COMMENTARY

Advances in Liver Disease

Digestive Disease Week (DDW) 2014

William F. Balistreri, MD

Disclosures

June 19, 2014

In This Article

Miscellaneous Observations of Note

Complications of Cirrhosis

The ravages of end-stage liver disease manifest as extrahepatic disease. For example, Rudnick and colleagues[27] found a 2%-3% overall prevalence of myocardial infarction (MI) in hospitalized patients with cirrhosis; non-ST-segment elevation MI (NSTEMI) accounted for 84%. In cirrhotic patients, in-hospital mortality from MI was 26%. Furthermore, among patients with type 2 NSTEMI, 50% did not survive the index hospitalization.

Chronic right-sided heart failure and Fontan physiology result in congestive hepatic fibrosis. Features of congestive hepatopathy include sinusoidal dilatation, which leads to stretch of hepatic stellate cells and chronic congestion; this leads to microvascular thrombosis with sinusoidal fibrin deposition.

Simonetto and colleagues[28] demonstrated the effects of mechanical stretch and fibrin on production and assembly of the provisional extracellular matrix protein fibronectin by hepatic stellate cells. Mechanical stretch and fibrin stimulate maturation of extracellular matrix by promoting fibronectin release or fibril assembly. These findings provide mechanistic insights in the pathogenesis of congestive hepatic fibrosis.

Malnutrition is a commonly encountered consequence of cirrhosis. Huynh and colleagues[29] evaluated the relationship among gastric emptying, glucose absorption, and postprandial appetite in patients with cirrhosis.

Delayed gastric emptying was common and was associated with reduced intestinal glucose absorption and delayed recovery of postprandial appetite, providing a potential explanation for the poor appetite, reduced oral intake, and risk for malnutrition observed in these patients. The higher postprandial blood glucose concentrations, however, indicate that peripheral insulin resistance is the main mediator of postprandial hyperglycemia in patients with cirrhosis.

Early detection and treatment of delayed gastric emptying may lead to improved nutritional status. Appetite may be further compromised by hypogeusia, which in turn may be related to zinc deficiency.

Sengupta and colleagues[30] found that zinc deficiency (serum zinc < 0.66 µg/mL) is highly prevalent in cirrhotic patients and correlates with the severity of liver disease and presence of infection. Zinc-deficient patients have worse transplant-free survival than nondeficient patients. The investigators recommend that serum zinc levels be assessed in patients with a Child-Pugh score of B or C or a Model for End-Stage Liver Disease (MELD) score ≥ 15. Further studies are needed to determine whether zinc supplementation changes the clinical outcomes of zinc-deficient patients.

Viral Hepatitis

Hepatitis B. Hepatitis B virus (HBV) reactivation, a well-described and preventable complication of immunosuppressive therapy, can lead to significant morbidity and mortality and interruption of cancer treatment.

Mehta and colleagues[31] analyzed the prevalence of HBV infection in approximately 12,000 patients with new-onset solid and hematologic malignancies before the initiation of immunosuppressive therapy. The overall prevalences of chronic HBV infection and previous exposure to HBV were 0.9% and 8.6%, respectively, across all medical oncology services (both hematologic and solid-tumor cancers). This study emphasizes the importance of assessing the HBV status of high-risk patients.

In the United States, screening for HBV infection in pregnant women is mandatory and nearly universal. However, little is known about the rates of postpartum maternal care and follow-up management. Chang[32] found that the prevalence of known HBV in pregnant women was 0.23%; most (62%) of these women underwent HBV screening in their first trimester. Of note, only one half of the women identified had postpartum follow-up laboratory testing for HBV after the index pregnancy; this finding did not vary by race, ethnicity, or birth outside of the United States. Given current clinical and public health standards, options to improve HBV testing and follow-up management in pregnant women are needed.

Hepatitis E. Historically, hepatitis E virus (HEV) was described as a waterborne disease, transmitted through fecally contaminated drinking water in endemic areas. The modes of HEV transmission for sporadic infection in industrialized countries are unknown but are postulated to involve zoonotic factors (wild and domestic animal exposure).

Diehl and colleagues[33] speculated that humans may be exposed to HEV through garden-grown foods contaminated with animal feces. Participants in the 2009-2010 NHANES who reported eating self-grown foods were more likely to be seropositive for HEV. Although a cross-sectional study does not demonstrate causation, this association supports a possible connection between eating homegrown produce (possibly contaminated with animal feces) and HEV. Self-grown foods should be carefully cleaned, or avoided entirely, by people at high risk for HEV, such as pregnant women, young children, and the immunosuppressed.

A Novel Mechanism of Cholestatic Liver Disease

Tight junction protein 2, a cytoplasmic protein essential for the assembly of cell-to-cell junctional structures, is encoded by TJP2. Homozygous protein-truncating mutations in TJP2 are present in patients with severe early-onset cholestatic liver disease.

Sambrotta and colleagues[34] explored the wider phenotypic spectrum associated with mutations in TJP2 in a cohort of 53 patients with severe early onset of normal GGT cholestasis. TJP2 deficiency was shown to be responsible for a wide spectrum of cholestatic disease phenotypes, ranging from minimal cholestasis to persistent severe disease requiring liver transplantation.

Hepatic Encephalopathy: We Have an App (and Maybe a Treatment) for That!

The mechanism of hepatic encephalopathy remains confusing. One study suggested that circulating bile acids may be involved. Although precisely how bile acids dysregulate brain function is unknown, circulating bile acids can disrupt the blood/brain barrier and enter the brain in models of acute and chronic liver failure, leading to neurologic impairment. Ashfaq and colleagues[35] reported that strategies to minimize the total bile acid pool and modulate the bile acid composition improved the outcome of patients with neurologic symptoms associated with liver failure.

Detection of subtle hepatic encephalopathy is elusive. The EncephalApp - Stroop Test was used to screen for covert hepatic encephalopathy. This device has 2 components: an easier "off" state and a difficult "on" state. The time required to complete both parts, OffTime+OnTime, determines impairment.

Allampati and colleagues[36] defined normative values for EncephalApp and performed sensitivity analyses. They reported that EncephalApp OffTime+OnTime is a valid method to screen for covert hepatic encephalopathy. This is quite "app"-licable, because I often feel encephalopathic when I attempt to manipulate electronic devices!

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