Mitochondrial diseases are genetic, often inherited, chronic disorders in which mitochondria fail to generate sufficient energy, causing cell death and organ dysfunction. They are caused by mutations in either mitochondrial DNA or nuclear DNA that encodes for mitochondrial constituents. Mitochondrial diseases vary widely in presentation and can manifest almost anywhere in the body, including cells of the brain, nerves, muscles, kidneys, heart, liver, eyes, ears and pancreas.
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Disease onset may have varying presentations and can occur at any age. Indications vary by affected organ(s) and severity, making diagnosis difficult and requiring physicians with experience in mitochondrial disorder to help navigate the diagnosis.
In this complex case, the immediate complications of what would later be confirmed as mitochondrial disease required Cleveland Clinic Children’s specialists to perform not one, but two, transplants that saved a young patient’s life.
A 3-year-old girl was referred to Cleveland Clinic Children’s with jaundice and abdominal distention. Liver function tests indicated elevated enzyme levels, with aspartate aminotransferase much higher than alanine aminotransferase.
“We couldn’t identify a cause for her acute liver failure, such as an autoimmune disease, infection or other genetic or metabolic causes,” says Cleveland Clinic Children’s pediatric gastroenterologist and hepatologist Kadakkal Radhakrishnan, MD, a member of the pediatric liver transplant team. “But we knew her condition was deteriorating quickly. We had to move fast to prepare her for liver transplant.”
A liver biopsy suggested mitochondrial depletion, which along with the abnormal pattern of her liver enzyme levels caused Dr. Radhakrishnan to suspect mitochondrial disease. An abnormal echocardiogram further supported his hypothesis.
Within 48 hours, the child was listed for liver transplantation and the search for a living donor began. However, because the patient was prioritized on the wait list due to the severity of her liver disease, she was matched with a deceased donor within six days.
Through a split-liver transplant, the child received the left lateral segment, which accounted for 20% of an adult liver.
One of the challenges in pediatric liver transplantation is the severe shortage of size-matched pediatric deceased donors, which increases the risk of waitlist mortality.
“Split-liver transplantation and living-donor liver transplantation can create a size-matched liver graft for small children from an adult donor,” says Koji Hashimoto, MD, PhD, Director of Pediatric Liver Transplantation and Living-Donor Liver Transplantation, who performed this patient’s split-liver transplant with Cristiano Quintini, MD, Cleveland Clinic’s Director of Liver Transplantation. “With the options of split-liver transplantation or living-donor liver transplantation, we can save sick children before they die or become too sick for transplant.”
In this case, thanks to close communication between donor and recipient transplant teams, the graft was accurately sized for the recipient.
The donor team performed an in situ split, which required special surgical expertise for the liver resection and transplant but allowed the organ to remain perfused until it was completely divided into two grafts.
“The shorter the ischemic time from donor to implant, the better the quality of the graft,” says Dr. Hashimoto. “We always try to maximize our chances of success. We began the recipient’s surgery as soon as we were notified that the donor liver was ready to go.”
Transplanting partial liver grafts into pediatric recipients brings additional challenges. The major vessels and bile duct are much smaller than in adult transplantation. Reattaching them requires experience and detailed suturing.
Following the surgery, the patient was transferred to the pediatric intensive care unit for monitoring to ensure her vital signs remained stable. She immediately began an immunosuppression regimen.
During this time, genetic testing on her native liver enabled a definitive diagnosis of mitochondrial disease.
Heart transplant and beyond
Days after liver transplant, the patient’s cardiac dysfunction — which had been detected soon after her admission to Cleveland Clinic Children’s — became more pronounced. She was readmitted to the pediatric intensive care unit with acute heart failure secondary to mitochondrial disease.
As her heart function continued to deteriorate, she was listed for heart transplant. A donor was identified and the heart transplant was performed three months after the patient’s liver transplant.
“The patient had been so sick and debilitated prior to her liver transplant that she recovered surprisingly quickly from the heart transplant,” says cardiologist Gerard Boyle, MD, Medical Director of Pediatric Heart Failure and Transplant. “Her recovery has been right on course.”
Three years later, the patient is an active 6-year-old who attends kindergarten. Weekly exams and blood tests monitor her heart and liver function.
“Her prognosis is good at this point,” says Dr. Radhakrishnan. “She is developing normally. There is no evidence of other organ dysfunction, although we’re watching closely.”
Because mitochondrial DNA in the donor liver and heart appear normal, the patient is unlikely to have future liver or heart failure due to mitochondrial disease.
The impact of mitochondrial disease on the patient’s other organs is yet to be determined.
“It is possible she could develop other organ dysfunction, but that was not — and should not be — a deterrent for transplantation,” says Dr. Radhakrishnan. “If we had not performed the liver and heart transplants, we would not have this child who has been thriving for the last three years. However, the decision to transplant patients in similar situations need to be well thought out.”
Patients with devastating illnesses, such as mitochondrial disease, receive the best outcomes from a multidisciplinary team that can provide coordinated care, including expert diagnosis and novel treatments, Dr. Radhakrishnan says.