Hepatitis C, cryoglobulinemia, and cutaneous vasculitis associated with unusual and serious manifestations

Hepatitis C viral infection is currently the leading cause of chronic hepatitis and cirrhosis. It also is a major predisposing factor for the development of hepatocellular carcinoma. It is estimated that approximately 1-2% of patients with hepatitis C infection have nonhepatic manifestations that are protean in nature. In this report, we describe six unusual cases of nonhepatic manifestations: abdominal vasculitis in two, peripheral neuropathy in two, and one patient each with central nervous system vasculitis and necrotizing cutaneous vasculitis. All patients had cutaneous vasculitis and cryoglobulinemia. None of our patients had cirrhosis, yet three of the six patients died. Because of the severe manifestations, aggressive therapy was instituted with interferon, immunosuppressive medications, i.v. immunoglobulin, and plasmapheresis. Our report underscores the importance of recognizing nonhepatic manifestations in patients with hepatitis C infection that may be associated with high morbidity and mortality.     

Epoetin alfa maintains ribavirin dose in HCV-infected patients: a prospective, double-blind, randomized controlled study

BACKGROUND & AIMS: Combination therapy with interferon alpha (IFN-alpha) and ribavirin (RBV) or pegylated IFN-alpha (PEG-IFN-alpha)/RBV for chronic hepatitis C virus (HCV) infection often causes anemia, prompting RBV dose reduction/discontinuation. This study assessed whether epoetin alfa could maintain RBV dose, improve quality of life (QOL), and increase hemoglobin (Hb) in anemic HCV-infected patients. METHODS: HCV-infected patients (n = 185) on combination therapy who developed anemia (Hb < or = 12 g/dL) were randomized into a U. S. multicenter, placebo-controlled, clinical trial of epoetin alfa, 40,000 U subcutaneously, once weekly vs. matching placebo. The study design used an 8-week, double-blind phase (DBP) followed by an 8-week, open-label phase (OLP), in which placebo patients were crossed over to epoetin alfa. RESULTS: At the end of the DBP, RBV doses were maintained in 88% of patients receiving epoetin alfa vs. 60% of patients receiving placebo (P < 0.001). Mean QOL scores at the end of the DBP improved significantly on all domains of the Linear Analog Scale Assessment (LASA) and on 7 of the 8 domains of the Short Form-36, version 2 (SF-36v2). Mean Hb increased by 2.2 +/- 1.3 g/dL (epoetin alfa) and by 0.1 +/- 1.0 g/dL (placebo) in the DBP (P < 0.001). Similar results were demonstrated in patients who switched from placebo to epoetin alfa in the OLP. Epoetin alfa was well tolerated; the most common adverse effects were headache and nausea. CONCLUSIONS: Epoetin alfa maintained RBV dose and improved QOL and Hb in anemic HCV-infected patients receiving combination therapy.     

Further characterization of platelet-type von Willebrand's disease in Japan

We studied four patients who showed aggregation of platelets in platelet-rich plasma at lower concentrations of ristocetin than those required for normal platelet-rich plasma and who demonstrated an increased capacity of the platelets to bind normal von Willebrand factor. The four patients were from two Japanese families. Platelets from one family aggregated spontaneously in vitro, and platelets from both families aggregated upon the addition of normal plasma and cryoprecipitate, in the absence of ristocetin or other agonists. Analysis of the multimeric composition of von Willebrand factor by sodium dodecyl sulfate-agarose gel electrophoresis revealed a decrease in large multimers or a decrease in both large and intermediate multimers in plasma, but normal multimers in platelets. 1-Deamino-[8-D- arginine]-vasopressin caused by an immediate appearance of larger multimers in plasma, followed by the rapid disappearance of these multimers from circulating plasma. Analysis of platelet membrane glycoproteins from the patients showed that there were two distinct bands in the glycoprotein I region; one migrated in a slower region and the other in a faster region than normal glycoprotein Ib. We suggest that the platelet receptor abnormality in these patients is related to this abnormality of glycoprotein Ib.     

Real-time analysis of shear-dependent thrombus formation and its blockade by inhibitors of von Willebrand factor binding to platelets

Two likely mechanisms for the initiation of arterial platelet thrombus formation under conditions of elevated fluid shear stresses are: (1) excessive adhesion and aggregation of platelets from rapidly flowing blood onto the exposed sub-endothelium of injured, atherosclerotic arteries; or (2) direct, fluid shear stress-induced aggregation of platelets in constricted arteries with intact endothelial cells. Mechanism (1) was simulated using a parallel plate flow chamber, fibrillar collagen type I-coated slides, and mepacrine-labeled (fluorescent) platelets in whole blood anticoagulated with citrate, hirudin, unfractionated porcine heparin, or low molecular weight heparin flowing for 1 to 2 minutes at wall shear rates of 100 to 3,000 seconds-1 (4 to 120 dynes/cm2). The precise sequence of interactions among von Willebrand factor (vWF), glycoprotein (GP)Ib, and GPIIb-IIIa during platelet adhesion and subsequent aggregation were resolved by direct real-time observation using a computerized epifluorescence video microscopy system. Adhesion at high shear rates was the result of the adsorption of large vWF multimers onto collagen and the binding of platelet GPIb to the insolubilized vWF. Aggregation occurred subsequently and required the binding of ligands, including vWF via its RGD binding domain, to GPIIb-IIIa. Mechanism (2) was modeled by producing shear stresses of 90 to 180 dynes/cm2 in a rotational cone and plate viscometer, which aggregates platelets from platelet-rich- plasma (PRP) anti-coagulated with citrate, hirudin, or either type of heparin in reactions that require large vWF multimers, Ca2+, adenosine diphosphate, and both GPIb and GPIIb-IIIa. Both vWF-mediated shear- aggregation in PRP and platelet-collagen adhesion in flowing whole blood (anticoagulated with citrate and hirudin) are inhibited by two potentially useful anti-arterial thrombotic agents: polymeric aurin tricarboxylic acid (ATA; 28.5 to 114 micrograms/mL), which binds to vWF and inhibits its attachment of GPIb, and a recombinant vWF fragment (rvWF445-733; 30 to 200 micrograms/mL) that binds to platelet GPIb (in the absence of any modulator) and blocks attachment of vWF multimers. Unfractionated heparin, but not low molecular weight heparin, apparently binds to rvWF445-733 and counteracts the inhibitory effects of the vWF fragment in vitro on shear-aggregation and platelet-collagen adhesion.     

Nonalcoholic steatohepatitis

Opinion statement Nonalcoholic steatohepatitis (NASH) is an important medical condition and there is great public health concern related to its increasing incidence and potential implications for the development of end-stage liver disease. NASH represents a progression beyond simple lipid deposition in the liver parenchyma, requiring histologic evidence for hepatocyte injury such as ballooning degeneration, Mallory bodies, and/or pericellular fibrosis that can potentially lead to progressive liver injury and eventually cirrhosis. It is believed that several insults contribute to the evolution of hepatic injury such as insulin dysregulation, lipid deposition, oxidative free radicals, and lipid perioxidation. Initial treatment protocols for NASH focus on various aspects of injury in an attempt to control insulin imbalances, improve lipid regulation, reduce free radicals, and ameliorate the inflammatory process. No therapy is conclusively beneficial in all individuals, but preliminary data suggest several approaches that hold promise.     

Anthropometric and Clinical Factors Associated with Mortality in Subjects with Nonalcoholic Fatty Liver Disease

Aim

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and may be associated with increased mortality. Our aim was to determine whether anthropometric measures are independently associated with mortality in NAFLD.

Methods

The third National Health and Nutrition Examination Surveys (1988–1994) data was used. Extensive radiologic, serologic and clinical data were available. NAFLD was defined as moderate-to-severe hepatic steatosis on the hepatic ultrasound in the absence of any cause of chronic liver disease (e.g. hepatitis C virus RNA negative, hepatitis B-surface antigen negative, normal transferrin saturation and alcohol consumption <20 gram/day). Anthropometric measures [body mass index (kg/m²), waist, hip, arm, and thigh circumferences (cm), waist-to-hip ratio, percentage of body fat, and sum of skinfolds (mm)], laboratory measures and clinico-demographic data were analyzed. Statistical analyses were conducted with SUDAAN 10.0.

Results

A total of 10,565 adult participants were included [2,510 (weighted 21 %) with NAFLD and 8,055 non-NAFLD controls]. In multivariate analysis, NAFLD was independently associated with being Mexican-American (including Hispanic or other ethnicity), larger waist circumference (cm), type-2 diabetes, insulin resistance and hypertension. After about 14 years (median) of follow up, liver-specific mortality was independently associated with NAFLD and being White.

Conclusions

Components of metabolic syndrome, and Mexican-American ethnicity are independently associated with NAFLD. Furthermore, NAFLD is an independent predictors of liver-specific mortality in men and Whites.     

Abdominal ultrasound for diagnosis of nonalcoholic fatty liver disease (NAFLD)

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease. The progressive subtype of NAFLD or nonalcoholic steatohepatitits (NASH), may progress to cirrhosis and its complications. Unfortunately, accurate noninvasive modalities for diagnosing NASH and monitoring its progression are unavailable, necessitating a liver biopsy. Abdominal ultrasound (US) is widely used for screening asymptomatic patients with an incidental elevation of liver enzymes. However, US cannot detect small amounts of hepatic steatosis and cannot establish the diagnosis of NASH or stage of hepatic fibrosis. In this issue of AJG, a new radiologic scoring system has been reported to have excellent performance in diagnosing NAFLD and visceral obesity. However, the utility of this scoring system in establishing the diagnosis of NASH and hepatic fibrosis, has not been shown. Additionally, validity of this scoring system to other populations (i.e. obese) and in the setting of private practice must be proven. In summary, this study provides some valuable data regarding the utility of radiologic modalities in detecting hepatic steatosis and abdominal fat but still falls short in answering some important diagnostic and prognostic questions in NAFLD. The evolving field of diagnostic imaging for NAFLD holds promise. A combination of serum biomarkers and radiologic modalities may one day provide the best diagnostic approach for patients with NAFLD, and potentially replace the necessity for liver biopsy in most patients.