Liver transplant, therapies mean longer life with hATTR, data show
60 years of records show treatments significantly improve survival
Undergoing a liver transplant and/or receiving disease-modifying treatments significantly improves survival in people with hereditary transthyretin amyloidosis (hATTR), a group of diseases that includes hATTR with polyneuropathy, or familial amyloid polyneuropathy (FAP).
Disease-modifying drugs were significantly associated with a 78% lower chance of death, while liver transplant was linked to a 61% reduced chance, according to data from a Swedish registry.
The study, “Sixty years of experience with hereditary transthyretin amyloidosis: Insights from the Swedish transthyretin amyloidosis registry,” was published in the Journal of Internal Medicine.
hATTR, also known as ATTRv, is typically caused by mutations in the TTR gene that result in the formation of a faulty transthyretin (TTR) protein, which is prone to forming toxic clumps called amyloid fibrils.
In people with hATTR with polyneuropathy, these fibrils mainly accumulate in the peripheral nerves (the nerves found outside the brain and spinal cord), causing nerve damage, or polyneuropathy. When these clumps build up mainly in the heart, the disease is called hATTR with cardiomyopathy (heart damage). People with hATTR can have both polyneuropathy and cardiomyopathy, known as a mixed phenotype.
Analyzing patient data
While there is no cure for hATTR, approved treatments, including liver transplant and medications designed to reduce TTR production, have substantially improved outcomes with the rare, progressive disease.
The researchers analyzed data from SveATTR, a Swedish web-based registry of ATTR patients. The registry was established in 2020, but includes data from a previous database that was started in the 1960s. The researchers estimated that it covers about 85% of Swedish people with ATTR.
Their analysis covered 1,055 hATTR patients who were registered up to December 2022. They were mainly men (65%), and had a mean age of 64 at disease onset and 68 at diagnosis.
Almost all (95%) carried the V30M mutation of the TTR gene, the most common FAP-causing mutation. Most (79%) had late-onset disease, meaning it occurred at age 50 or older. Polyneuropathy was the most common symptom (87% of patients), followed by heart problems (10%).
“Our study confirms that the Swedish patient cohort is characterized by late-onset ATTRV30M amyloidosis with … mixed phenotype,” the researchers wrote.
Heart problems were significantly more frequent in men (12%) than in women (7%) and in participants without polyneuropathy (37%) than in those with the condition (6%). Those with late-onset disease also had a significantly higher incidence of heart issues (12%) than those with the early-onset form (3%) and a lower frequency of polyneuropathy symptoms (86% vs. 94%).
Heart involvement was only documented in participants diagnosed from 1990 onwards and affected up to 55% of them. Overall, 122 patients, most of them men, received a pacemaker — a device used to help regulate heartbeat — as a preventive measure or to treat abnormal heart rhythm.
Some 159 participants (15%) underwent liver transplants at a median of about two years after diagnosis. Six people had heart transplants, and two received kidney transplants.
A total of 223 people (22%), 70% of them men, received disease-modifying medications. These included tafamidis (14%), diflunisal (11%), Onpattro (patisiran, 4%), doxycycline and ursodeoxycholic acid (2%), and Tegsedi (inotersen, 2%). The median time from diagnosis to initiation of the first treatment was about eight months.
Ten patients underwent liver transplants and received disease-modifying drugs.
By the end of the study, 32% of participants were still alive, with a median survival time of 11.6 years since disease onset. Median survival time was 11.5 years for men and 12.5 years for women. For people with late-onset disease, survival time was 10.4 years, compared with 21.5 years for those with early-onset disease.
The most frequent causes of death included unspecified complications of amyloidosis (39%), heart failure (15%), and infection (11%).
Statistical analyses showed that age at disease onset, polyneuropathy at disease onset, carrying a non-V30M mutation, and diagnostic period were significant predictors of mortality. Having a non-V30M variant was linked to a nearly five times higher chance of death, while not having polyneuropathy at onset was linked to a 54% higher chance.
“Patients without peripheral polyneuropathy at disease onset and patients with non-V30M variants will require tailored management to further improve their clinical outcomes,” the researchers wrote.
Compared with patients diagnosed before 1990, those diagnosed after had a lower risk of death: 35% in the 1990-2010 period and 61% in the 2011-2022 period, likely reflecting advancements in treatment strategies, the team noted.
“Future studies will hopefully be able to include most follow-up variables and present more detailed evaluations of the disease-modifying therapies,” the researchers wrote.
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