Hepatology highlights

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How Does FIC1 Dysfunction Account for PFIC1?

Progresive Familial Intrahepatic Cholestasis 1 (PFIC1) is associated with disabling mutations of FIC1, a transporter which switches phospholipids between inner and outer leaflets of the cell membrane's lipid bilayer. Demeilliers et al. studied explanted liver from two children who underwent liver transplantation for PFIC1 as well as one example each of biliary atresia and PFIC2 which is caused by genetic abnormalities of the bile salt export pump (BSEP). Compared with levels in hepatocytes, expression of ATP8B1, the gene coding for FIC1 protein, was markedly increased in bile duct-lining cholangiocytes (20-fold higher) and gallbladder epithelium (200-fold). This broadly correlates with the proportion of each cell's surface area that is exposed to bile as well as with the detergency of bile and lends strong support to the notion that the primary function of FIC1 is replenishment of leached phospholipids within the luminal leaflet of all surfaces exposed to bile. Study of the regulation of expression of bile salt transporters showed that, as anticipated in intrahepatic cholestasis, hepatic expression of the farnesoid X receptor (FXR), small heterodimer partner (SHP) and CYP7A1 were downregulated by circa.90% in all four livers. However, repression of the bile salt transporters NTCP and BSEP was significantly less in PFIC1 than in the other conditions (See Fig.). This suggests that bile acid transport is relatively better preserved in PFIC1, and this was confirmed by the finding of higher biliary bile acid concentration (3mmol/L) in bile from a PFIC1 patient. The notion that in PFIC1, an intact entero-hepatic circulation of bile acids is sustained within the limits set by residual FIC1 activity and in association with enhanced ileal expression of the apical sodium dependent bile salt transporter (ASBT) accords well with the recent report in HEPATOLOGY by Stapelbroek et al. (HEPATOLOGY 2006;43:525) that temporary interruption of the entero-hepatic circulation by naso-biliary drainage resolved the cholestasis of PFIC1 in more mildly affected individuals. The cystic fibrosis transmembrane conductance regulator (CFTR), was found exclusively in cholangiocytes, (not hepatocytes) and its expression markedly was reduced only in PFIC1 livers. In a biliary epithelial cell line, invalidating expression of ATP8B1by small interfering RNA was associated with downregulation of CFTR. Such downregulation of CFTR, occurring as a direct consequence of the primary PFIC1 defect, may thus account for the classical findings encountered in PFIC1 which are reminiscent of cystic fibrosis such as Byler's bile and manifestations of pancreatic and intestinal dysfunction. (See HEPATOLOGY 2006;43:1125-1134.) 1

Illustration 1.

Adrenal Insufficiency as a Factor in Multiorgan Failure With Cirrhosis

Patients with cirrhosis who decompensate are typically closely screened for failure of various organs but not necessarily for adrenal insufficiency. Tsai et al. performed a short corticotrophin stimulation test on 101 critically ill patients with cirrhosis and severe sepsis. Adrenal insufficiency was defined as a baseline blood cortisol value of less than 15 μg/dL or an increment of less than 9 μg/dL for those with a baseline value between 15 and 34 μg/dL. The cumulative rates of survival at 90 days were 15.3% and 63.2% for those with or without adrenal insufficiency respectively (See Fig.). The cortisol response correlated inversely with various disease severity scores, of which the sequential organ failure assessment (SOFA) was most discriminatory in predicting adrenal insufficiency. Mean arterial pressure, serum bilirubin, vasopressor dependency and bacteremia independently predicted adrenal insufficiency in this cohort. Impaired responsiveness to norepinephrine is a well known characteristic of adrenal insufficiency. It is not known whether augmentation of corticosteroid blood levels would improve survival in critically ill patients with cirrhosis complicated by sepsis and relative adrenal insufficiency but on this evidence a prospective trial would appear justified. (See HEPATOLOGY 2006;43:673-681.) 2

Illustration 2.

Interplay of Liver and the Metabolic Syndrome

There is an increasing body of evidence that relates the liver to extrahepatic manifestations of the metabolic syndrome and conversely ascribes to the metabolic syndrome a promotional role in progression and exacerbation of liver diseases other than that which is directly attributable to nonalcoholic fatty liver disease. As an example of the former, Ioannou et al. have shown that elevation of serum alanine aminotransferase (ALT) in the absence of viral hepatitis or excessive consumption of alcohol is associated with a significantly increased 10-year probability of coronary heart disease as measured by the Framingham Risk Score (FRS). The threshold ALT values above which there is an increased FRS is notably lower in women (>30 IU/L) than in men (>43 IU/L). (See HEPATOLOGY 2006;43:1145-1151.)

Conversely Lai and colleagues found that in a high prevalence area for hepatocellular carcinoma (HCC) there was a significant association between pre-existing type 2 diabetes mellitus and development of HCC in those who were negative for hepatitis C virus infection and in those with hypercholesterolemia. (See HEPATOLOGY 2006;43:1295-1302.)

Child's A Cirrhosis Has Better Outlook When Due to NASH Rather Than HCV

Patients with cirrhosis due to NASH may enjoy a prolonged interval of well compensated disease during which the histological characteristics of NASH largely resolve leaving a bland picture of cryptogenic cirrhosis. Despite having excluded such patients with cryptogenic cirrhosis, support for this clinical impression is provided by a study in which the prognosis of patients with cirrhosis and continuing histological features of NASH was compared with that of a matched group with cirrhosis caused by hepatitis C virus (HCV). For compensated cirrhosis the 10-year mortality was 3/74 (4%) for NASH versus 15/75 (20%) for HCV (P<.004 [Fisher exact test]). NASH was associated with a higher cardiovascular mortality but a lesser 10 year risk of progressing to decompensated cirrhosis and hepatocellular carcinoma. Decompensation was most commonly manifest as ascites and once decompensation had occurred there was no significant difference in the rate of progression to liver failure and death between the two groups. (See HEPATOLOGY 2006;43:682-689.)

Lack of Acute Response to NOS Inhibition in HPS

The hepatopulmonary syndrome (HPS) occurs in the presence of portal hypertension and is characterised by pulmonary capillary dilatation resulting in arterial hypoxemia. Several case reports and animal studies have suggested that inhibition of pulmonary nitric oxide (NO) production is able to ameliorate the problem, giving credence to the hypothesis that NO is active as a component of its pathogenesis, in promoting sustained pulmonary vasodilatation. The report by Gómez et al. strongly refutes this notion, at least in as far as an acute effect on gas exchange is involved. Ten patients with varying degrees of HPS were studied. Baseline characteristics included a reduced diffusing capacity (45±17%), increased alveolar-arterial oxygen gradient (19-76 mm Hg) and reduction in pulmonary vascular resistance. A single dose of N-nitro-L-arginine methyl ester (L-NAME) was administered via a continuous flow nebuliser over 12 minutes and measurements repeated 30 and 120 minutes later. Efficacy of L-NAME was shown by a reduction in exhaled NO by approximately 50% at both 30 and 120 minutes. Cardiac output and heart rate were reduced in association with increases of both systemic and pulmonary vascular resistance. Disappointingly, despite this evidence that L-NAME had modified the systemic hyperdynamic circulatory state and ameliorated pulmonary vasodilation no changes were seen in pulmonary gas exchange (See Fig.). The authors argue that their findings dispute the relevance to humans of the animal model in which NO-induced vasodilatation sustains the arterial hypoxemia of HPS. The contrary view proposed is that a structural derangement of the alveolar-capillary interface due to vasculogenic remodelling of the pulmonary vascular bed accounts for the impaired diffusing capacity for carbon monoxide which was unaffected by L-NAME in this study and has previously been described to persist beyond the point when ventilation-perfusion inequalities have resolved following liver transplantation. (See HEPATOLOGY 2006;43:1084-1091.) 3

Illustration 3.

Posttransplant Chronic Hepatitis in Children

In a prospective study on the outcome of orthotopic liver transplantation(OLT) in childhood, 135 liver biopsies were obtained at 5 years and 64 at 10 years post-OLT. Normal or near normal histology was reported in only 31% of biopsies at 10 years. There was a trend for the incidence of chronic hepatitis and fibrosis to increase progressively with longer post-OLT follow-up such that 15% had progressed to cirrhosis at 10 years. Although there was a tendency for those with chronic hepatitis on biopsy to have higher aspartate aminotransferase (AST) levels in blood, this did not achieve statistical significance when compared to those with normal liver histology. Seropositivity for smooth muscle, anti-nuclear and liver–kidney microsomal autoantibodies was predictive of chronic hepatitis being found in 10% and 80% (P<.0001) of those with normal histology or chronic hepatitis at 10 years post-OLT. Those focussed on semantics may debate whether this is auto-immune, allo-immune or simply rejection of the allograft. In only 4 patients was the elevation of IgG and AsT sufficient to fulfill criteria for diagnosis of de novo auto-immune hepatitis. The question of whether routine withdrawal of corticosteroids at 3 months post-OLT as practiced in this cohort has permitted a higher incidence of allograft injury than may otherwise have ensued should be addressed by comparison with other large cohorts of patients for whom a comparably consistent policy of immunosuppression has been sustained. (See HEPATOLOGY 2006;43:1109-1117.)

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