AIH resulting in CC is a possibility. It remains conjectural that, the classic histology of AIH may be altered or lost once the disease progresses to cirrhotic stage.

Metabolic syndrome in liver-transplanted patients: Relation to immunosuppression and aetiology

Background and aims. Excessive weight gain, hypertension, hyperlipidaemia and impaired glucose tolerance occur early and can be frequently observed in liver transplanted (OLT) patients. The origin of these alterations, all related to insulin resistance and metabolic syndrome is under debate. Both immunosuppression and a metabolic disorder that produces previous non-alcoholic-steatohepatitis, putative cause of cryptogenic cirrhosis are possibly involved. However, so far, no definite data on markers of metabolic syndrome after OLT have been reported.

Flare-up of Nonalcoholic Steatohepatitis After Hepatectomy Resulted in Hepatic Failure in a Patient with Type 2 Diabetes Mellitus

Nonalcoholic steatohepatits (NASH) is seen in roughly 30% of obese patients and may progress to cirrhosis in 5–30% [1, 2]. Although the clinical spectrum of NASH has not been fully clarified, so far typical NASH is usually considered to be static or only slowly progressive [1, 2]. Accumulating data suggest that NASH is a possible cause of cryptogenic cirrhosis [2, 3]. On the other hand, several case reports have indicated that some of the patients with suspected silent NASH represent progressive liver failure due to an acute exacerbation [4–6]. However, to our knowledge there has been no histopathological evidence demonstrating that cryptogenic cirrhosis turns into frank NASH. We report herein an autopsy case of flare-up NASH after hepatectomy for hepatocellular carcinoma in an obese

Current Pharmacological Treatment of Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) is a frequent and potentially progressive chronic liver disease that occurs in subjects who do not abuse alcohol. NAFLD is often associated with obesity, metabolic syndrome and insulin resistance and its more aggressive form, nonalcoholic steatohepatitis (NASH) is a major cause of cryptogenic cirrhosis. NAFLD/NASH are commonly detected because of elevated serum aminotransferase levels, ultrasonographic fatty liver and, at liver histology, steatosis, inflammation, and occasionally fibrosis that may progress to cirrhosis. No established treatment exists for this potentially serious disorder. Current management of NAFLD/NASH is largely conservative and includes diet regimen, aerobic exercise, and interventions towards the associated metabolic abnormalities. The main concern is therefore to decrease liver steatosis and its progression toward steatohepatitis and fibrosis, and the risk of "cryptogenic" cirrhosis. Among the most promising medications, weight reducing drugs, insulin sensitizers and lipid-lowering agents, antioxidants, bile salts, co-factors increasing the mitochondrial transport of fatty acids are being considered. Among them, thiazolidinediones are the most promising drug family that act by activating PPARgamma nuclear receptors and by regulating both microsomal and peroxisomal lipid oxidative pathways. Pharmacological treatment of obesity and probiotics should be considered as potential therapeutic options. In this review, after summarizing the general background on fatty liver, the most current and attractive pharmacological approaches to the problem of NAFLD/NASH are discussed.

Cryptogenic Cirrhosis and NAFLD: Are They Related?

Cryptogenic cirrhosis (CC), literally meaning cirrhosis of obscure or unknown origin, is a diagnosis of exclusion. The circumstantial evidence indicates that nonalcoholic fatty liver disease (NAFLD) is perhaps one of the important causes of CC. There is also evidence, especially from the European literature, that some patients with CC may have undiagnosed or burnt-out autoimmune hepatitis (AIH). Other rare causes may include "unknown" viral (non-A, non-B, non-C) hepatitis, and occult alcoholism. In this review, we examine the role of NAFLD and other causes in the pathogenesis of CC, and the impact of obesity on patients with chronic liver disease.

Amelioration of non‐alcoholic steatohepatitis and glucose intolerance in ob/ob mice by oral immune regulation towards liver‐extracted proteins is associated with elevated intrahepatic NKT lymphocytes and serum IL‐10 levels

Non-alcoholic steatohepatitis (NASH) is a common cause of cryptogenic cirrhosis in the Western world. In an animal model of NASH, leptin-deficient ob/ob mice present with alterations in number and function of hepatic NKT and peripheral CD4 lymphocytes. Oral immune regulation is a method to alter the immune response towards orally administered antigens. To determine the effect of oral immune regulation towards liver-extracted proteins on the metabolic disorders in ob/ob mice, ob/ob mice and their lean littermates were orally administered liver extracts from wild-type or ob/ob mice or bovine serum albumin for 1 month. The effect of treatment on hepatic fat content was measured by magnetic resonance imaging (MRI) and using a histological steatohepatitis grading scale. Glucose tolerance was measured by an oral glucose tolerance test (GTT). T lymphocyte subpopulations were assessed by flow cytometry analysis. Induction of immune regulation by oral presentation of liver-extracted proteins resulted in a significant 18% reduction of the hepatic fat content in ob/ob mice fed with either wild-type or ob/ob liver extracts for 1 month. The MRI signal intensity index in treated mice decreased to 0.48 and 0.51, respectively, compared with 0.62 in BSA-fed controls (p = 0.037 and p = 0.019, respectively), while the histological steatohepatitis score decreased in both treated groups to 2.0, compared with 2.4 in BSA-fed controls (p = 0.05). A significant improvement in GTT was noted in treated ob/ob mice. These changes were accompanied by a marked increase in the intrahepatic NKT lymphocyte population in mice fed with proteins extracted from both wild-type and ob/ob mice (46.96% and 56.72%, respectively, compared with 26.21% in BSA-fed controls; p < 0.05) and a significant elevation in serum IL-10 levels. Oral immune regulation towards liver extracted proteins in leptin-deficient mice resulted in a marked reduction in hepatic fat content and improved glucose tolerance. This effect was associated with a significant increase in the intrahepatic NKT lymphocyte population and serum IL-10 levels, suggesting a Th1 to Th2 immune shift. Immune regulation towards disease-associated antigens holds promise as a new mode of therapy for NASH.

Stéatopathies hépatiques non alcooliques

Non alcoholic fatty liver disease (NAFLD) is part of a spectrum of liver damage, ranging from simple steatosis to advanced fibrosis and cirrhosis similar to those of alcoholic liver disease but in the absence of significant alcohol intake. Non alcoholic steatohepatitis (NASH) is characterised by liver fatty infiltration with various degrees of inflammation, necrosis, and fibrosis. NAFLD is one of the most common causes of abnormal liver tests and NASH has been proposed as a possible cause of cryptogenic cirrhosis and hepatocellular carcinoma. The prevalence of NAFLD ranges from 10% to 24% among western general populations, whereas that of NASH is about 3%. Insulin resistance is regarded as a hallmark and a causal factor of NAFLD. Several etiologic mechanisms have been proposed as causal factors of NAFLD, including increased afflux of free fatty acids to the liver, reduced free fatty acid-oxidation, and increased lipid-peroxidation. NAFLD is associated with several underlying medical disorders: most commonly type 2 diabetes, dyslipidemia, and obesity. The diagnosis of NAFLD, rarely proposed by clinicians, is generally made when the liver biopsy reveals unexplained abnormalities. Once alcoholic abuse is ruled out, the diagnosis of NAFLD raises two questions: what is the cause? and what is the prognosis ? Although most patients have a benign disease that does not progress, others may develop fibrosis or even cirrhosis. There is no established treatment for NAFLD. Treatment is usually directed toward optimising body weight. The role of pharmacologic agents remains to be established.

Oxidative Stress in Nonalcoholic Fatty Liver Disease: Pathogenesis and Antioxidant Therapies

Nonalcoholic fatty liver disease is a common cause of chronic liver disease, a common finding on liver biopsy in those patients with abnormal blood transaminase levels, and a common cause of cryptogenic cirrhosis in the United States. The prevalence of this disorder is expected to rise with the increase in obesity, and the clinical spectrum can range from simple steatosis (fatty liver) to cirrhosis of the liver. Insulin resistance is thought to be pivotal for the development of steatosis, and oxidative stress may be a potential factor that can promote hepatic necroinflammation and fibrosis. Preliminary studies have examined the role of oxidative stress and antioxidants in animal and human studies of this disorder. Efforts to improve the hepatic antioxidant system could be achieved by optimizing the patient's diet, by supplementation with precursors for antioxidants, or by supplementation with essential metals and/or antioxidants. Randomized, controlled trials are required to examine these potential approaches using patients with this disorder.

Revealing the cause of cryptogenic cirrhosis by posttransplant liver biopsy

Introduction Because of the tendency for preexisting diseases to recur following liver transplantation, studying the course of patients who were transplanted for their cryptogenic cirrhosis may reveal features of the original cause. We examined the clinicopathological posttransplant progression of patients transplanted due to cryptogenic cirrhosis with emphasis on the detection of posttransplant steatosis and steatohepatitis. Methods The data on all patients transplanted for cryptogenic cirrhosis and their routine 1-year posttransplant liver biopsies were compared to a control group of a randomized sample of patients transplanted for other indications matched for length of follow-up. The posttransplant histological diagnosis was based on the latest available biopsy. Results Among 1710 patients, 39 present with cryptogenic etiology survived at least 1 year after transplantation. The control group consisted of 78 patients. The mean ages of the two groups were 50.7 and 49.3 years and the mean follow-up periods 6.2 and 5.7 years, both of which were similar. There was a significantly greater prevalence of posttransplant steatosis and steatohepatitis among the cryptogenic group (37.5 vs 16.7%, P = .048). The difference in patients with at least moderate steatosis was more pronounced (18.8 vs 3.3%, P = .035). Half of these cases progressed to fibrosis and cirrhosis after 48 months. Conclusions This study found a greater incidence of allograft steatosis and steatohepatitis among patients transplanted for cryptogenic cirrhosis compared with a control group. A significant proportion of these patients developed a picture resembling nonalcoholic steatohepatitis, which progressed to fibrosis and cirrhosis.

Probiotics: a potential target for the prevention and treatment of steatohepatitis.

The accumulation of fat in hepatocytes with a necroinflammatory component-steatohepatitis-that may or may not have associated fibrosis is becoming a frequent lesion. Although steatohepatitis is currently recognized to be a leading cause of cryptogenic cirrhosis, the pathogenesis has not been fully elucidated. Among the various factors implicated, intestinal bacterial overgrowth may play a role. Indeed, various rat models of intestinal bacterial overgrowth have been associated with liver lesions similar to NASH, and bacterial overgrowth has been observed significantly more often in patients with NASH compared with control subjects. The authors discuss the relationship among intestinal bacterial overgrowth, steatohepatitis development, and probiotic treatment.

Nonalcoholic steatohepatitis: Summary of an AASLD Single Topic Conference

Fatty liver disease that develops in the absence of alcohol abuse is recognized increasingly as a major health burden. This report summarizes the presentations and discussions at a Single Topic Conference held September 20-22, 2002, and sponsored by the American Association for the Study of Liver Diseases. The conference focused on fatty liver disorders. Estimates based on imaging and autopsy studies suggest that about 20% to 30% of adults in the United States and other Western countries have excess fat accumulation in the liver. About 10% of these individuals, or fully 2% to 3% of adults, are estimated to meet current diagnostic criteria for nonalcoholic steatohepatitis (NASH). Sustained liver injury leads to progressive fibrosis and cirrhosis in a fraction, possibly up to one third, of those with NASH, and NASH may be a cause of cryptogenic cirrhosis. NASH is now a significant health issue for obese children as well, leading to cirrhosis in some. The diagnostic criteria for NASH continue to evolve and rely on the histologic findings of steatosis, hepatocellular injury (ballooning, Mallory bodies), and the pattern of fibrosis. Generally recognized indications for biopsy include establishing the diagnosis and staging of the injury, but strict guidelines do not exist. Liver enzymes are insensitive and cannot be used reliably to confirm the diagnosis or stage the extent of fibrosis. Older age, obesity, and diabetes are predictive of fibrosis. The pathogenesis of NASH is multifactorial. Insulin resistance may be an important factor in the accumulation of hepatocellular fat, whereas excess intracellular fatty acids, oxidant stress, adenosine triphosphate (ATP) depletion, and mitochondrial dysfunction may be important causes of hepatocellular injury in the steatotic liver. Efforts are underway to refine the role of insulin resistance in NASH and determine whether improving insulin sensitivity pharmacologically is an effective treatment. An altered lifestyle may be a more effective means of improving insulin sensitivity. The research agenda for the future includes establishing the role of insulin resistance and abnormal lipoprotein metabolism in NASH, determining the pathogenesis of cellular injury, defining predisposing genetic abnormalities, identifying better noninvasive predictors of disease, and defining effective therapy. (H epatology 2003;37:1202-1219.)