Gastroenterology and Hepatology Board Review: Pearls of Wisdom, Third Edition


CHAPTER 45. Acute Liver Failure and Liver Transplantation

Timothy M. McCashland, MD

Image What are the hallmark diagnostic signs of acute liver failure (ALF)?

Encephalopathy and coagulopathy. When the international normalization ratio (INR) is greater than 1.5 and encephalopathy is present within 8 weeks of the beginning of the illness, the diagnosis is secure.

Image Criteria for poor outcome in cases of acetaminophen-induced ALF include:

Prothrombin time > 50 s, pH < 7.3, and grade 4 encephalopathy.

Image A 43-year-old woman with Wilson’s disease presents with grade 3 encephalopathy and jaundice. Family members discover that she has not taken her penicillamine over the last few weeks. What treatment does her current clinical condition require?

Liver transplantation. Restarting penicillamine has shown little efficacy in this setting.

Image A 25-year-old woman in her third trimester of pregnancy presents with jaundice, confusion, and right upper quadrant (RUQ) pain. Laboratory evaluation reveals marked anemia, severe thrombocytopenia, and elevated liver tests. What would be the most appropriate management?

Rapid delivery of the baby with appropriate clotting factor support. HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) is associated with rapid liver failure, usually in the third trimester of pregnancy, and is a medical emergency.

Image When should a patient with ALF be transferred to a transplant center?

Any patient with encephalopathy of grade 2 or more.

Image What are the most common causes of ALF in the United States?

Acetaminophen toxicity, indeterminate, other medications, and acute viral hepatitis (types A and B).

Image What is the most common cause of death in ALF while awaiting liver transplantation?

Cerebral edema. Cerebral edema is reported in 80% of those dying from ALF.

Image True/False: Survival after liver transplantation for ALF is comparable to transplantation for end-stage liver disease.

False. Survival after transplantation for ALF ranges from 46% to 89% (66% average). The lower survival is related to the presence of multiple organ failure at the time of transplantation.

Image The neurological exam of a patient with ALF begins to deteriorate. What should you do?

Sequential management of cerebral edema includes elevation of head of bed 10–20 degrees, hyperventilation, administration of mannitol, and induction of a pentobarbital coma. Intracranial pressure monitoring may be very helpful in this situation.

Image True/False: Survival of patients with ALF is related to their grade of encephalopathy at the time of transplantation.

True. Grade 1—90%, grade 2—71%, and grade 3 or 4—48%.

Image Poor prognostic variables in non-acetaminophen-induced ALF include:

An INR >3.5, age <10 or >40, drug-induced, indeterminate cause, duration of jaundice >7 days, and bilirubin >30 mg/dL.

Image True/False: A 40-year-old man with ALF of unknown etiology (indeterminate) is febrile and has an elevated leukocyte count. He should immediately be listed for liver transplantation.

False. Contraindications to liver transplantation include active infection and severe cerebral edema. Infection at the time of transplantation has contributed to death in about 11% of patients. Up to 36% of patients with ALF have been reported to develop bacteremia. Cerebral perfusion pressure of <40 mmHg for longer than 1 h makes neurological recovery unlikely.

Image What are the most common infections that occur in ALF?

Pneumonia (50%) followed by bacteremia (26%) and urinary tract infection (22%).

Image A 35-year-old woman with acetaminophen-induced ALF is persistently febrile despite being on broad-spectrum antibiotics. What infectious organism should you suspect?

Fungal infections are common in ALF (13%–32%). Candida albicans is the most common fungal organism identified.

Image What is the cause of renal failure associated with ALF?

Renal failure develops in 43%–80% of cases, depending on the etiology of liver failure. Acetaminophen may cause direct injury to the distal tubules of the kidney; however, most cases result from a decrease in renal blood flow as a consequence of vasoconstriction. This is similar to what occurs in hepatorenal syndrome.

Image The use of what medications/substances, when taken chronically, results in a higher risk of ALF with concomitant acetaminophen use?

Any medication that induces the cytochrome P450 system in the liver may enhance ALF with acetaminophen. The most common medications in this setting are alcohol, phenytoin, and antidepressants.

Image A 20-year-old male bodybuilder presents with jaundice, confusion, and bruises. What is the most likely cause of ALF in this setting?

Anabolic steroids, when used in high doses, may result in ALF.

Image A family of campers that just recently returned from a camping trip presents to their physician with diarrhea and confusion. Liver tests and serum creatinine are elevated. What are your diagnosis, treatment, and prognosis?

Amanita phalloides poisoning presents with diarrhea, neurological changes, and signs of hepatorenal failure. Children below the age of 10 have the highest rate of fatality with an overall death rate of 20%. Initial management with high-dose penicillin has shown some benefit.

Image A 45-year-old woman presents to your office 4 days following laparoscopic cholecystectomy with nausea, vomiting, fever, and diffuse myalgias. Evaluation reveals the aminotransferase levels to be over four times greater than normal. What diagnosis do you suspect?

Idiosyncratic hepatic injury due to anesthetic drugs is reported in up to 1 in 9000 cases. The usual interval from surgery to presentation is 3–5 days but can be up to 15 days. Halothane is considered the classic example of anesthetic-induced liver injury.

Image What is the single most important factor limiting liver transplantation in the United States?

The availability of cadaveric donors. Approximately 6000 liver transplants are performed each year; however, up to 10,000 potential candidates are identified each year. As many as 15% of patients die, waiting for a liver transplant.

Image Liver transplant candidates are matched to the cadaveric donor by what variables?

Weight (liver size limit) and blood type.

Image How does a transplant center prioritize who receives a transplant?

The United Network for Organ Sharing (UNOS) in 2002 implemented the Model for End Stage Liver Disease (MELD) score as the means to prioritize candidates on the waiting list. Highest priority is for fulminant liver failure as status 1 patients. All others are allocated by MELD scores, with patients with the highest score receiving the highest priority.

Image What are contraindications to liver transplantation?

Extrahepatic malignancy, sepsis, active alcoholism, psychosocial issues, and advanced cardiorespiratory disease.

Image For patients with alcoholic liver disease, what is the usual period of abstinence before consideration of liver transplantation?

Most programs require a period of abstinence of at least 6 months with adequate support systems and compliance with medical care.

Image True/False: Spontaneous bacterial peritonitis is a contraindication to liver transplantation.

False. Antibiotic treatment for 2–5 days is associated with high bacteriologic cure.

Image True/False: Hepatorenal syndrome is a contraindication to liver transplantation.

False. Hepatorenal syndrome may be reversed by liver transplantation.

Image True/False: Waiting times for liver transplantation are equal throughout the United States.

False. There is great variability in waiting times due to availability of donors in the UNOS designated geographical regions.

Image What are the most common medications used for immunosuppression after liver transplantation?

Cyclosporine, tacrolimus (FK 506), mycophelolate mofetil, and prednisone.

Image What is the mechanism of action of cyclosporine and tacrolimus (FK 506)?

Both inhibit early T-cell signal pathways and interleukin-2 production and release.

Image True/False: A 32-year-old female presents to the emergency room with nausea, vomiting, and mildly decreased mental status. Liver tests are notable for an alanine aminotransferase (ALT) of 5120 U/L, aspartate aminotransferase (AST) of 3560 U/L, bilirubin of 6.9 mg/dL, and INR of 3.5. Acute viral serologies are negative, as are antinuclear antibody, antismooth muscle antibody, drug screen, and acetaminophen levels. N-Acetylcysteine use has been shown to improve the survival of patients in this scenario.

True. Intravenous N-acetylcysteine (NAC) was shown to improve transplant-free survival in patients with early stage encephalopathy (grades I–II) in nonacetaminophen-related ALF patients. Survival in the NAC group was 52% versus 30%. Indeterminate etiology is the third leading cause of ALF in the United States.

Image A 52-year-old female with a history of tuberculosis presents to the hospital with new onset rash, confusion, and severe jaundice. Liver tests reveal an ALT of 3210 U/L, AST of 2505 U/L, bilirubin of 20.5 mg/dL, and INR of 4.0. Further history reveals she started treatment for the tuberculosis 3 weeks prior. What are the most common causes of drug-induced liver injury–ALF (DILI-ALF)? What is the prognosis in patients with nonacetaminophen DILI?

The most common causes of DILI-ALF are antimicrobials (antituberculosis > sulfa drugs > nitrofurantoin > antifungal), psychoactive drugs, nonprescription medications, dietary supplements, and weight loss treatments. Transplant-free survival is extremely poor, approximately 25%, in DILI cases.

Image Multiple prognostic models have been proposed to predict outcome and requirement for emergency liver transplantation in ALF. The most common model applied is the Kings College Hospital criteria for acetaminophen and nonacetaminophen etiologies. What variables are used in the Kings College Hospital criteria?

Nonacetaminophen: Prothombin time (PT) >100 s (INR >6.5) and encephalopathy or any three of the following: Patient age <10 or >40 years, bilirubin >30 mg/dL, duration of jaundice >7 days, PT >50 s (INR >3.5), nonhepatitis A/B, or drug etiology.

Acetaminophen: Arterial pH <7.3, PT >100 s (INR>6.5), serum creatinine >3.0 mg/dL, and encephalopathy grade III–IV.

Image What diseases for which transplantation is performed may recur following liver transplantation?

Hepatitis C is the most common recurrent disease. Hepatitis B can recur if not adequately treated posttransplant. Autoimmune diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis have also been reported to recur after transplant.

Image At present, what liver disease represents the most common indication for liver transplantation?

Chronic hepatitis C, followed by hepatocellular carcinoma (HCC), alcoholic liver disease, cholestatic liver disease, cryptogenic liver disease, and metabolic liver disease.

Image How is recurrent hepatitis B prevented following liver transplantation?

Excellent patient and graft survival is now possible with pre- and postliver transplant use of nucleos(t)ide medications with posttransplant use of hepatitis B immune globulin (HBIG).

Image True/False: Survival following liver transplant for chronic hepatitis C (HCV) is inferior to non-HCV chronic liver disease causes.

True. One- and five-year survival after transplantation for chronic hepatitis C is generally good; however, survival is slightly worse (10%–15% lower) compared to other nonmalignant chronic liver disease etiologies.

Image True/False: A 50-year-old man with chronic hepatitis C presents with worsening ascites. Ultrasound reveals a single 3-cm lesion in the right lobe of the liver. This patient is still a liver transplant candidate.

True. The following variables have been found to correlate with poor prognosis: single tumor size greater than 5 cm, multiple lesions (>3), vascular invasion, and noncircumscribed shape. Nevertheless, survival remains comparable to other etiologies for liver transplantation if the patient falls within Milan HCC criteria (single lesion <5 cm, 3 or fewer lesions, the largest <3 cm).

Image A potential liver transplant recipient asks you during a clinic visit about differences in the risks and complications between living-related liver transplantation versus deceased-donor liver transplantation. What are the differences?

Living-related liver transplantation in comparison to deceased-donor liver transplantation is associated with higher rates of biliary leak (31% versus 10%), unplanned re-exploration (26% versus 17%), hepatic artery thrombosis (6.5% versus 2.3%), and portal vein thrombosis (3% versus 0%). Despite these potential complications, the 1-year patient and graft survival of living-related transplantation and deceased-donor transplantation is similar.

Image What are the two biliary anastomosis methods used in liver transplantation and when are they used?

Choledochocholedochostomy (CDC) and Roux-en-Y choledochojejunostomy. Roux-en-Y choledochojejunostomy is commonly employed when the recipient has biliary tract disease (eg, primary sclerosing cholangitis) and in retransplants.

Image A 45-year-old woman presents with fever, shortness of breath, and increased liver tests 20 days following liver transplantation. She had steroid resistant rejection 1 week prior and is being treated with antilymphocyte medication. What is the most likely diagnosis?

Cytomegalovirus (CMV) pneumonitis and hepatitis is common after aggressive immunosuppression and usually occurs within the first month of transplantation. Those highest at risk are patients who are CMV-negative and receive a liver from a CMV-positive donor. Most centers now provide prophylaxis against infection with acyclovir.

Image What are the most common biliary complications following liver transplantation?

Biliary strictures and leaks are the most common biliary complications. Eighty percent develop within the first 6 months. Biliary strictures at the anastomosis may be dilated or stented and rarely require surgical revision. Biliary leaks are managed with nasobiliary tubes, stents, or sphincterotomy.

Image What vaccines are not safe after liver transplantation?

Live or attenuated vaccines should be avoided (measles, mumps, rubella, oral polio, BCG). Hepatitis A, B, and pneumococcal vaccines, if not given prior to transplantation, should be given.

Image True/False: Pregnancy is possible in patients following liver transplantation and pregnant transplant recipients should continue their immunosuppression medications.

True. However, pregnancy after liver transplantation is complicated by a higher rate of prematurity and low birth weight. Immunosuppressive agents should be continued throughout pregnancy.

Image What are the most common neoplasms that occur in recipients of liver transplants?

The most common neoplasms after liver transplant are skin cancers (both squamous and melanoma) and solid organ tumors (lymphoma > colon > genital/urinary > lung > oropharyngeal/larynx).

Image A 56-year-old male returns to your clinic after receiving a liver transplant 6 months prior with pruritis, mild jaundice, and slightly elevated liver tests. The patient states he received a DCD liver and wonders if this has something to do with his symptoms. What is a DCD donor and what are the common complications associated with DCD donors?

DCD refers to donation after cardiac death. The use of DCD donors is increasing and now composes more than 5% of all liver transplants in the United States. The most common complications associated with DCD donors are diffuse intrahepatic biliary strictures (similar to primary sclerosing cholangitis) due to ischemia to the bile ducts, a higher risk of primary graft nonfunction, and a higher risk of need for retransplantation.

Image A 60-year-old Asian male with a history of hepatitis B presents with a 4-cm single lesion in the liver by screening ultrasound. Alpha fetoprotein is 250 mg/mL and MRI shows a 4-cm lesion with a washout phase consistent with HCC. What are the listing criteria for HCC for liver transplantation?

Listing for liver transplantation for patients with HCC is by UNOS policy of patients with T2-defined lesions (2–5 cm) with either a biopsy-proven diagnosis or imaging study consistent with HCC with a washout phase. A MELD score of 22 is assigned to the patient meeting criteria if the patient’s calculated MELD score is less than 22. A sequential increase of 10% is applied to the MELD score every 3 months to those remaining on the waiting list.

Image What are the most likely causes of hyperlipidemia following liver transplantation?

Long-term use of corticosteroids, frequent use of bolus steroids for episodes of rejection, pretransplant hyperlipidemia, and possibly the use of cyclosporine versus tacrolimus. Nearly 40% of patients develop hyperlipidemia posttransplant and require some form of treatment.


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Polson J, Lee WM. AASLD position paper: the management of acute liver failure. Hepatology. 2005;41:1179-1197.

Thuluvath PJ, Guidinger MK, Fung JJ, et al. Liver transplantation in the United States, 1999–2008. Am J Transplantation. 2010; 10(Part 2):1003-1019.