Stephen H. Caldwell

Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace.

Hepatocellular carcinoma (HCC) is a common cancer worldwide that primarily develops in cirrhosis resulting from chronic infection by hepatitis B virus and hepatitis C virus, alcoholic injury, and to a lesser extent from genetically determined disorders such as hemochromatosis. HCC has recently been linked to non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of obesity and related metabolic disorders such as diabetes. This association is alarming due to the globally high prevalence of these conditions and may contribute to the rising incidence of HCC witnessed in many industrialized countries. There is also evidence that NAFLD acts synergistically with other risk factors of HCC such as chronic hepatitis C and alcoholic liver injury. Moreover, HCC may complicate non-cirrhotic NAFLD with mild or absent fibrosis, greatly expanding the population potentially at higher risk. Major systemic and liver-specific molecular mechanisms involved include insulin resistance and hyperinsulinemia, increased TNF signaling pathways, and alterations in cellular lipid metabolism. These provide new targets for prevention, early recognition, and effective treatment of HCC associated with NAFLD. Indeed, both metformin and PPAR gamma agonists have been associated with lower risk and improved prognosis of HCC. This review summarizes current evidence as it pertains to the epidemiology, pathogenesis, and prevention of NAFLD-associated HCC.

A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis

OBJECTIVES:Troglitazone is a thiazolidinedione and peroxisome proliferator–activated receptor gamma (PPARγ) ligand used to treat diabetes mellitus type II. Because hyperinsulinemia may be a factor in nonalcoholic steatohepatitis (NASH), we postulated that troglitazone could have beneficial effects in this disorder. Our study was initiated before reports of idiosyncratic hepatitis induced by this agent and was completed before its recent withdrawal from the market.METHODS:We studied 10 female patients (age 44 ± 16) with histological NASH. All but two were obese (mean body mass index, BMI = 38 ± 6). One had type 2 diabetes, and three had well-compensated cirrhosis with NASH. Troglitazone was given at a dose of 400 mg/day for ≤6 months. Responders (defined as normal ALT at the end of treatment) were rebiopsied. Paired specimens were compared in blinded fashion. Mitochondria were quantitated using ultrathin electron microscopy.RESULTS:Seven of ten patients responded with normal ALT at the end of treatment. One of three nonresponders initially normalized ALT but returned to pretreatment level at 3 months. In this patient, therapy was stopped, and the ALT has remained at the baseline level with no other clinical or laboratory findings. In the responders, ALT fell from 87 ± 38 before to 39 ± 9 at the end of treatment (p = 0.01), and AST decreased from 77 ± 23 to 30 ± 8 (p = 0.002). Biopsy comparisons before and after therapy showed persistent steatohepatitis in all cases, although four of seven showed a one-point improvement in the necroinflammatory grade. Electron microscopy revealed elongation of the mitochondria after therapy.CONCLUSIONS:Normal ALT was seen in 70% of NASH patients at the end of treatment, but this biochemical response was associated with only mild histological improvement, and all follow-up biopsies had evidence of NASH. Normalization of the liver enzymes in patients with NASH who are treated with thiazolidinediones should be viewed with reservation. Follow-up biopsy is essential to evaluate the efficacy of these agents, which, at the histological level, appears to be relatively modest.

Mitochondrial abnormalities in non-alcoholic steatohepatitis

BACKGROUND/AIMS We assessed mitochondrial morphology by electron microscopy and the prevalence of a mitochondrial gene deletion in patients with non-alcoholic steatohepatitis (NASH), alcohol-related liver disease and non-fatty liver diseases. Respiratory chain function using a cytoplasmic hybrid (cybrid) assay was further studied in NASH patients and healthy controls. METHODS Electron microscopy was performed in 26 specimens. Fifteen patients were studied by polymerase chain reaction to detect a 520-bp deletion product of the mitochondrial genome (dmtDNA). Cybrids were created by fusion of platelets with anaerobic neuroblastoma cells in six NASH patients and 12 controls. RESULTS Eight of ten NASH, one of seven alcoholics and two of nine other patients had linear crystalline inclusions in megamitochondria (p<0.05). Three of five patients with alcohol-related liver disease had dmtDNA compared to one of five NASH patients and one of five non-steatohepatitis controls. Cybrid respiratory chain function in platelets was not different from that of controls. CONCLUSIONS Respiratory chain dysfunction, if present in NASH, is not expressed in platelet-derived mitochondria. In contrast to alcohol-related liver disease with active drinking, NASH patients do not commonly express the 5-kb mitochondrial DNA gene deletion in liver tissue. As previously described in early alcohol-related liver disease, crystalline inclusions of unknown composition are seen in hepatic mitochondria in NASH. Their presence suggests either an adaptive process or mitochondrial injury.

Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis.

BACKGROUND/AIMS Non-alcoholic steatohepatitis (NASH) is a growing public health problem. Evaluation of risk factors for fibrosis in NASH will help to target resources to reduce development of cirrhosis. This study had two aims; the first to compile longitudinal histological data to characterize the natural history of fibrosis progression in NASH, and second, to identify predictive factors for progression to advanced fibrosis (stage 3 or greater) in NASH. METHODS Subjects had to have a histological diagnosis compatible with NASH on their initial biopsy, received no intervention of proven histological benefit, and undergone two liver biopsies with at least an interval of one year between them. RESULTS Ten studies were selected comprising 221 patients. 37.6% had progressive fibrosis over a mean follow-up interval of 5.3 years (SD, 4.2 years, median, 3.7 years, range 1.0-21.3 years). Proportional hazards regression analysis demonstrated that age (HR=0.98, p=0.009) and inflammation on initial biopsy (any inflammation, HR=2.5, p=0.001; grade 1, HR=2.5, p=0.001; grade 2, HR=2.4, p=0.003) are independent predictors of progression to advanced fibrosis. Other traditional parameters (e.g. obesity, diabetes, hypertension) were not statistically significant predictors. CONCLUSIONS Presence of inflammation on the initial biopsy and age are independent predictors of progression to advanced fibrosis in patients with NASH.

Coagulation disorders and hemostasis in liver disease: Pathophysiology and critical assessment of current management

Normal coagulation has classically been conceptualized as a Y‐shaped pathway, with distinct “intrinsic” and “extrinsic” components initiated by factor XII or factor VIIa/tissue factor, respectively, and converging in a “common” pathway at the level of the FXa/FVa (prothrombinase) complex. Until recently, the lack of an established alternative concept of hemostasis has meant that most physicians view the “cascade” as a model of physiology. This view has been reinforced by the fact that screening coagulation tests (APTT, prothrombin time – INR) are often used as though they are generally predictive of clinical bleeding. The shortcomings of this older model of normal coagulation are nowhere more apparent than in its clinical application to the complex coagulation disorders of acute and chronic liver disease. In this condition, the clotting cascade is heavily influenced by numerous currents and counter‐currents resulting in a mixture of pro‐ and anticoagulant forces that are themselves further subject to change with altered physiological stress such as super‐imposed infection or renal failure. This report represents a summary of a recent multidisciplinary symposium held in Charlottesville, VA. We present an overview of the coagulation system in liver disease with emphasis on the limitations of the current clinical paradigm and the need for a critical re‐evaluation of the current tenets governing clinical practice. With the realization that there is often limited or conflicting data, we have attempted to represent diverse opinion and experience from the perspectives of both hepatology and hematology beginning with a brief update on the physiology of normal coagulation. (HEPATOLOGY 2006;44:1039–1046.)

Intensive care of patients with acute liver failure: Recommendations of the U.S. Acute Liver Failure Study Group

Objective:To provide a uniform platform from which to study acute liver failure, the U.S. Acute Liver Failure Study Group has sought to standardize the management of patients with acute liver failure within participating centers. Methods:In areas where consensus could not be reached because of divergent practices and a paucity of studies in acute liver failure patients, additional information was gleaned from the intensive care literature and literature on the management of intracranial hypertension in non-acute liver failure patients. Experts in diverse fields were included in the development of a standard study-wide management protocol. Measurements and Main Results:Intracranial pressure monitoring is recommended in patients with advanced hepatic encephalopathy who are awaiting orthotopic liver transplantation. At an intracranial pressure of ≥25 mm Hg, osmotic therapy should be instituted with intravenous mannitol boluses. Patients with acute liver failure should be maintained in a mildly hyperosmotic state to minimize cerebral edema. Accordingly, serum sodium should be maintained at least within high normal limits, but hypertonic saline administered to 145–155 mmol/L may be considered in patients with intracranial hypertension refractory to mannitol. Data are insufficient to recommend further therapy in patients who fail osmotherapy, although the induction of moderate hypothermia appears to be promising as a bridge to orthotopic liver transplantation. Empirical broad-spectrum antibiotics should be administered to any patient with acute liver failure who develops signs of the systemic inflammatory response syndrome, or unexplained progression to higher grades of encephalopathy. Other recommendations encompassing specific hematologic, renal, pulmonary, and endocrine complications of acute liver failure patients are provided, including their management during and after orthotopic liver transplantation. Conclusions:The present consensus details the intensive care management of patients with acute liver failure. Such guidelines may be useful not only for the management of individual patients with acute liver failure, but also to improve the uniformity of practices across academic centers for the purpose of collaborative studies.

Improved outcome of orthotopic liver transplantation for chronic hepatitis B cirrhosis with aggressive passive immunization

Passive immunization with hepatitis B surface antibody (anti-HBs) is important to prevent hepatitis B virus (HBV) recurrence after orthotopic liver transplantation for chronic HBV cirrhosis. Hepatitis B immune globulin (HBIG) dosing regimens have been poorly defined, utilize numerous routes of administration, and result in a high rate of HBV relapse and mortality. Twenty-five of 27 (93%) patients transplanted (four retransplants) for chronic HBV cirrhosis show no evidence of recurrent HBV (range, 2-55 months). Anti-HBs titers necessary to minimize the risk of hepatitis B surface antigen detectability were >500 IU/L for days 0 to 7, >250 IU/L for days 8 to 90, and >100 IU/L thereafter. Pretransplant HBV E antigen (HBeAG)-positive patients required more HBIG to achieve these goals than HBeAG-negative individuals. The elimination of anti-HBs changed continually for the initial 3 posttransplant months. The anti-HBs half-life increased from 0.7 days to 14.1 days. Anti-HBs elimination was significantly different in HBeAG+ and HBeAG- patients for the first week, but was subsequently indistinguishable after week 1. After 3 months, the half-life was statistically less for HBeAG+ patients, but the difference did not influence the clinical treatment regimens. Quantitative hepatitis B DNA levels did not predict the amount of HBIG required. HBV recurrence after orthotopic liver transplantation can be reduced by aggressive passive immunization. Pharmacokinetic analysis of anti-Hbs elimination can improve immunoglobulin therapy and prevent recurrence of clinical hepatitis.

Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds

PURPOSE Familial forms of cryptogenic cirrhosis have been described. We have cared for families in which several members were afflicted with cryptogenic cirrhosis as well as the more recently recognized entity of nonalcoholic steatohepatitis. To examine the familial patterns of these disorders, we reviewed patients with nonalcoholic steatohepatitis, with and without cirrhosis, or cryptogenic cirrhosis to assess how frequently their relatives were afflicted with these disorders. SUBJECTS AND METHODS Eighteen members of eight kindreds containing 2 or more afflicted members were studied. Diagnoses were based on histology in all but 3 patients (2 elderly women with liver atrophy and severe cirrhotic ascites diagnosed clinically with cryptogenic cirrhosis and 1 adult man with abnormal serum aminotransferase levels and hepatomegaly that was diagnosed as fatty liver by ultrasound). Other forms of liver disease were excluded by extensive serologic testing. RESULTS There were 8 index patients (1 man, 7 women; 2 with cryptogenic cirrhosis, 4 with nonalcoholic steatohepatitis with cirrhosis, and 2 with nonalcoholic steatohepatitis without cirrhosis) and 10 relatives (4 men, 6 women; 2 with cryptogenic cirrhosis and 8 with nonalcoholic steatohepatitis). Nonalcoholic steatohepatitis and nonalcoholic steatohepatitis with cirrhosis coexisted within four kindreds, one of which also had an afflicted member with cryptogenic cirrhosis. Nonalcoholic steatohepatitis and cryptogenic cirrhosis coexisted within three additional kindreds. Patterns of afflicted patients included mother-daughter, sister-sister, sister-brother, father-daughter, and male-female cousins. Fifteen (83%) of the 18 subjects were obese, and 11 (61%) had type 2 diabetes mellitus. CONCLUSIONS The coexistence of nonalcoholic steatohepatitis with and without cirrhosis and cryptogenic cirrhosis within these kindreds suggests a common pathogenesis and possible genetic risk. These disorders were frequently but not invariably associated with female sex, obesity, and type 2 diabetes.

Coagulopathy does not fully protect hospitalized cirrhosis patients from peripheral venous thromboembolism

OBJECTIVE:Despite the endogenous coagulopathy of cirrhosis, some patients with cirrhosis experience thrombophilic states. This study aims to determine the incidence and predictors of venous thromboembolism (VTE), such as deep vein thrombosis (DVT) and pulmonary embolism, in hospitalized patients with cirrhosis.METHODS:A retrospective case-control study was performed in a tertiary-care teaching hospital over an 8-yr period. A total of 113 hospitalized patients with cirrhosis with a documented new VTE were compared to controls. Risk factors for VTE were determined using univariate and multivariate statistical analyses.RESULTS:Approximately 0.5% of all hospitalized patients with cirrhosis had a VTE. Traditional markers of coagulation such as INR and platelet count were not predictive of VTE. In the univariate analysis, serum albumin level was significantly lower in cases than controls (2.85 vs. 3.10 g/dL, respectively, p = 0.01). In the multivariate analysis, serum albumin remained independently predictive of VTE, with an odds ratio of 0.25 (95% CI 0.10–0.56).CONCLUSIONS:Approximately 0.5% of admissions involving cirrhosis patients resulted in a new thromboembolic event. Low serum albumin was strongly predictive of increased risk for developing VTE, independent of international normalized ratio or platelet count. Serum albumin deficiency may indicate low levels of endogenous anticoagulants.

Epidemiology and Natural History of Non-Alcoholic Steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition in many parts of the world. This article describes the epidemiology and natural history of this disorder. It also describes current diagnostic and treatment methods and describes future implications NAFLD may have.