Donald J. Hillebrand

Nephrogenic fibrosing dermopathy after liver transplantation successfully treated with plasmapheresis

Nephrogenic fibrosing dermopathy (NFD) is a recently described cutaneous fibrosing disorder associated with renal dysfunction. It appears similar to scleromyxedema but with some notable exceptions, including the lack of involvement of the face and absence of plasma cells on histology, systemic involvement, and paraproteinemia. Patients can present with thickened or edematous skin with indurated papules and plaques involving the extremities and the trunk. We report the first three cases of NFD after liver transplantation successfully treated with plasmapheresis. Two patients underwent liver transplantation for hepatitis C virus–induced cirrhosis and one for hepatitis B virus–induced cirrhosis. All the patients had encephalopathy, refractory ascites, and malnutrition prior to transplantation. Like those patients with NFD, all three of our patients had renal dysfunction and required hemodialysis before and after transplantation. Two were not dependent on dialysis at the time of diagnosis, however. These patients had excellent liver allograft function, but the other patient had allograft failure secondary to recurrent hepatitis C. Immunosuppression therapy consisted of basiliximab, mycophenolate mofetil, calcineurin inhibitor, and prednisone. The patients developed “woody” skin induration of the distal extremities, erythematous papules, and contractures at 1, 2, and 120 months after transplantation. Skin biopsies resembled NFD. No paraproteinemia was evident. One to three 5-day courses of plasmapheresis resulted in moderate to marked clinical improvement. The improvement of the kidney function in two of our patients did not appear to correlate with that of the skin disorder, because the kidney function was improving at the time the diagnosis of NFD was made. In conclusion, we report the first three cases of NFD after liver transplantation. Plasmapheresis was moderately successful in resolving the skin-indurated papules, severe skin induration, and associated joint contractures. Preliminary studies (unpublished data) show that decreasing plasma levels of transforming growth factor-&bgr;1 after plasmapheresis appear to correlate with the amelioration of this clinical condition.

Overweight and obesity, hepatic steatosis, and progression of chronic hepatitis C: a retrospective study on a large cohort of patients in the United States

BACKGROUND Hepatic steatosis has been associated with chronic hepatitis C (CHC), but its prevalence, risk factors, and clinical significance remain to be determined. AIMS The present study determined the frequency of, and risk factors for hepatic steatosis and its association with activity and progression of CHC in a large cohort of U.S. patients. METHODS This is a retrospective study that utilized systematic chart review and statistical analyzes to investigate 324 U.S. patients with CHC from a university medical center and a regional VA medical center. RESULTS The frequency of hepatic steatosis was 66.0%. We demonstrated that not only being obese, but also overweight (i.e. body mass index > or =25 kg/m(2)) was independently associated with hepatic steatosis. In our cohort of patients with CHC, hepatic steatosis, especially grade II/III steatosis, was significantly associated with elevated aspartate aminotransferase at entry, persistently elevated alanine aminotransferase, and stage III/IV fibrosis. Grade II/III steatosis, was significantly associated with a higher histology activity index as well. Multivariate analysis indicated that steatosis, especially grade II/III steatosis, was independently associated with stage III/IV fibrosis. CONCLUSIONS Being overweight/obese serves as an independent risk factor for hepatic steatosis in U.S. patients with CHC. Steatosis accelerates activity and progression of CHC, and is independently associated with stage III/IV hepatic fibrosis in these patients.

Clinical Significance of Elevated Alpha-Fetoprotein (AFP) in Patients with Chronic Hepatitis C, but not Hepatocellular Carcinoma

BACKGROUND:Although elevated serum alpha-fetoprotein (AFP) is often seen in patients with chronic hepatitis C (CHC), its prevalence, risk factors, and clinical significance remain to be determined.AIMS:The present study assessed the frequency of, the risk factors for, and the clinical significance of elevated AFP in patients with CHC, but not hepatocellular carcinoma.METHODS:This retrospective study utilized systematic chart review and statistical analyses to investigate 357 U.S. patients with CHC from a university medical center and a regional veteran administration medical center.RESULTS:The prevalence of elevated serum AFP (i.e., ≥10.0 μg/L) was 23.0%, including 15.3% (28/183), 24.5% (25/102), and 42.0% (29/69) in patients with chronic hepatitis C and stage 0–II, III, and IV hepatic fibrosis, respectively. After adjusting for age, HCV load, and hepatic steatosis, stage III/IV fibrosis, elevated aspartate aminotransferase (AST), and prolonged prothrombin time as measured by international normalized ratio (INR) remained independently associated with elevated serum AFP in these patients. A serum AFP level of 15.0 μg/L was 22.8% sensitive and 94.5% specific for stage III/IV fibrosis.CONCLUSIONS:In patients with chronic hepatitis C, 23.0% had elevated serum AFP that is independently associated with stage III/IV hepatic fibrosis, elevated level of AST, and prolonged INR.

Tumor necrosis factor-α, interleukin-6, and nitric oxide in sterile ascitic fluid and serum from patients with cirrhosis who subsequently develop ascitic fluid infection

Ascitic fluid infection probably results from repeated episodes of bacteremia and seeding of ascitic fluid. The outcome of these episodes of colonization is probably a function of serum and ascitic fluid defense mechanisms and the virulence of the organism. Patients who develop spontaneous bacterial peritonitis may have serum and ascitic fluid characteristics that are different from those who do not develop infection. We prospectively collected serum and ascitic fluid specimens at the time of admission from patients with sterile cirrhotic ascites, and tested these specimens for interleukin-6, tumor necrosis factor-α, and nitric oxide and compared these results as well as other characteristics of patients who did not develop infection to those who did. An elevated baseline serum tumor necrosis factor-α as well as an increased proportion of polymorphonuclear leukocytes in sterile ascitic fluid from patients who subsequently developed infection probably represent a subclinical activation of defense mechanisms from prior silent colonizations with bacteria.

Factors associated with hepatic fibrosis in patients with chronic hepatitis C: a retrospective study of a large cohort of U.S. Patients.

Goals To determine the risk factors for stage 3 and 4 fibrosis in a large cohort of U.S. patients with chronic hepatitis C (CHC). Background Multiple host and viral factors affect the outcomes of CHC. Further defining the pathogenic roles of these factors in CHC progression will lead to improving management of this disease. Study Retrospective study of a large cohort of US patients with CHC. Results Of the 460 patients, 331 were males and 129 were females with mean age of 48.4±8.0 years, and 191 (41.7%) had stage 3 and 4 fibrosis. Clinically, a multivariate analysis revealed that age of ≥60 years at presentation, the estimated duration of hepatitis C virus (HCV) infection ≥25 years, a body mass index ≥30 kg/m2, and a history of diabetes mellitus were independently associated with stage 3 and 4 fibrosis, after adjusting for history of alcohol use. Laboratorially, a multivariate analysis revealed that aspartate aminotransferase (AST) ≥2×upper limit of normal (ULN), alpha fetoprotein ≥15 μg/L, and presence of grade 2 and 3 steatosis were independently associated with stage 3 and 4 fibrosis, after adjusting for alanine aminotransferase ≥2×upper limit of normal, AST/alanine aminotransferase ratio ≥1, HCV genotyping, transferrin saturation, and a histology activity index score ≥7. Conclusions The present study indicated that elderly, longer duration of HCV infection, obesity, and history of diabetes mellitus are independent clinical parameters associated with advanced fibrosis, whereas elevated AST, alpha fetoprotein, and presence of grade 2 and 3 steatosis are independent laboratorial parameters associated with stage 3 and 4 fibrosis in patients with CHC.

Nitric oxide in ascitic fluid is an independent predictor of the development of renal impairment in patients with cirrhosis and spontaneous bacterial peritonitis

Background/aims Cirrhotic patients with spontaneous bacterial peritonitis show a marked activation of the cytokine cascade, and cytokines induce the synthesis of nitric oxide in vitro. Our aim was to assess whether patients with ascitic fluid infection show increased levels of nitric oxide, and whether this is related to the development of renal impairment. Methods Retrospective analysis of prospectively collected specimens from 168 patients with cirrhosis and presence of sterile or infected ascitic fluid. Routine biochemical data together with nitric oxide metabolites, tumour necrosis factor and interleukin-6 were measured. Univariate and multivariate analyses were performed to identify factors related to the development of renal impairment. Results Patients with infected ascites showed increased serum and ascitic-fluid levels of nitric oxide metabolites and cytokines compared with patients with sterile ascites. A significant direct correlation was observed between serum and ascitic fluid nitric oxide metabolite levels. Multivariate analysis identified ascitic-fluid nitric oxide metabolites as an independent predictor of renal impairment. Conclusions The increased serum and ascitic fluid nitric oxide found in patients with infected ascites might induce a deterioration of the increased peripheral vasodilation found in this setting, leading to the development of renal impairment in a series of patients with spontaneous bacterial peritonitis.

Clinical presentation of chronic hepatitis C in patients with end-stage renal disease and on hemodialysis versus those with normal renal function

BACKGROUND:The natural history of chronic hepatitis C (CHC) remains to be defined in patients with end-stage renal disease (ESRD).AIMS:To determine the clinical presentation of CHC and the factors associated with stage III-IV fibrosis in patients with CHC and ESRD.METHODS:The study included patients with CHC and ESRD (n = 91) or normal renal function (NRF, n = 159). Both groups were matched for mean age, gender, history of alcohol use, and estimated duration of hepatitis C virus (HCV) infection.RESULTS:Presentation of CHC and ESRD was independently associated with non-Caucasian ethnicity (OR = 3.24, p= 0.0003), a history of diabetes mellitus (DM, OR = 7.911, p < 0.0001), and lower frequencies of being obese (OR = 0.457, p= 0.035), of having hepatic steatosis (OR = 0.372, p= 0.003), and stage III-IV fibrosis (OR = 0.403, p= 0.016). After adjusting for serum levels of alpha-fetoprotein (AFP) and HCV RNA, CHC, and ESRD were independently associated with lower frequencies of elevated alanine aminotransferase (ALT, OR = 0.175, p= 0.02) and aspartate aminotransferase (AST, OR = 0.169, p= 0.04), but higher frequencies of AST/ALT ratio >1 (OR = 7.173, p= 0.002) and hypoalbuminemia (OR = 9.567, p= 0.0007). Compared to patients with NRF and stage III-IV fibrosis, those with ESRD and stage III-IV fibrosis had a significantly higher frequency of a history of DM (OR = 8.014, p= 0.0031) and lower frequency of elevated AST (OR = 0.054, p= 0.004), which were independent of the frequencies of lower levels of ALT and albumin, and AST/ALT ratio >1. In patients with CHC and ESRD, the presence of stage III-IV fibrosis was significantly associated with hepatic steatosis (OR = 4.523, p= 0.012) and thrombocytopenia (OR = 4.884, p= 0.044), which were independent of the frequencies of a history of DM, splenomegaly, and a higher level of AST.CONCLUSIONS:CHC and ESRD are independently associated with a higher frequency of a history of DM, but lower frequencies of being obese, and having hepatic steatosis, stage III-IV fibrosis, and elevated transaminases. In patients with CHC and ESRD, stage III-IV fibrosis is not associated with a history of DM, but is independently associated with hepatic steatosis and thrombocytopenia.

CASE REPORT: Fatal Spontaneous Gallbladder Variceal Bleeding in a Patient with Alcoholic Cirrhosis

Gallbladder varices are unusual ectopic varices that may develop in patients with portal hypertension, particularly in those with portal vein occlusion. In rare instances, these varices may cause hemobilia, life-threatening bleeding, or even rupture of the gallbladder. We report the first case of a 41-year-old man with alcoholic cirrhosis and patent portal vein who developed massive hemoperitoneum from spontaneous rupture of varices in the gallbladder fossa. The diagnosis of gallbladder varices eluded conventional imaging and was made only at autopsy. Gallbladder variceal hemorrhage is a rare, but potentially catastrophic complication of cirrhosis.

Charcoal-based hemodiabsorption liver support for episodic type C hepatic encephalopathy.

OBJECTIVES:Episodic (acute) type C hepatic encephalopathy (AHE) fails to respond to 5 days of medical therapy in 10–30% of patients and carries a 10–30% mortality rate. We prospectively studied extracorporeal liver support for AHE failing to respond to medical therapy to assess its safety and efficacy and the role of anticoagulation.METHODS:A series of patients with cirrhosis and AHE failing to respond to at least 24 h of medical therapy underwent a maximum of three 6-h charcoal-based hemodiabsorption (Liver Dialysis Unit) treatments. A standard anticoagulation protocol, with heparin dosing based on activated clotting time (ACT) determinations, heparin dose–response curve, and target ACT of 275–300 s, was developed. Therapy was terminated if patients met a predetermined clinical response, deteriorated, or underwent transplantation.RESULTS:Eighteen patients with grade 2–4 AHE despite 5.9 ± 3.9 days of medical therapy underwent a mean of 1.6 treatments. In 2.6 ± 1.9 days, 16 patients (88.9%) improved to less than grade 2 HE or achieved at least a 50% hepatic encephalopathy index (HEI) reduction. Median mental status (grade 2 vs 1, p < 0.05) and HEI (0.634 ± 0.194 vs 0.363 ± 0.263, p < 0.005) improved significantly. Survival was 94.4% and 72.2% at 5 and 30 days, respectively. Use of our developed anticoagulation protocol resulted in less platelet (14.2% ± 2.8% vs 32.5% ± 5.8%, p < 0.005) and fibrinogen consumption (12.1% ± 3.5% vs 43.3% ± 8.6%, p < 0.0005) and blood product use (6.2 ± 1.8 vs 19.0 ± 5.6 units, p < 0.05) compared with treatments according to manufacturers guidelines.CONCLUSIONS:Charcoal-based hemodiabsorption treatments in which a standardized anticoagulation protocol is used is safe and effective treatment for AHE not responding to standard medical therapy.

Spontaneous bacterial peritonitis: keys to management.

Infection of ascitic fluid in patients with cirrhosis can be rapidly fatal. Survival after the initial episode has improved dramatically in recent years, largely because of earlier diagnosis, betteflodefined diagnostic criteria, and the widespread use of paracentesis and empiric antibiotic therapy. Antibiotic use may prevent recurrences. Despite these advances, the long-term outlook is grim for most patients.