EM@3AM: Liver Transplant Complications

Answer: Hepatic artery thrombosis. Differential for liver complications post-transplant should include infection, organ rejection, transplant medication side effects, hepatic artery thrombosis or stenosis, and bile strictures, leaks, and bilomas.

Epidemiology

• There are ~100,000 living liver transplant patients as of 2020²
  • 2nd most common solid organ transplantation behind renal transplants
  • 2020— 8907 transplants performed and 12,800 newly waitlisted patients
    • 8,416 from deceased and 491 from alive persons
  • Alcoholic liver disease is the most common cause for transplantation in US adults²
  • Biliary atresia is the most common cause for transplantation in US children³
  • One year survival post-transplant is approximately 93.6%²
    • Highest mortality post-transplant attributed to infections⁴
•  One study following liver transplant patients found that probability of ED visits and admissions were 43.6% and 49% at 1 year post op, respectively⁵

Anatomy

Image 2: Illustration of surgical anastomosis sites during liver transplant surgery⁶

• Donor liver takes place of diseased liver
• Surgical complications can occur at any site of anastomosis
• Anastomoses are used between the donor and recipient:
  • Upper/lower IVC
  • Hepatic artery
  • Portal vein
  • Biliary ducts
    • Modifications include hepaticojejunostomy/choledochojejunostomy

Complications

• Complications specific to liver transplant patients as opposed to other types of transplants are typically mechanicaland related to vascular or biliary complications
• Vascular Complications
  • Hepatic artery is the main blood supply to biliary epithelium
    • Biliary ischemia will lead to bilomas, which are collections of bile outside of the biliary tree, strictures, and leaks⁷
  • Hepatic artery thrombosis
    • Early thrombosis period within approximately two months post-op⁷
      • Incidence in adults approximately 4.4%, in children (8.3%)⁸
      • Devastating effects with >50% requiring retransplant and >30% mortality^9,10
      • Presentation may display signs of fulminant liver failure
    • Late thrombosis starts after one month and can be a more mild in presentation, can result with biliary complications^11,12
    • Doppler ultrasound will show absent/low flow in hepatic artery
      • In early hepatic artery thrombosis within 7 days post-op, sensitivity reaches close to 100%¹⁰
      • Sensitivity decreases over time or with late thrombosis
      • Findings should be confirmed with contrast ultrasound or CTA
    • Findings of CTA will show narrowing or occlusion of hepatic artery¹³
      • Sensitivity upwards of 90%¹⁴
  •  Hepatic artery stenosis
    • Presentation of stenosis is more similar to that of delayed thrombosis⁷
    • Most common vascular complication post-op ranging from 5-13%¹¹
    • Doppler US has lower sensitivity at around 70% sensitivity showing high peak velocity^15,16
      • CTA may be needed if high index of suspicion or if doppler is inconclusive
  •  Hepatic pseudoaneurysm
    • Incidence is rare–around 0.6-2.3%
    • May be an incidental finding on imaging or present with severe intra-abdominal hemorrhage¹⁷
    • US will show cystic structure arising from hepatic artery with disorganized flow on doppler¹⁸
    • CTA will show increased contrast uptake in cyst-like structure¹⁵
•  Biliary complications
  • Biliary complications affect approximately 5-32% of liver transplant patients¹⁹
    • Associated mortality ~10%²⁰
  • Commonly present with RUQ pain, sometimes with fever and pain¹⁵
  • Clinically significant as these can lead to cholangitis, liver dysfunction, hyperbilirubinemia
  • Doppler ultrasound has high positive predictive value in the presence of dilated biliary ducts, however has low sensitivity of 38%-66%^15,19,21
    • MRCP has a much higher sensitivity²² (96%) and specificity (94%) at detecting biliary complications^15,23
  • Strictures
    • May be anastomotic (more common) or non-anastomotic which may be secondary to a vascular complication like hepatic artery thrombosis
    • Stenting is treatment +/- ballooning^7,24
  • Bile Leaks
    • Occur in up to 20% of transplants²⁴
    • Most commonly at anastomosis, can occur elsewhere with ischemia or obstruction^7,24
    • Bilious ascites should raise suspicion¹⁹
    • Findings of biliary leakage seen on cholangiography MR/ERCP^7,19
  • Other complications include sphincter of oddi dysfunction and bilomas
•  Other common complications for transplant patients in general include:
  • Infection
    • Primary cause of death in liver transplant patients²⁵
      • Nosocomial/surgical present <1month post-transplant
      • Peak immunosuppression/opportunistic infections 1-6 months
      • Community acquired generally >6 months¹⁵

Table 1. Infections to Consider in Liver Transplant Patients^15,26

• Rejection
  • Allografted livers has a higher immunologic tolerance compared to other transplanted organs²²
    • Anti-inflammatory response to lipopolysaccharide, which exhausts active T-cells and generates regulatory T-cells
  • Most commonly occurs within the first 90 days²⁵
  • May present similar to the above complications, however diagnosis made with liver biopsy²⁶
  • Ask if patient is compliant with taking medications, or if recent changes were made to immunosuppression therapy²⁵
• Medication complications
  • Consider patient’s immunosuppressive agents
    • Side effects or medication interactions may be present
  • Symptoms may range from renal dysfunction, anemia, metabolic syndrome, GI symptoms^15,25

Table 2. Common Immunosuppressive Agents in Transplant patients^15,25

Clinical Presentation

• A study of 290 liver transplant recipients revealed the most common presenting complaint to be GI related such as nausea, vomiting, or abdominal pain^25,28
  • 69% of these patients were hospitalized
• Symptoms of allograft dysfunction from above complications range from asymptomatic to severe cholangitis to fulminant liver failure
• Jaundice, dark urine, abdominal pain, pruritus, or fatigue may point towards allograft disfunction or rejection

Evaluation

• It is imperative to obtain a detailed history e.g. timing of transplant, prior complications
  • Associated symptoms of allograft rejection include jaundice, fever, nausea, vomiting, diarrhea, abdominal pain, dark urine, edema²⁵
• Laboratory testing should include at least CBC, CMP, INR²⁵
  • Look for elevated INR, elevated LFTs, thrombocytopenia, elevated bilirubin
  • Other helpful tests depending on presentation include hepatitis panel, tacrolimus trough
  • ESR/CRP have limited utility unless historically trended²⁵
• Lack of fever does not rule out infection^15,28
  • Infection may present with leukocytosis or leukopenia
• Imaging
  • Physicians should have a low threshold for imaging, especially with lab abnormalities
  • Doppler US is helpful for detecting vascular/biliary complications
    • Cons: user dependent, low sensitivity in some circumstances^15,19,17
    • CT with contrast or CTA have higher sensitivities^{7, 14}
  • Admitted patients may need MR/ERCP for definitive diagnosis

Treatment

• There should be a low threshold to contact patient’s transplant team
• Reduced dosages of acetaminophen may be used for pain control, granted the patient is not showing signs of live failure
  • Opiates (fentanyl and hydromorphone preferred) may also be used for pain control, however reduce dosages/frequency to avoid accumulation
  • Avoid NSAIDs, as patients on immunosuppressives are at high risk of AKI
• Cultures, broad spectrum antibiotics if concerned for systemic infection²⁵
• Biliary/artery stenosis may need ERCP/stenting⁷
• Arterial thrombosis/stenosis may require IR/vascular surgery consultation²⁵
• Bile leaks may require surgical consultation or stenting⁷
• Rejection may require IV methylprednisolone 500 to 1000 mg IV initial dose¹⁵

Disposition

• Liver transplant patients are at a high risk of admission²³
• Early consultation with patient’s transplant surgery/hepatobiliary team

Pearls

• US is a great first line imaging tool for these patients, however CT may be necessary
• Contact the patient’s transplant/hepatobiliary team early in the ED course
• Perform a detailed history/exam, as allograft dysfunction has a broad range of symptoms
• Hepatic artery thrombosis is much more common in children, and has devastating consequences
• Allograft complications can occur at every site of anastomosis

A patient with hepatocellular carcinoma secondary to chronic hepatitis C infection underwent an orthotopic liver transplantation. He presents to the clinic reporting episodes of fever and abdominal pain 5 months later. A CT scan shows ductal dilation and a liver abscess. What is the most likely cause of this patient’s presentation?

A) Acute rejection

B) Biliary anastomosis stricture

C) Hepatic artery thrombosis

D) Portal vein thrombosis

Answer: C

This patient likely has a stricture of the common bile duct and liver abscesses. The blood supply to the common bile duct comes from the hepatic artery. Hepatic artery thrombosis is a dreaded complication of liver transplantation resulting in stricture of the duct. Although the liver has a dual blood supply with the portal vein and hepatic artery, thrombosis of the hepatic artery can result in hepatic parenchymal necrosis, which can later turn into an abscess. Hepatic artery thrombosis is managed conservatively with antibiotics for patients with bacteremia and percutaneous drainage for liver abscesses, but retransplantation is usually required.

Acute rejection (A) following liver transplant is uncommon and less likely than hepatic artery stenosis as the etiology of bile duct stricture and abscess formation. Biliary anastomosis stricture (B) as the result of a technical error is possible but will usually manifest immediately after surgery with obstructive cholangiopathy. Portal vein thrombosis (D) presents with signs and symptoms of portal hypertension, including encephalopathy and varices. It does not cause biliary stricture.