Overall Bottom Line

Routine monitoring of liver tests throughout the early and late post-transplantation period is essential in screening for allograft dysfunction.
Many causes of graft dysfunction including rejection and hepatic artery thrombosis do not cause symptoms.
Liver test elevations are usually the first indication of a problem, and early diagnosis and intervention can be crucial in preventing graft loss.
This chapter summarizes the diagnostic approach to abnormal liver tests following transplantation.
Specific management for each diagnosis is addressed in separate chapters.

Section 1: Background

Definition of disease

The differential diagnosis of abnormal LFTs following transplantation differs depending on the time period following transplantation.

Disease classification

Time course of graft dysfunction following LT

0–3 days:	Primary graft non-function
	Hepatic artery thrombosis
	Hyperacute rejection (rare)
3–4 days:	Acute cellular rejection
	Hepatic artery thrombosis
	Bile leak, cholangitis
	Portal vein thrombosis
	Drug hepatotoxicity
14 days–3 months:	Rejection (acute)
	Recurrent HCV
	Biliary complications
	Drug hepatotoxicity
	Delayed hepatic artery thrombosis (less common after first month)
3–12 months:	Rejection (acute or chronic)
	Recurrent hepatitis C (including fibrosing cholestatic hepatitis)
	Infection: CMV, EBV, adenovirus
	Outflow obstruction
	Hepatic artery stenosis
>12 months:	Rejection (acute or chronic)
	Recurrent HCV
	Reactivation of HBV (cAb + graft)
	Biliary stricture (anastomotic or ischemic)
	Hepatic artery stenosis
	De novo autoimmune hepatitis
	Plasma cell hepatitis
	Drug hepatotoxicity
	Steatohepatitis

Etiology

Causes of abnormal liver tests after transplantation can be related to allograft integrity (primary graft non-function, delayed graft function), vascular problems (hepatic artery thrombosis, outflow obstruction), biliary problems (bile leak, biliary strictures), infections, immune reactions (allo and autoimmune) and recurrent disease.
Most biliary complications occur within the first 3–6 months following transplantation.
Infections are most likely to occur within the first year, particularly following withdrawal of prophylaxis.
Acute and chronic rejection is diagnosed by liver biopsy. The threshold to perform a liver biopsy is low in the transplantation recipient due to benefits of early intervention in improving long-term graft survival when rejection is treated in a timely manner. The risk for acute rejection is highest during the first year after transplantation, but can occur at any time. Untreated acute rejection leads to bile duct loss and chronic rejection, which can manifest as cholestatic liver test elevation with or without pruritus.
Many diseases (hepatitis C, PSC, AIH, PBC, NASH and HCC) can recur following transplantation.
Recurrent HCV can cause liver test elevations as early as within the first 2 weeks following transplantation, although clinically significant disease usually takes at least several weeks to manifest. An uncommon form of recurrent viral hepatitis called fibrosing cholestatic hepatitis can occur within the first year in patients transplanted for HCV. This is associated with jaundice, accelerated graft dysfunction and poor patient survival. Biopsy findings in the patient with recurrent HCV can overlap with rejection, making the diagnosis challenging. While recurrent HCV remains a significant clinical problem, recurrent HBV is now rare with the advent of HBIg and effective antiviral agents.

Pathology/pathogenesis

The time frame of liver enzyme abnormalities after transplantation can be helpful in determining the cause.

Early post-transplantation period (first 6 months)

Aminotransferases, bilirubin and INR should improve daily following LT. AST is generally the first hepatic enzyme to normalize. A peak AST >5000 IU/L following transplantation is associated with lower rates of patient and graft survival.
Hepatic artery thrombosis and primary graft non-function are causes of persistently abnormal tests in the first 24–72 hours following transplantation. Hepatic artery thrombosis is diagnosed using Doppler US of the hepatic artery. If Doppler evaluation is equivocal, angiography may be needed to diagnose suspected hepatic artery thrombosis.
Primary graft non-function is a clinical diagnosis based on failure of adequate bile production, hemodynamic instability, encephalopathy, and lactic acidosis in combination with abnormal liver tests (AST >3000) and coagulopathy (INR >2.5). This can occur in the setting of hepatic artery thrombosis or due to donor-related problems such as small size or prolonged ischemia time.
Hyperacute rejection, caused by preformed antibodies and complement-mediated destruction of endothelial cells followed by graft thrombosis, presents within minutes to hours following transplantation and is rarely seen. Risk factors include transplantation of an ABO incompatible graft.
Most cases of acute cellular rejection occur between 7 and 28 days following transplantation. Symptoms are absent early in the course and the only indication may be elevation of liver tests, hence the need for frequent monitoring of laboratory tests during the first month after transplantation. Diagnosis is made by liver biopsy demonstrating a triad of endothelialitis, bile duct injury and mixed inflammatory infiltrate (see Chapter 44).
Other considerations if liver biopsy does not demonstrate evidence of rejection include:
- Delayed graft function, particularly if the allograft comes from an extended criteria donor (donation after cardiac death, prolonged ischemia time, older age, steatosis >30%).
- Sepsis.
- Drug toxicity.
- Technical complications including bile leak.
Delayed hepatic artery thrombosis or hepatic artery stenosis can lead to biliary strictures, cholangitis, and hepatic abscesses. More sensitive imaging including MRCP, MRA or CT angiography may aid in diagnosis if a bile duct or hepatic artery problem is suspected despite a normal US.