Background & Aims: The outcome of portal vein thrombosis in relation to associated prothrombotic states has not been evaluated. We assessed current outcome and predictors of bleeding and thrombotic ...events in a cohort of 136 adults with nonmalignant, noncirrhotic portal vein thrombosis, of whom 84 received anticoagulant therapy. Methods: Multivariate Cox model analysis for event-free survival and analysis taking into account multiple events were used. Results: Median follow-up was 46 months. The incidence rate of gastrointestinal bleeding was 12.5 (95% confidence interval CI, 10–15) per 100 patient-years. Large varices were an independent predictor for bleeding. Anticoagulant therapy did not increase the risk or the severity of bleeding. The incidence rate of thrombotic events was 5.5 (95% CI, 3.8–7.2) per 100 patient-years. Underlying prothrombotic state and absence of anticoagulant therapy were independent predictors for thrombosis. In patients with underlying prothrombotic state, the incidence rates of splanchnic venous infarction were 0.82 and 5.2 per 100 patient-years in periods with and without anticoagulant therapy, respectively (P = 0.01). Two nonanticoagulated patients died of bleeding and thrombosis, respectively. Conclusions: In patients with portal vein thrombosis, the risk of thrombosis is currently as clinically significant as the risk of bleeding. The benefit-risk ratio favors anticoagulant therapy.
GASTROENTEROLOGY 2001;120:490-497
According to a recent hypothesis, venous thrombosis results from the concurrence of several factors. This hypothesis was assessed in patients with portal or hepatic venous thrombosis by ...simultaneously investigating most of the currently identified prothrombotic disorders, local precipitating factors, and other risk factors such as oral contraceptive use. Patients with a tumorous obstruction and patients with cirrhosis with portal vein thrombosis were excluded. The prothrombotic disorders that were investigated included classical and occult myeloproliferative disorders; antiphospholipid syndrome; protein C; protein S and antithrombin deficiency; factor V Leiden; factor II; and methylene‐tetrahydrofolate‐reductase gene mutations. We found 1 or several prothrombotic disorders and a local precipitating factor in 26 and 10 of the 36 patients with portal vein thrombosis, respectively; and in 28 and none of the 32 patients with hepatic vein thrombosis, respectively. We found a combination of prothrombotic disorders in 5 and 9 patients with portal and hepatic vein thrombosis, respectively, whereas such a combination is expected in less than 1% of asymptomatic subjects. Of the 10 patients with a local precipitating factor, 8 had a prothrombotic disorder. Of the 13 patients who use oral contraceptives, 10 had a prothrombotic disorder. We conclude that portal or hepatic venous thrombosis should be regarded as an index for 1 or several prothrombotic disorders, whether or not local precipitating factors or oral contraceptive use are found. Concurrence of prothrombotic disorders is more common than expected. Extensive investigation of prothrombotic disorders and anticoagulation should be considered in patients with portal or hepatic venous thrombosis.
Inherited disorders of bilirubin metabolism might reduce bilirubin uptake by hepatocytes, bilirubin conjugation, or secretion of bilirubin into bile. Reductions in uptake could increase levels of ...unconjugated or conjugated bilirubin (Rotor syndrome). Defects in bilirubin conjugation could increase levels of unconjugated bilirubin; the effects can be benign and frequent (Gilbert syndrome) or rare but severe, increasing the risk of bilirubin encephalopathy (Crigler–Najjar syndrome). Impairment of bilirubin secretion leads to accumulation of conjugated bilirubin (Dubin–Johnson syndrome). We review the genetic causes and pathophysiology of disorders of bilirubin transport and conjugation as well as clinical and therapeutic aspects. We also discuss the possible mechanisms by which hyperbilirubinemia protects against cardiovascular disease and the metabolic syndrome and the effects of specific genetic variants on drug metabolism and cancer development.
The elegant paper by Fickert et al. on bile duct ligated mice provides convincing evidence for the hypothesis that bile acids retained in the serum during cholestasis and excreted through the kidneys ...are toxic to collecting duct cells. The authors propose that bile acids initiate a chain of reactions leading to tubulointerstitial nephritis and fibrosis. Mice with cholestasis were protected by prefeeding with the hydrophilic bile acid norursodeoxycholic acid, an observation which suggests a potential therapeutic option for cholemic nephropathy.
The authors show, in an elegant population-based study, a significant association between intrahepatic cholestasis of pregnancy and liver and biliary cancer. This association is most probably related ...to the high frequency of hepatitis C and gallstone disease in women with intrahepatic cholestasis of pregnancy, both being risk factors for liver and biliary cancer. In addition, the study clearly shows an increased risk of diabetes mellitus and autoimmune diseases, such as thyroid diseases, psoriasis, autoimmune arthropathies and Crohn's disease, and a small increase in cardiovascular diseases. In practice, a follow-up of liver function tests 6-12 weeks after delivery is strongly recommended to detect a possible associated liver disease.
The authors report the case of a child with extreme elevation of serum bile acid concentration, without pruritus, symptomatic cholestasis, liver disease, or abnormalities of liver function tests. ...Sequencing of the SLC10A1 gene, encoding NTCP (the sinusoidal uptake transporter of conjugated bile acids) revealed a single homozygous point mutation in the coding sequence of the gene resulting in an arginine to histidine substitution at position 252. This mutation resulted in a markedly reduced uptake activity of taurocholic acid. This is the first report of a new inborn error of bile acid transport, due to a mutation of NTCP.
Low phospholipid-associated cholestasis and cholelithiasis (LPAC) is a genetic disorder characterized by cholesterol gallbladder and intrahepatic stones. It is caused by a mutation of the gene ABCB4, ...which encodes the canalicular protein ABCB4/MDR3, a flippase that plays an essential role in the secretion of phosphatidylcholine into bile. Failure of this protein leads to secretion of bile that is poor in phospholipids and, hence, highly lithogenic, with potent detergent properties. This, in turn, leads to cholangiocyte luminal membrane injury and biliary lesions causing cholestasis. The diagnosis should be suspected when at least two of the following criteria are present: onset of symptoms before the age of 40 years; recurrence of biliary symptoms (biliary colic, jaundice, cholangitis, acute pancreatitis) after cholecystectomy; presence of echogenic foci within the liver indicative of intrahepatic stones or biliary sludge; previous episode(s) of intrahepatic cholestasis of pregnancy; and family history of gallstones in first-degree relatives. Intrahepatic stones can be demonstrated by ultrasonography with color Doppler examination, computed tomography and magnetic resonance imaging with magnetic resonance cholangiography, and the diagnosis confirmed by ABCB4 genotyping. Therapy with ursodeoxycholic acid offers prompt relief of symptoms and usually prevents complications. In some cases, however, surgery may be necessary.
The aim of this study was to assess the influence of human immunodeficiency virus (HIV) infection on chronic hepatitis B. In a series of 132 (65 anti‐HIV positive) homosexual non–drug addicted men ...with chronic hepatitis B, the liver function was assessed with biochemical tests; the degree of hepatitis B virus (HBV) replication was assessed with serum HBV DNA level and with immunoperoxidase staining of hepatitis B core (HBc) antigen on liver specimens; and the severity of liver lesions was assessed with an histology activity index. Anti‐HIV–positive and anti‐HIV–negative patients were not different for serum aspartate transaminase activity, bilirubin, prothrombin, and histology activity index. Anti‐HIV–positive patients had lower serum alanine transaminase activity levels (P = .0001), lower serum albumin levels (P = .0009), and higher serum HBV DNA levels (P = .01). There was a higher prevalence of cirrhosis in anti‐HIV–positive patients (P = .04). In homosexual men with chronic hepatitis B, HIV infection is associated with a higher level of HBV replication and a higher risk for cirrhosis without increased liver necrotico‐inflammatory process.
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