Support of the failing liver

Failing liver

A failing liver is a serious condition that warrants a multimodal approach (see Chapter 77 ). The best treatment for a failing liver in the setting of acute liver failure (ALF; no history of liver disease) or acute-on-chronic liver failure (ACLF; history of chronic liver disease or cirrhosis) is liver transplantation (see Chapter 105 ). Supportive therapy, however, in ALF, ACLF, and posthepatectomy liver failure (PHLF) may be used to determine whether liver function will return to baseline or to bridge the patient until an organ becomes available (see Chapter 77 ).

The incidence of ALF in the United States is more than 2500 persons per year, but the number is much higher for patients with ACLF (>200,000). The outcome of ALF varies by etiology. Those with favorable prognoses are acetaminophen overdose, hepatitis A, and ischemia, with approximately 60% spontaneous survival. Etiologies with poor prognoses are drug-induced ALF, hepatitis B, and idiopathic cases, with approximately 25% spontaneous survival (see Chapter 77 ).

The aim of support therapy in the setting of liver failure is to return the patient to the compensated state. Several promising approaches to supportive therapy have been and continue to be evaluated, including cell transplantation and the application of extracorporeal liver support. These approaches are most promising in the setting of ALF and PHLF because of the possibility of complete recovery without imposing adverse sequelae, such as lifelong immunosuppression with liver transplantation. A failing liver may not regenerate or recover completely; therefore buying time to bridge to liver transplantation can be lifesaving. The interest in liver-assist devices is great because of high mortality rates, increasing wait lists, an expansion of indications for transplantation, and major liver resections.

This chapter emphasizes novel and promising techniques, such as extracorporeal liver support, cell transplantation, and tissue engineering. A historic summary of the different attempts to support the failing liver is also reviewed. Extracorporeal liver support is divided into biologic and nonbiologic systems.

Nonbiologic liver support

Historic blood purification options

Throughout the 1960s and 1970s, it was believed that small (molecular weight cut-off <5 kDa) dialyzable molecules caused coma in ALF. ^, As a result, numerous attempts were made to treat ALF patients with hemodialysis and charcoal hemofiltration for removal of these small toxins. Although case reports and controlled studies of both therapies have shown reversal of hepatic encephalopathy and improved survival, neither therapy has been proven successful in prospective randomized trials of either ALF or ACLF.

Plasma exchange and hemodiafiltration

Plasma exchange was a natural outgrowth of the less effective blood-exchange transfusion technique. The goals of plasma exchange in ALF are to reduce the level of circulating toxins and to replace deficient essential factors, such as clotting factors produced by the liver. Plasma exchange is achieved by apheresis, with removal of the patient’s jaundiced plasma and replacement with normal plasma. The results of early clinical trials were discouraging; encephalopathy often improved temporarily, but patient survival was not affected. Therapeutic gains, such as reduction in serum bilirubin and partial recovery from coma, were short lived and seen predominantly in patients with drug-induced ALF. In addition, a significant complication rate was reported with plasma exchange, including chemical toxicity, viral infections, and death from lung and brain complications.

Clemmesen and colleagues investigated the effect of repeated, high-volume (15% of body weight) plasma exchange in 23 patients: 14 patients with ALF and 9 with ACLF ( Table 78.1 ). The etiologies of ALF were acetaminophen in 8, hepatitis in 3, and nonhepatitis (A, B, C) in 3. Of the patients with acetaminophen intoxication, 25% died, and 21% were bridged to transplantation.

TABLE 78.1

Overview of Important Nonbiologic and Biologic Extracorporeal Liver Support Device Trials

						SURVIVAL %
NONBIOLOGIC DEVICES	TYPE OF TRIAL	AUTHOR	YEAR	NO. OF PATIENTS	INDICATION	DEVICE + SMT	SMT
Charcoal hemoperfusion	RCT	O’Grady et al.	1988	62	ALF	34% (10/29)	39% (13/33)
BioLogic-DT	CT	Ellis et al.	1999	10	ALF	0% (0/5)	0% (0/5)
Plasma exchange	Uncontrolled	Clemmesen et al.	1999	23	ALF, ACLF	53%* (8/15)
Plasma Exchange	RCT	Larsen et al.	2016	182	ALF	59% ^a (54/92)	48% ^a (43/90)
Plasma Exchange		Zhou et al.	2017		ALF
MARS	RCT	Heemann et al.	2002	23	ACLF	92% (11/12)	55% (6/11)
MARS	RCT	Saliba et al. FULMAR trial	2013	102	ALF	85% ^a (45/53)	76% ^a (37/49)
MARS	RCT	Banares et al. RELIEF trial	2013	180	ACLF	61% (58/95)	59% (55/94)
Prometheus	Uncontrolled	Rifai et al.	2003	11	ACLF, HRS	27% (8/11)
Prometheus	Uncontrolled	Grodzicki et al.	2009	52	ALF, PHLF	54% ^a (28/52)
Prometheus	RCT	Kribben et al. HELIOS Trial	2012	145	ACLF	66% (51/77)	63% (43/68)
						SURVIVAL %
BIOLOGIC DEVICES	TYPE OF TRIAL	AUTHOR	YEAR	NO. OF PATIENTS	INDICATION	BAL + SMT	SMT
ELAD	CT	Ellis et al.	1996	240	ALF, PNF	78% ^a (7/9)	33% (1/3)
ELAD	RCT	Thompson et al.	2018	203	ALF (alcoholic hepatitis)	51% (49/96)	50% (53/107)
HepatAssist	RCT	Demetriou et al.	2004	171	ALF, PNF	71% ^a (60/85)	62% ^a (53/86)
Latvian Trial	CT	Margulis et al.	1989	126	ALF, ACLF, Sepsis	67% (37/59)	40% (27/67)
TECA-Hybrid Artificial Liver Support System	Uncontrolled Phase 1	Xue Y et al.	2001	6	ALF, ACLF, PHLF	33% (2/6)
BLSS	Uncontrolled Phase 1	Mazariegos et al.	2001	4	ALF, ACLF	25% ^a (1/4)
AMC-BAL	Uncontrolled Phase 1	van de Kerkhove et al.	2002	12	ALF	100% ^a (12/12)
RFB	Uncontrolled Phase 1	Morsiani et al.	2002	7	ALF, PNF	86% ^a (1/7)
MELS	Uncontrolled Phase 1	Sauer et al.	2003	8	ALF, ACLF	100% ^a (8/8)
Hybrid-BAL	Uncontrolled Phase 1	Ding et al.	2003	12	ALF	75% (3/12)

ACLF, Acute-on-chronic liver failure; ALF, acute liver failure; AMC-BAL, Amsterdam Medical Center Bioartificial Liver; BLSS, Bioartificial Liver Support System; CT, controlled trial; ELAD, extracorporeal liver-assist device; HRS, hepatorenal syndrome; MARS, Molecular Adsorbent Recycling System; MELS , modular extracorporeal liver support; Phase I, safety assessment trial; PHLF, post-hepatectomy liver failure; PNF, primary nonfunction; RCT, randomized controlled trial; RFB, Radial-Flow Bioreactor; SMT, standard medical therapy; TECA, Hong Kong TECA LTD Co.

a Survivors include patients bridged to liver transplantation.

A recent multicenter, prospective, randomized control trial in Europe recruited 182 ALF patients and randomized them to high volume-plasma exchange (HVP) versus standard medical treatment (SMT) groups. Overall survival between HVP and SMT groups was 59% versus 48%. A significant survival benefit was seen in a subgroup of patients who did not receive a liver transplant. This study further demonstrated significantly reduced proinflammatory cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-6, IL-4, IL-10, and transforming growth factor [TGF]-β) in the HVP group, which may represent a decreased systemic inflammatory response and explain the favorable outcome in these patients.

Despite its limitations and unproven efficacy, plasma exchange continues to be a frequently used method of liver support in patients with ALF. It is used for the correction of coagulopathy and for nonspecific removal of accumulated toxins.

Albumin dialysis

The Molecular Adsorbent Recycling System (MARS) and Prometheus liver dialysis systems are two extracorporeal therapies that facilitate removal of nonpolar toxins by albumin in patients with ALF and ACLF.

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