Norman L. Sussman

Successful liver transplantation following medical management of portopulmonary hypertension: a single-center series.

Severe portopulmonary hypertension (POPH) is an absolute contraindication to orthotopic liver transplantation (OLT). Vasodilators have been used, but the safety of subsequent transplantation and the reversibility of pulmonary hypertension after transplantation are uncertain. This study examined the feasibility and post‐transplant effects of liver transplantation following medical control of POPH. Eight consecutive patients (three females and five males, ages 39–51) with POPH as their only contraindication to transplantation were treated with continuous intravenous epoprostenol. Liver transplantation was considered if the mean pulmonary artery pressure (PAM) was lowered to <35 mmHg. Epoprostenol 2–8 ng/kg/min successfully improved hemodynamics in seven of eight patients, usually within 6.5 months of initiating therapy. PAM declined from an average of 43–33 mmHg (p = 0.03); mean pulmonary vascular resistance declined from 410 to 192 dyn s cm−5 (p = 0.01) and cardiac output increased from 6.6 to 10 L/min (p = 0.02). Six of the seven responders were actively listed for liver transplantation. Two died on the waiting list; the remaining four were transplanted and remain alive and well 9–18 months post‐OLT—two without vasodilators, and two on oral medication. We conclude that pulmonary vasodilators permit safe liver transplantation in some cases, and that POPH may be reversible after transplantation.

Extracorporeal liver support. Application to fulminant hepatic failure.

Artificial liver support is urgently needed. Mechanical devices such as hemodialysis and hemoperfusion do not correct the metabolic abnormalities that exist in endstage liver disease, and biologically active devices have been impracticable because of limitations in the availability and viability of cultured liver cells. This deficit in the medical armamentarium is a major concern best illustrated by current management of fulminant hepatic failure (FHF). Medical treatment for FHF is largely unsuccessful, and orthotopic liver transplantation (OLT) is the intervention against which all future therapeutic interventions must be judged. The OLT procedure, however, is not benign. The cost is high, and survivors face a lifetime of immunosuppression and medical supervision. By comparison, patients who survive without surgery recover full liver function and have a normal life expectancy. A device that provides liver support during the critical stages of FHF would stabilize patients until a suitable donor organ was found and might negate the need for transplant altogether if the liver were able to regenerate. We review theoretical and practical aspects of biologically active devices using FHF as a paradigm of liver disease.

Portopulmonary hypertension: An update

Portopulmonary hypertension (POPH) is a serious complication of cirrhosis that is associated with mortality beyond that predicted by the Model for End‐Stage Liver Disease (MELD) score. Increased pulmonary vascular resistance (PVR) may be initiated by pulmonary vasoconstriction, altered levels of circulating mediators, or shear stress, and can eventually lead to the classic vascular remodeling (plexiform lesion) that characterizes POPH. Portal hypertension is a prerequisite for the diagnosis of POPH, although the severity of pulmonary hypertension is unrelated to the severity of portal hypertension or the nature or severity of liver disease. POPH precludes liver transplantation (LT) unless the mean pulmonary artery pressure (MPAP) can be reduced to a safe level. The concept of an acceptable pressure has changed: we now consider both MPAP and PVR in the diagnosis, and we include the transpulmonary pressure gradient so that we can factor in fluid overload and left ventricular failure. Pulmonary vasodilator therapy includes oral, inhaled, and parenteral agents, and one or more of these agents may significantly lower pulmonary artery pressures to the point that LT becomes possible. The United Network for Organ Sharing recommends MELD exception points for patients with medically controlled POPH, but this varies by region. Patients who undergo LT need specialized intraoperative and postoperative management, which includes the availability of intraoperative transesophageal echocardiography for assessing right ventricular function, and rapidly acting vasodilators (eg, inhaled nitric oxide and/or epoprostenol). Published case series suggest excellent outcomes after LT for patients who respond to medical therapy. Liver Transpl , 2012.

A fluorescent cell-based assay for cytochrome P-450 isozyme 1A2 induction and inhibition.

High throughput lead optimization requires simple, homogeneous cell-based assays capable of defining the drug-like properties of first-round screening hits. Induction and inhibition of the Phase I drug-metabolizing enzymes are central to this process. We report here an assay for induction and inhibition of cytochrome P-450 (CYP) isozyme 1A2 that meets these requirements. It utilizes HepG2/C3A, a human liver cell line, and ethoxyresorufiln. Using methylcholanthrene, CYP1A2 can be induced dramatically, and it is inhibited by furafylline, a mechanism-based inhibitor of this enzyme.

Mathematical modeling of liver injury and dysfunction after acetaminophen overdose: early discrimination between survival and death.

Acetaminophen (APAP) is the leading cause of acute liver injury in the developed world. Timely administration of N‐acetylcysteine (N‐Ac) prevents the progression of serious liver injury and disease, whereas failure to administer N‐Ac within a critical time frame allows disease progression and in the most severe cases may result in liver failure or death. In this situation, liver transplantation may be the only life‐saving measure. Thus, the outcome of an APAP overdose depends on the size of the overdose and the time to first administration of N‐Ac. We developed a system of differential equations to describe acute liver injury due to APAP overdose. The Model for Acetaminophen‐induced Liver Damage (MALD) uses a patients aspartate aminotransferase (AST), alanine aminotransferase (ALT), and international normalized ratio (INR) measurements on admission to estimate overdose amount, time elapsed since overdose, and outcome. The mathematical model was then tested on 53 patients from the University of Utah. With the addition of serum creatinine, eventual death was predicted with 100% sensitivity, 91% specificity, 67% positive predictive value (PPV), and 100% negative predictive value (NPV) in this retrospective study. Using only initial AST, ALT, and INR measurements, the model accurately predicted subsequent laboratory values for the majority of individual patients. This is the first dynamical rather than statistical approach to determine poor prognosis in patients with life‐threatening liver disease due to APAP overdose. Conclusion: MALD provides a method to estimate overdose amount, time elapsed since overdose, and outcome from patient laboratory values commonly available on admission in cases of acute liver failure due to APAP overdose and should be validated in multicenter prospective evaluation. (HEPATOLOGY 2012)

Regulation of Intestinal and Hepatic Apoprotein Synthesis after Chronic Fat and Cholesterol Feeding

Although diet influences levels of lipoproteins and their corresponding apoproteins, its effects on the molecular regulation of apoprotein synthesis are relatively unknown. Male Sprague-Dawley rats were fed an atherogenic diet containing cholesterol and propylthiouracil (PTU). Intestinal apo AI and AIV mRNA concentrations were decreased by the atherogenic diet, but apo AI and AIV synthesis was increased in vitro (organ explants) and in vivo (polysome runoff), consistent with regulation at the translational level. In contrast, hepatic apo E mRNA concentration and synthesis were increased after the atherogenic diet, consistent with pretranslational regulation. The response to cholesterol feeding for hepatic apo AI and E showed a third pattern of regulation, in which synthesis increased and mRNA content remained stable or fell, again suggesting translational control, but polysome runoff synthesis was unchanged. The apparent importance of translational regulation in the intestine is consistent with the necessity for the tissue to respond rapidly to changes in intraluminal content.

Extracorporeal Liver Assist in the Treatment of Fulminant Hepatic Failure

Our goal in developing a liver assist device is to provide liver support and improve the metabolic state of the patient so that the native liver has the opportunity to regenerate. Failing this, the patient should at least remain in satisfactory health so that liver transplantation can be performed safely. We have no idea how much metabolic support will be required to sustain life, but we have a set a goal of 20% of the normal hepatocyte mass. Our initial results suggest that this is an appropriate number, and a clinical trial to determine safety and efficacy is under way at the Texas Medical Center.

Long-term follow-up of portopulmonary hypertension patients after liver transplantation

Portopulmonary hypertension (POPH) occurs in 5.3% to 8.5% of patients with advanced liver disease. The rate of survival in the absence of orthotopic liver transplantation (OLT) is reportedly 38% at 3 years and 28% at 5 years. Moderate to severe POPH [mean pulmonary artery pressure (MPAP) ≥ 35 mm Hg] is associated with a perioperative mortality rate of 50%. Single‐center series have demonstrated the feasibility and short‐term efficacy of OLT after POPH is controlled with vasodilators, but long‐term outcomes have not been reported. Our aim was to determine graft and patient survival rates and the effects of OLT on pulmonary hypertension (PHT) in patients undergoing transplantation for POPH at our center. Four hundred eighty‐eight adult patients underwent transplantation between June 2004 and January 2011, and 7 underwent transplantation for POPH after their MPAP was reduced to ≤35 mm Hg with vasodilators. These 7 patients included 3 men and 4 women with ages ranging from 39 to 54 years at the time of OLT. All patients received IV EPO or inhaled EPO during the perioperative period, and all were weaned off EPO over the course of 3 days to 8 months. Both the graft and patient survival rates were 85.7% after a median follow‐up of 7.8 years. One patient had recurrent hepatitis C virus cirrhosis and recurrent POPH and died from multiorgan failure unrelated to PHT. Four of the remaining 6 patients required oral vasodilator therapy for persistent PHT. Only 2 of the 7 patients (4.4 and 8.5 years after OLT) did not have PHT. In conclusion, patients with POPH responsive to vasodilator therapy may have excellent long‐term graft and patient survival after OLT. Despite the alleviation of portal hypertension by OLT, most patients have persistent or recurrent PHT that can be controlled with oral vasodilators. Liver Transpl 20:724‐727, 2014.

The end of hepatitis C.

We are at a turning point in the management of the hepatitis C virus (HCV) epidemic. HCV can be cured, but treatment up to this point has required a toxic combination of drugs. This is about to change; the second generation of direct-acting antiviral agents promises high cure rates with few side effects. This gives us the historical opportunity to eradicate HCV from the entire population. Our article addresses the advantages of universal eradication of HCV infection from the United States and the steps required to achieve this goal.

Pulmonary complications in cirrhosis

Purpose of reviewTo summarize the pulmonary complications seen in cirrhosis. Recent findingsThe definition of portopulmonary hypertension (POPH) has been refined to exclude cardiac disease. POPH may be treated with a variety of agents; inhaled agents are particularly useful in the peri-transplant period. Hepatopulmonary syndrome (HPS) remains refractory to medical therapy. SummaryCirrhosis may be complicated by one of two pulmonary vascular complications, portopulmonary hypertension (POPH) and hepatopulmonary syndrome (HPS). POPH is a syndrome of increased vascular resistance, initiated by pulmonary vascular spasm. HPS is caused by intrapulmonary arteriovenous shunting with resultant hypoxemia. Both conditions are associated with portal hypertension, but are unrelated to the degree of portal hypertension, the nature or severity of the liver disease, and are associated with mortality in excess of the model for end-stage liver disease score. POPH is usually responsive to vasodilators, while HPS remains resistant to therapeutic agents. Both conditions are improved or cured by liver transplantation.