Bernard J. Dubray
Christopher D. Anderson
Presentation
You are the on-call surgeon covering a rural community when you receive a page from the local emergency room (ER). The ER physician states there is a young girl he would like you to evaluate. “Eight years old. Her mother brought her in complaining that her skin has turned yellow and she’s been itching incessantly over the last 12 hours.” The emergency department (ED) physician goes on to explain his examination and notes that she has a “quite a tremor” along with “gingival bleeding.”
You arrive on the scene and conduct a thorough history and physical examination. This was a previously healthy girl who this morning awoke complaining of itching along with nausea and some malaise. Throughout the course of the day, her mother noted the change in skin color. When prompted, the girl admits her urine has also been “coke-colored.” On exam, you note scleral icterus as well as the gingival bleeding the ED physician had told you about. A nonlateralizing pill-rolling tremor is also present. This does not extinguish with movement, and when you ask the girl to walk across the room, she stumbles slightly. Her chest is clear and heartbeat regular. Your abdominal exam is notable for hepatomegaly.
In light of your findings, you probe the mother further prior to initiating a workup. She reveals that her sister “had a liver problem” when she was young, but “she got a transplant and is doing fine now.”
Differential Diagnosis
Interference with the metabolism and excretion of bilirubin results in clinical jaundice, which can be categorized as prehepatic, hepatic, or posthepatic. Development of a differential diagnosis requires a thorough understanding of the physiologic mechanisms involved and should include the most likely, as well as the most morbid, diagnoses. The combination of acute jaundice and coagulopathy in an adolescent should raise the suspicion for hepatic dysfunction. Further workup and management, however, is dependent upon the precise etiology, which differs quite dramatically between adults and adolescents (Table 1). In adults, almost 50% of the cases of acute liver failure (ALF) can be attributed to acetaminophen overdose versus <20% in children. Other common causes in adults include nonacetaminophen drug toxicity and acute hepatitis B virus. Etiologies common in children include infectious hepatitis, metabolic disease, and autoimmune disease.
TABLE 1. Differential Etiologies of ALF
Evidence of palmar erythema, clubbing, gynecomastia, testicular atrophy, ascites, or spider nevi suggests a chronic component to hepatic dysfunction. Slit lamp examination can detect Kayser-Fleischer rings in patients presenting with Wilson’s disease. Their presence, however, is only seen in 50% to 60% of patients with isolated hepatic involvement compared to 90% of patients with neurologic involvement.
Detection and monitoring of hepatic encephalopathy are another important exam tool that can guide further workup and management. Patients should undergo an initial assessment but then have serial examinations to detect subtle changes. Categorization of hepatic encephalopathy is based on changes in behavior, cognition, and neurologic exam and ranges from stages 0 (minimal to no evidence of encephalopathy) to 4 (coma) (Table 2).
TABLE 2. States of Hepatic Encephalopathy
Workup
The preliminary diagnostic workup in a patient suspected of having ALF begins with a battery of biochemical tests aimed at differentiating the possible etiologies. General tests to assess blood counts, electrolytes, and renal function are important. More specific tests include the liver function panel as well as a coagulation profile. Further laboratory tests that help differentiate etiologies of liver failure include a hepatitis panel, acetaminophen level, serum ceruloplasmin level, and serum copper level.
The development of encephalopathy within 8 weeks of liver injury in a person with a previously normal liver defines fulminant disease. The treatment of patients in this category is largely supportive but is dictated by the severity of the liver failure. Admission to a highly skilled, intensive care unit is necessary in all patients with fulminant liver failure in order to monitor the effects on multiple organ systems. Principles of care are aimed at ameliorating reversible causes of hepatocellular injury while supporting the multiorgan complications of liver failure.
ALF secondary to acetaminophen toxicity is an example of a potentially reversible injury. Hepatic glutathione stores are reduced following acetaminophen overdose, which are restored by administering N-acetylcysteine. If given within 8 hours of ingestion, N-acetylcysteine is likely to prevent serious hepatotoxicity and death from acetaminophen overdose.
The young girl’s initial laboratory investigations are notable for a moderate transaminitis, elevated total bilirubin, and an INR of 3.5. Additionally, the patient’s serum ceruloplasmin level is <5 mg/dL. Given the constellation of laboratory findings, your suspicion for a case of fulminant Wilson’s disease is elevated.
Wilson’s disease is a rare autosomal recessive genetic disorder of copper accumulation that typically presents in a 4:1 female:male ratio in patients between 5 and 50 years of age. Reduced biliary excretion of copper leads to its accumulation in the liver as well as other tissues, principally the brain. Hepatic dysfunction is the usual presenting feature; however, neuropsychiatric and hematologic complaints may also be involved. The time course of presentation is variable, but can be acute, especially in children.
Diagnosis is dependent upon a high degree of clinical suspicion and can be made through a combination of physical and laboratory findings. The classic presentation of a young patient with decreased ceruloplasmin level and Kayser-Fleischer rings is only seen in about 50% of those diagnosed with Wilson’s disease. Guidelines for diagnosing Wilson’s disease have been proposed by the American Association for the Study of Liver Diseases and are useful in nonfulminant cases.
Whereas patients diagnosed with Wilson’s disease following workup for elevated liver enzymes can undergo medical treatment to increase copper excretion, management of fulminant cases is similar to all causes of fulminant hepatic failure.
Diagnosis and Treatment
The onset of hepatic encephalopathy distinguishes fulminant liver failure from acute liver dysfunction. Any patient admitted with liver dysfunction who develops encephalopathy should be moved to an intensive care unit in a hospital with a liver transplant program. Nitrogenous substances that produce ammonia within the gastrointestinal tract are thought to contribute to the development of hepatic encephalopathy. Ammonia, which is a known neurotoxin, is efficiently cleared from the portal circulation in the healthy liver. Buildup, however, can occur in cases of ALF and contribute to encephalopathy. Medical treatments aim to either remove nitrogenous substances or prevent ammonia production, and are most effective in patients with a component of chronic liver failure.
Cerebral edema develops in 75% to 80% of patients with grade IV encephalopathy, which can have devastating consequences in ALF. Cerebral edema results in increased intracranial pressure (ICP) and brainstem herniation, which are among the leading causes of mortality from ALF. Initial management focuses on reducing excess stimulation, protein intake, and avoiding sedating medications. Head elevation, hyperventilation, and hyperosmolarity are additional adjuncts in treatment. ICP monitoring in ALF remains controversial due to its invasive nature and failure to improve survival. Epidural catheters can significantly reduce bleeding complications and offers the safest approach. Currently, over 50% of U.S. transplant programs routinely use ICP monitoring to guide therapy in ALF.
Metabolic disturbances are common in ALF and include acid–base disorders as well as electrolyte abnormalities. An inability of the failing liver to clear lactate results in a lactic acidosis; however, this is often coupled with a respiratory alkalosis, producing a mixed acid/base disorder. Additionally, hypoglycemia can manifest as the liver begins to lose its ability to perform hepatic gluconeogenesis. Especially in the pediatric patient, maintenance of serum glucose is a paramount component of clinical management. Common electrolyte disturbances include hyponatremia, hypophosphatemia, and hypokalemia.
Hematologic complications arise from ALF as the ability of damaged hepatocytes to synthesize the proteins is diminished. Both pro- and anticoagulant proteins are reduced, which may explain the low risk of bleeding despite the elevations in PT/INR. Although there remains clinical management debate, many authors advocate avoidance of aggressive correction of coagulopathy except in cases of active bleeding. The correction of coagulopathy has not been shown to improve mortality and the volume load from plasma transfusion may worsen cerebral edema.
With advanced critical care monitoring and support, spontaneous recovery from ALF has increased from 15% to 40%. The introduction of liver transplantation improves survival to 60%, though deciding who will benefit from transplant remains problematic. Selection of patients for orthotopic liver transplantation (OLT) for ALF attempts to identify those least likely to have spontaneous recovery. Allografts remain a precious resource and the 1-year survival for those transplanted for ALF is less (60% to 80%) than those transplanted for chronic disease (80% to 90%). Multiple systems have been developed to help determine who is likely to have spontaneous recovery from ALF and while no system is flawless, the King’s College criteria are the most widely accepted in predicting death/need for transplantation (Table 3).
TABLE 3. King’s College Criteria
Surgical Approach
Liver transplantation is a highly coordinated, multidisciplinary endeavor. Explanation regarding U.S. policy on organ allocation, donor hepatectomy, and organ preservation is beyond the scope of this chapter. The remainder will briefly describe the techniques of recipient hepatectomy and engrafting (Table 4).
TABLE 4. Key Technical Steps and Potential Pitfalls to Orthotopic Liver Transplantation
Bicaval Liver Transplantation
OLT classically utilizes a bicaval technique, using vena cava interposition, and consists of the recipient hepatectomy followed by engraftment of the donor liver. Exposure is gained through a bilateral, subcostal incision with an upper midline extension—aptly referred to as the “Mercedes incision.” Following inspection for any contraindication to transplant (i.e., extrahepatic malignancy), the ligamentous attachments of the liver can be divided for an unobstructed view of the porta hepatis. Essential dissection of the porta includes isolation and division of the common hepatic artery, common bile duct and portal vein.
With the liver free from ligamentous attachments, the retrohepatic cava can be encircled and clamped to gain vascular control. Division of the suprahepatic and infrahepatic vena cava frees the specimen, which can be removed from the operative field. The donor allograft, which has been prepared on the back table during the recipient hepatectomy, is then introduced into its orthotopic position in the right, upper quadrant. Anastomosis of the supra- and infrahepatic vena cava is performed using nonabsorbable, monofilament suture in a running fashion. As the infrahepatic caval anastomosis is nearing completion, the portal vein is flushed with either normal saline or lactated ringers solution to clear the graft of air and intravascular perfusate. Following completion of the portal anastomosis, if there is no evidence of bleeding, the bicaval clamps can be removed and the graft reperfused with portal circulation.
Depending on the arterial anatomy of the donor, the recipient hepatic artery is typically anastomosed at the junction of the gastroduodenal artery. Principles utilized during the venous anastomoses are adhered to for arterialization. Finally, the bile duct is reconstructed either primarily or via a Roux-en-Y biliary enterostomy.
Caval Preservation Techniques
The “piggyback” technique of OLT is an alternative method of venous reconstruction that obviates the need for venovenous bypass. Improvements in hemodynamic stability are achieved by keeping the retrohepatic cava in place, thus allowing increased venous return during the case. Instead of encircling the supra and infrahepatic cava during the recipient hepatectomy, the hepatic veins are isolated and ligated. A cloaca is then fashioned from the divided hepatic veins to receive the donor suprahepatic cava. After oversewing the infrahepatic donor vena cava, the remainder of the case proceeds as in the classic technique. The addition of a temporary portocaval anastomosis to the piggyback techniques is often employed. This improves hemodynamic stability and decreases mesenteric congestion during the anhepatic phase of the operation.
Split Liver Transplantation
Given the shortage of quality allografts for transplant, the utilization of split livers has become an important method to meet recipient demand. The liver is typically divided at the falciform ligament with the left lateral section going to a child and the remaining portion going to an adult. Utilization of this method requires an optimal graft and is not recommended in the setting of steatosis or extended criteria donors.
Special Intraoperative Considerations
Venovenous Bypass
Some centers that utilize the classic bicaval technique will bypass routinely, while others selectively. Centers that use venovenous bypass selectively have specific indications for bypass including hypotension following test clamp of the vena cava despite appropriate volume resuscitation, significant intraoperative mesenteric or intestinal edema, or fulminant hepatic failure. Venovenous bypass decompresses the splanchnic circulation while preserving cardiac preload from the lower extremities during the anhepatic phase. Cannulation of the femoral vein by Seldinger’s technique bypasses systemic venous return from the lower extremities, which is received by the intrajugular vein. Likewise, the portal vein may be cannulated to bypass the portal venous system.
Portal Vein Thrombosis
Cases of thrombosed portal veins may be encountered frequently during the recipient engrafting and require special consideration. In the majority of cases, a portal endovenectomy can be performed to restore adequate inflow via the portal vein. When a thrombectomy or an endovenectomy cannot be performed, donor iliac veins vessels provide a suitable conduit, which can be anastomosed to the recipient superior mesenteric vein to bypass the thrombosis.
Aberrant Arterial Anatomy
Replaced hepatic arteries occur in 15% to 20% of the general population and require construction of a common inflow channel to receive the recipient hepatic artery. During the donor hepatectomy, iliac vessels are harvested should aberrant anatomy require vascular reconstruction in the recipient. Should the inflow be insufficient from the recipient, donor iliac vessels can also be used to fashion a conduit from the native aorta to the donor liver.
Biliary Considerations
Often the recipient bile duct is not suitable for end-to-end anastomosis, which can present an intraoperative challenge. In such circumstances, a Roux-en Y choledochojejunostomy should be fashioned to complete the biliary reconstruction. Patients with primary biliary disorders (e.g., primary sclerosing cholangitis) will also require a biliary–enteric anastomosis to avoid using a diseased recipient bile duct.
Postoperative Management
Attention in the early postoperative period is focused on graft function. Signs that the new liver is working include production of bile in the operating room, ability to wean vasopressor support, awakening from anesthesia, clearance of lactic acidosis, and normalization of liver function tests. Within the first 24 hours, the serum transaminases will be elevated but then should trend toward normal. Additionally, one should appreciate normalization of INR and resolution of hypoglycemia as the graft begins to assume its synthetic and endocrine functions. Deviations from the typical postoperative course should be taken seriously and evaluated fully.
Allograft Dysfunction
Functional delays from donor steatosis or prolonged preservation times can be anticipated in some cases following OLT. This, however, must be distinguished from structural problems. Whereas functional delays typically respond to supportive measures, structural problems are often related to vascular complications, which only worsen and have the potential to jeopardize the allograft. Failure to clear neurologically, hemodynamic instability, increasing liver function tests, and hypoglycemia are signs of graft dysfunction that deserve full evaluation.
Vascular Complications
Vascular complications following OLT can be devastating and are related to either inflow or outflow problems. Complications with hepatic inflow typically stem from either hepatic artery or portal vein thrombosis. Many centers routinely examine the liver with Doppler ultrasound 24 hours postoperatively to assess vessel patency, although rising serum transaminases should alert the clinician to the possibility of thrombosis. Early portal vein thrombosis or hepatic artery thrombosis (HAT) should prompt surgical exploration when detected. However, successful thrombectomy and restoration of allograft function is difficult and these patients usually require early retransplantation. Allografts that are salvaged are at increased risk of biliary complications and cholangiopathy following HAT as the blood supply to the bile duct is potentially compromised. Hepatic outflow problems produce a Budd-Chiari–like syndrome. Acute presentations elevate transaminases and cause hepatic congestion, whereas chronic obstruction presents with ascites and portal hypertension.
Case Conclusion
The patient was listed for liver transplantation emergently (Status 1 listing). A donor organ became available within 48 hours, and the patient underwent OLT using a bicaval technique. Her mental status normalized within 3 days, and she remains clinically well now 3 years following transplant.
TAKE HOME POINTS
· Coagulopathy in the setting of recent onset of jaundice should raise the clinical suspicion for hepatic dysfunction and/or impending failure.
· Development of encephalopathy in a patient with acute hepatic dysfunction should prompt transfer to an intensive care unit in a hospital with a liver transplant program.
· OLT is a technically demanding operation that requires adaptability and ingenuity to reconcile disparities in donor–recipient anatomy.
SUGGESTED READINGS
Koffron A, Stein JA. Liver transplantation: indications, pretransplant evaluation, surgery, and posttransplant complications. Med Clin North Am. 2008;92(4):861–888, ix.
Lee WM. Acute liver failure. N Engl J Med. 1993;329(25): 1862–1872.
Stravitz RT. Critical management decisions in patients with acute liver failure. Chest. 2008;134(5):1092–1102.
Trey C, Davidson CS. The management of fulminant hepatic failure. Prog Liver Dis. 1970;3:282–298.
Vaquero J, et al. Complications and use of intracranial pressure monitoring in patients with acute liver failure and severe encephalopathy. Liver Transpl. 2005;11(12):1581–1589.