Liver transplantation: indications/evaluation

How can I be sure that the patient has sufficient indications for liver transplantation?

Patients that are candidates for liver transplantation have either acute or chronic end-stage liver disease. Manifestations of end-stage liver disease include synthetic dysfunction, inflammatory activity, and complications of portal hypertension.

1. Coagulopathy. Prolongation of the prothrombin time and international normalization ratio (INR) due to decreased synthesis of vitamin K-dependent factors.

2. Jaundice/Icterus. Yellow discoloration of the skin/sclerae and mucosa due to abnormalities in the uptake, conjugation, or secretion of bilirubin.

3. Elevation of aminotransferases (transaminases). This elevation translates into continued inflammatory activity and hepatocyte dysfunction and death.

4. Fluid retention.Due to the imbalance in the activity of the renin-angiotensin-aldosterone system, as well as splanchnic vasodilation, resulting in the accumulation of peripheral fluid (edema) and fluid in the peritoneal cavity (ascites). Right-sided pleural effusions (hepatic hydrothorax) can occur.

5.Gastrointestinal bleeding secondary to the development of portal hypertension. The increased resistance to blood flow through the liver forces the blood through collateral circulation in the gastric, esophageal, and azygos territory, forming dilated vessels in these areas (varices). Varices can also form in the duodenum and in the hemorrhoidal plexus, forming ectopic varices and hemorrhoids

6. Encephalopathy. Neuropsychiatric changes caused by failure of the liver in clearing protein by-products, such as ammonia. Ammonia penetrates the blood-brain barrier and, once in the central nervous system, it acts as a false neurotransmitter, causing neuropsychiatric changes that may progress from confusion and lethargy to frank somnolence and coma. Encephalopathy is divided in four grades: grade I being confusion and grade IV, coma.

A tabular or chart listing of features and signs and symptoms

End-stage liver disease is a general indication for liver transplantation. The causes of end-stage liver disease are varied, and include the following:

• Chronic viral hepatitis: hepatitis B, C, and D

• Alcohol-induced cirrhosis (Laennec’s)

• Autoimmune hepatitis

• Cholestatic liver disease: primary sclerosing cholangitis, primary biliary cirrhosis

• Metabolic and genetic liver disease: Wilson’s disease, hemochromatosis, alpha one antitrypsin deficiency, nonalcoholic steatohepatitis, and some glycogenoses

• Fulminant liver failure of diverse etiology: acetaminophen, viruses, prescribed and over-the-counter drugs

• Neoplasia: hepatoblastoma, hepatocellular carcinoma, and biliary tract malignancies

Criteria for liver transplantation are based on the Model of End Stage Liver Disease Score (MELD score). This score is based on a mathematical model that takes into account total bilirubin, INR, and creatinine. Originally designed to predict survival of patients after transjugular intrahepatic portosystemic shunt (TIPS), MELD score has been shown to predict a 3-month survival in patients with end-stage liver disease. It is considered that patients with less than 15 MELD points have a better survival with their native liver, and it is the minimal score required for listing as a liver transplant candidate.

How can I confirm the diagnosis?

Almost all patients with end-stage liver disease have abnormal liver function tests: hyperbilirubinemia, elevated aminotransferases (AST and ALT), elevated alkaline phosphatase (in cholestatic liver disease, alkaline phosphatase predominates), hypoalbuminemia with normal or elevated globulins, prolongation of prothrombin time and INR.

The physical examination reveals various signs of chronic liver failure: muscle wasting, jaundice, ascites, peripheral edema, spider angiomata, hepatomegaly, splenomegaly, encephalopathy, and gastrointestinal bleeding.

Clinical signs. When end stage liver disease is advanced, the diagnosis can be made on a clinical basis. If the disease is not advanced, the clinical signs can be subtle and patients can be asymptomatic. In these cases, diagnosis has to be based on the result of a liver biopsy and/or selective imaging studies. Recently, ultrasound based transient elastography has been approved for the diagnosis of hepatic fibrosis in certain etiologies of chronic liver disease (viral chronic hepatitis and non-alcoholic steatohepatitis).

In liver disease, the biochemical changes vary, depending on and whether the liver injury is acute or chronic.

1. Hepatocellular inflammatory activity is typically expressed by elevation of both aminotransferases. Depending on the etiology of the liver disease, one of the aminotransferases might predominate. Acute liver injury such as that caused by hepatitis, drug injury, or ischemia can result in a marked elevation of transaminase levels. Chronic liver injury often presents with fluctuating lower levels of enzyme elevations. This pattern is reflective of fatty liver disease, alcoholic injury, and nonalcoholic fatty liver disease.

2. Alkaline phosphatase elevations reflect obstruction of the bile flow through the liver canaliculi and are common in patients with cholestatic liver disease, primary sclerosing cholangitis (PSC), and primary and secondary biliary cirrhosis. In these instances, gamma-glutamyl-transpeptidase (gGT) parallels the alkaline phosphatase elevation and in some instances, such as early stages of primary biliary cirrhosis (PBC), can be the only enzyme that stays elevated.

3. Synthetic dysfunction is characterized by a low concentration of plasma proteins, the most important being albumin. Coagulation proteins, mainly those that require vitamin K for synthesis, are particularly affected — resulting in prolongation of the prothrombin time and INR.

4. Hyperlipidemia can be prominent in cholestatic liver disease. Striking elevations of serum cholesterol is often a feature of primary biliary cirrhosis.

5. Hepatocellular carcinoma (HCC) is a complication of chronic liver disease of almost any etiology. The present consensus is to survey with liver ultrasound every 6 months. In the U.S.,alpha-fetoprotein (AFP) elevations occur in approximately 50% of all cases of HCC. Serial determinations of this marker are important in monitoring individual cases.

Histologic diagnosis. In cases of acute liver failure, because it is a disease that presents in patients with previously healthy liver, the histologic diagnosis is based in the presence of more than 60% hepatocyte necrosis. With few exceptions, histologic confirmation is not required for a secure diagnosis of acute liver failure. The hallmark of acute liver failure is the presence of encephalopathy.

Radiology. The patient with end-stage liver disease that is being considered for a liver transplant should have images of the liver and its vasculature.

1. Abdominal ultrasound (US). This is a noninvasive method to document liver size, morphology, vascular patency (when Doppler technique is included), and presence of masses within the hepatic parenchyma.

2. CAT scan. The tri-phase technique (arterial, portal, and delayed imaging) is very useful when a mass, specifically HCC, is suspected in the liver transplant candidate and cannot be confirmed by US.

3. Magnetic resonance imaging (MRI) can confirm the presence of a malignancy in the liver parenchyma. The characteristics of HCC show isointensity in T1 sequences and hyperintensity in T2 sequences and delayed washout after arterial contrast enhancement.

Endoscopy. Patients with end-stage liver disease have portal hypertension as a complication of their chronic condition. This can be documented by esophago-gastroduodenoscopy. The findings supporting this diagnosis are esophageal varices in the two lower thirds of the esophagus, congestion of the gastric mucosa (seen as a “reticular” or a “snake skin” mucosal pattern), and varices in the fundus of the stomach. All of these abnormalities are distributed in the territory supplied by the portal vein.

Colonoscopy must be carried out in all patients that fulfill accepted screening criteria or belong to high risk categories.

Laboratory tests, radiographic studies, and endoscopic evaluations

Tests to evaluate indications for end-stage liver disease and liver transplantation include the following.

Laboratory: Liver function tests – increased bilirubin. In cases where the conjugating capabilities of the liver are compromised, a predominance of nonconjugated fraction can be seen. Increased AST and ALT are the biochemical hallmark of hepatocellular inflammation. Increased alkaline phosphatase, normally accompanied by increased gGT, indicates the presence of cholestasis.

1. A metabolic panel is mandatory. Serum creatinine is a major determinant in the MELD scoring system. Creatinine is a marker of muscle mass and kidney function. The presence of muscle wasting with the resultant lower serum creatinine should be taken into account when interpreting glomerular filtration rate (GFR).

2. Diabetes mellitus is associated with increased morbidity and mortality after liver transplantation. Therefore, optimum glucose control is required in patients who are candidates for liver transplantation.

3. It is not unexpected to find pan-cytopenia in patients with chronic liver disease because a large proportion of this population has associated splenomegaly and hypersplenism. A complete blood count is mandatory.

Radiology. US can show a nodular appearance of the liver surface and heterogeneity of the parenchymal echotexture, presence of nodules, and increased velocity in the blood flow of the portal vein or hepatic artery. US can also suggest the presence of liver neoplasms and lack of blood flow in the portal system or hepatic veins. If the findings of the US are abnormal, further evaluation with CAT scan or MRI is necessary.

Vaccination. The individuals considered for liver transplant should be immune to hepatitis A (HAV) and hepatitis B (HBV); vaccination against these viruses should be provided as part of the evaluation. Also immunization against pneumococcus is recommended in the pre-transplant period.

Cardiac evaluation/CAD. The patients considered for liver transplantation should also have a cardiac evaluation that should include an echocardiogram to evaluate the ventricular ejection fraction. Ideally the left ventricle, ejection fraction (LVEF) should be above 60%. The presence of systemic hypertension, diabetes mellitus and obesity should be carefully evaluated to rule out pre-existing coronary artery disease (CAD). Patients with CAD should have a full evaluation by cardiology. The extent of the evaluation will depend on the potential cardiac risk factors presented by each candidate. The adequacy of blood pressure control and recommendations for improved control is very important to the evaluation process.

1. In patients 55 years or older and/or in patients at increased risk for CAD, more specialized tests of coronary artery structure and function should be considered.

Endoscopic evaluation. Endoscopic evaluation of the upper digestive tract is important in patients with portal hypertension to confirm the presence of esophageal varices, portal hypertensive gastropathy, and/or fundic varices. When treatment is necessary, specifically in the presence of large esophageal varices or a history of GI bleeding, endoscopic banding is the treatment of choice. This technique carried out in one to four sessions can eradicate the esophageal varices.

What other diseases, conditions, or complications should I look for in patients who are candidates for liver transplantation?

All cases of patients with end-stage liver disease who are evaluated for liver transplantation should be discussed by the whole liver transplant team, which includes the transplant hepatologist, transplant surgeon, nurse coordinator, psychologist and/or psychiatrist, social worker, financial adviser, and pharmacy specialist. The aim of this discussion is to determine if the patient is an adequate candidate for receiving a liver transplant. At this point, other diseases that might constitute a contraindication for the procedure should be ruled out. Some of these diseases are not absolute but relative contraindications, and all of them should be resolved or controlled prior to listing.

Pulmonary. All candidates are evaluated by the pulmonary team. Screening pulmonary function tests are routine. The presence of pulmonary hypertension mandates detailed estimates of pulmonary pressures. If pulmonary hypertension is present, the degree of hypertension and the potential for reversibility must be determined prior to listing. An echocardiogram is useful in the evaluation of pulmonary pressure. The mean pulmonary pressure is expected to be below 35 mmHg. Higher mean pulmonary pressures are associated with poor prognosis and high mortality rates after the transplant. When pulmonary pressures are in a “gray area”, between 35 and 40 mmHg, right heart catheterization is in order to determine the actual pulmonary pressures.

Hepatopulmonary syndrome. The pathophysiology of this syndrome is associated with the presence of pulmonary vasodilatation and presence of intrapulmonary shunts. Hepatopulmonary syndrome is reversible after liver transplantation.

Diabetes mellitus. A careful estimate of glycemic control and its effect on post-transplant morbidity and mortality is central to determining the potential for listing of the candidate.

Chronic renal disease. Patients with end-stage renal disease should be considered as potential candidates for combined liver/kidney transplantation. The calcineurin inhibitors are immunosuppressant agents with nephrotoxic potential.

Hepatorenal syndrome. The pathophysiology of this syndrome is associated with hepatic and circulatory dysfunctions that can be reversed by liver transplantation itself, although approximately 20% of the patients with this complication have residual kidney disease after the liver transplant.

Complications after liver transplantation

Complications can be divided in two main groups: (1) surgical and (2) medical complications.

1. Surgical. Surgical complications include biliary leaks and fistulas, biliary stenosis, hepatic artery thrombosis, or anastomotic dehiscence. Primary nonfunction or delayed function can be precipitated by factors inherent to the graft or by prolonged cold and warm ischemia times and reperfusion injury. The small-for-size syndrome is more prevalent if a living donor is used and is related to the use of less-than-optimal amounts of liver parenchyma for the procedure.

2. Medical. The medical complications can be of diverse etiology. Immunosuppression can lead to opportunistic infections as well as primarily bacterial infections attributed to the immediate post-transplant period. These usually occur within the first 6 months post-surgery. Infections that occur after the first year are usually community acquired. Immunosuppression is associated with the development of hypertension and hyperglycemia. De novo cancer appearance, particularly skin cancer as the result of immunosuppression, warrants careful surveillance. Recurrence of the primary liver disease occurs in approximately 10% to 15% of transplanted patients, particularly in those transplanted for PBC, PSC, and autoimmune hepatitis.

3. Hepatitis C. Hepatitis C deserves a separate comment. This is the most common cause of chronic liver disease in the western hemisphere. Infected patients who receive a liver transplant historically have a 100% reinfection rate and up to 65% of them might present with different stages of progressive disease including cirrhosis. With the recent introduction of direct acting antivirals (DAA), the most recent recommendations for the treatment of hepatitis C from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Disease Society of America specifically addresses the viral genotype to guide the therapy to reach more than 96% sustained viral response rate in patients with no previous treatment (treatment naïve).

The guidelines do not recommend the use of Pegylated interferon in combination with ribavirin or the use of first generation direct acting antivirals: Bocepevir and Telaprevir. See Table I.

Table I.n

The following treatments are not recommended for treatment naïve patients:

• a) PEG IFN and RBV for 24 to 48 weeks

• b) Monotherapy with PEG IFN, RBV or DAA

• c) Telaprevir or boceprevir-based regimens in patients with genotype 3 HCV

The role of other DAA like Ledipasvir is yet to be determined.

4. Hepatitis B is a disease that requires continuous treatment from the early post-transplant period with hepatitis B immune globulin combined with nucleoside or nucleotide analogs.

What's the evidence?

Lucey, MR, Brown, KA, Everson, GT. “Minimal criteria for placement of adults on the liver transplant waiting list: a report of a national conference organized by the American Association for the Study of Liver Diseases”. Liver Transpl Surg. vol. 3. 1997. pp. 628-37.

Malinchoc, M, Kamath, PS, Gordon, FD. “A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts”. Hepatology. vol. 31. 2000. pp. 864-71.

Morel, B, Dufour, JF. “Liver transplantation − when and for whom it should be performed”. Ther Umsch. vol. 68. 2011. pp. 707-13.

Martinez-Palli, G, Cardenas, A. “Pre-operative cardio pulmonary assessment of the liver transplant candidate”. Ann Hepatol. vol. 10. 2011. pp. 421-33.

Bozbas, SS, Eyuboglu, F. “Evaluation of liver transplant candidates: a pulmonary perspective”. Ann Thorac Med. vol. 6. 2011. pp. 109-14.

Alqahtani, SA, Larson, AM. “Adult liver transplantation in the USA”. Curr Opin Gastroenterol. vol. 27. 2011. pp. 240-7.

Lawitz, E, Mangia, A, Wyles, D. “Sofosbuvir for previously untreated chronic hepatitis C infection”. N Engl J Med. vol. 368. 2013. pp. 1878-1887.

Jacobson, IM, Ghalib, RH, Rodriguez-Torres, M. “SVR results of a once-daily regimen of simeprevir (TMC435) plus sofosbuvir (GS-7977) with or without ribavirin in cirrhotic and non-cirrhotic HCV genotype 1 treatment-naïve and prior null responder patients: The COSMOS study. Hepatology: Special Issue: The 64th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2013”. vol. 58. 2013. pp. 1379A

Jacobson, IM, Gordon, SC, Kowdley, KV. “Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options”. N Engl J Med. vol. 368. 2013. pp. 1867-1877.

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