Kris V. Kowdley

Association of hepatic iron overload with invasive fungal infection in liver transplant recipients

Invasive fungal infection is a serious complication of orthotopic liver transplantation, but its risk factors remain incompletely defined. Iron overload has already been associated with increased risk of fungal infections, but it has not yet been assessed as a risk factor in liver transplantation. We retrospectively studied a cohort of 153 consecutive patients who underwent their first liver transplantation at a single center and who survived at least 7 days after transplantation. The association between various pretransplant patient characteristics, including hepatic explant iron and risk of invasive fungal infections, was analyzed by univariate and multivariate models. Iron in the hepatic explant was assessed by Perls Prussian blue stain by a pathologist blinded to clinical outcome. During the first year after transplantation, 28 of 153 patients developed a total of 31 invasive fungal infections, of which 21 (68%) were caused by Candida, 7 (23%) by Aspergillus, 2 (6%) by Cryptococcus, and 1 (3%) by Saccharomyces. Stainable iron in the hepatic explant was found in 48 patients (31%). Stainable iron in the hepatic explant was found to be strongly and independently associated with posttransplantation fungal infections in multivariate analysis (hazard ratio 3.09; 95% confidence interval 1.45‐6.56; P = 0.003). Hepatic iron overload is strongly and independently associated with posttransplantation invasive fungal infections. Studies to confirm this finding in other centers and define the mechanism are warranted. Liver Transpl 12:1799‐1804, 2006.

Hepatic reticuloendothelial system cell iron deposition is associated with increased apoptosis in nonalcoholic fatty liver disease

The aim of this study was to examine the relationship between the presence of hepatic iron deposition, apoptosis, histologic features, and serum markers of oxidative stress (OS) and cell death in nonalcoholic fatty liver disease (NAFLD). Clinical, biochemical, metabolic, and independent histopathologic assessment was conducted in 83 unselected patients with biopsy‐proven NAFLD from a single center. Apoptosis and necrosis in serum was quantified using serum cytokeratin 18 (CK18) M30 and M65 enzyme‐linked immunosorbent assays and in liver by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining in situ. Serum malondialdehyde (MDA) and thioredoxin‐1 (Trx1) levels were measured to evaluate OS. Presence of reticuloendothelial system (RES) cell iron in the liver was associated with nonalcoholic steatohepatitis (P < 0.05) and increased hepatic TUNEL staining (P = 0.02), as well as increased serum levels of apoptosis‐specific (M30; P = 0.013) and total (M65; P = 0.006) CK18 fragments, higher MDA (P = 0.002) and lower antioxidant Trx1 levels (P = 0.012), compared to patients without stainable hepatic iron. NAFLD patients with a hepatocellular (HC) iron staining pattern also had increased serum MDA (P = 0.006), but not M30 CK18 levels or TUNEL staining, compared to subjects without stainable hepatic iron. Patients with iron deposition limited to hepatocytes had a lower proportion of apoptosis‐specific M30 fragments relative to total M65 CK18 levels (37% versus ≤25%; P < 0.05). Conclusions: Presence of iron in liver RES cells is associated with NASH, increased apoptosis, and increased OS. HC iron deposition in NAFLD is also associated with OS and may promote hepatocyte necrosis in this disease. (HEPATOLOGY 2013)

Effect of iron depletion on serum markers of fibrogenesis, oxidative stress and serum liver enzymes in chronic hepatitis C: results of a pilot study.

Background: Hepatic iron deposition has been associated with decreased response to interferon‐α monotherapy, and has been speculated to contribute to disease progression in chronic hepatitis C (CHC). We performed this study to evaluate the effect of iron depletion on biochemical and virologic markers, and markers of lipid peroxidation and fibrogenesis.

Primary Placement of Palmaz Long Medium Stents in Transjugular Intrahepatic Portosystemic Shunts

PURPOSEnTo describe our results with primary placement of the long-medium Palmaz stent for transjugular intrahepatic portosystemic shunts (TIPS).nnnMATERIALS AND METHODSnBetween December 1997 and December 1998 primary placement of long-medium Palmaz stents was performed for TIPS procedures in 17 patients. Patency was determined with ultrasound, angiography, or pathologic examination in the event of transplant.nnnRESULTSnPrimary patency was achieved in 13 of 17 patients (76.5%) (follow up, 1-399 days; mean, 99 days). Secondary patency was achieved in 17 of 17 patients (100%) (follow-up, 1-399 days; mean, 110 days). Among the four patients who required revision, the mean time to revision from initial shunt creation was 81 days (range, 13-125 days). Two of these four patients had symptoms of worsening ascites as well as abnormal ultrasound findings prior to their revision; the other two patients were asymptomatic and had abnormal ultrasound findings only. Revisions were performed for intimal hyperplasia within the stent in three of the patients and acute thrombus within the stent in the remaining patient. Kaplan-Meier survival analysis for primary patency yielded mean survival time of 265 days (standard error, 52 days).nnnCONCLUSIONnThe long-medium Palmaz stent is a viable stent for creation of TIPS shunts.

Retrospective comparison of the patency of Wallstents and Palmaz long-medium stents used for TIPS

AbstractPurpose: To compare patency rates of transjugular intrahepatic portosystemic shunts (TIPS) after placement of long-medium Palmaz stents or Wallstents.n Methods: We performed a retrospective review of TIPS performed at our institution between December 1997 and December 1998. During this time period we placed long-medium Palmaz stents for TIPS procedures in 17 patients and Wallstents in 20 patients as the initial stent. Patency was determined on follow-up by ultrasound, angiography, or pathologic examination in the event of transplant.n Results: Primary patency in the Palmaz stent group was 70.6% (12/17 patients) (follow-up 1–399 days, mean 127 days). Both primary assisted and secondary patency in the Palmaz group was 100% (17/17 patients) (follow up 1–399 days, mean 154 days). Primary patency in the Wallstent group was 50% (10/20 patients) (follow up 1–370 days, mean 65 days). Primary assisted patency in the Wallstent group was 80% (16/20 patients) (follow up 1–601 days, mean 141 days). Secondary patency in the Wallstent group was 100% (20/20 patients) (follow up 2–601 days, mean 142 days). Kaplan-Meier analysis of the two groups of patients yielded a primary patency of 266 days (standard error 45 days) for TIPS with the Palmaz stent and 139 days (standard error 45 days) for the Wallstent (p = .04). The 3, 6, and 12-month primary patency rates were .84, .63, and .42 respectively for the Palmaz stents and .36, .36, and .18 respectively for the Wallstent. There was no significant difference in primary assisted or secondary patency between the two stent groups. The mean tract curvature in the patients with Palmaz stents was 23.5° (SD 18.2°, range 0–69.0°) compared with 57° (SD 34.5°, range 7.0–144.0°) in patients with Wallstents (p = .01).Conclusions: Our nonprospective, nonrandomized study suggests that TIPS created with the long-medium Palmaz stent have a higher primary patency than those created with the Wallstent in tracts that are relatively straight.

Current and future therapy in haemochromatosis and Wilson's disease.

There have been several new developments in the treatment of iron and copper overload disorders, such as haemochromatosis, thalassaemia and Wilson’s disease. Clinical trials of orally administered iron chelators, both as monotherapy and in combination with deferoxamine, are in progress around the world. Several new chelators are now being introduced in clinical trials. Future therapies for iron overload may comprise of oral iron binding agents capable of preventing dietary iron absorption from the diet. The characterisation of specific iron transporters such as the divalent metallic transporter and ferroportin may hold promise for the development of ‘smart’ compounds capable of blocking iron transport. Several new agents are now available for the management of Wilson’s disease, including trientine, zinc and tetrathiomolybdate. This review, will discuss the pathogenesis, and current and future therapies for iron and copper overload disorders.