Hepatology
British expert lives for the liver
You can survive without your gallbladder or appendix, but you can’t live without your liver. The vital organ has as many as 500 functions – from the production of hormones and decomposition of red blood cells to detoxification, production of biochemicals (such as bile) for digestion, synthesis of proteins and the storage of energy.
Unfortunately, the liver is also susceptible to disease, with more than 100 disorders capable of affecting the blood-filled gland. Some are rare syndromes, while others are alcohol-related liver disease; autoimmune diseases in which the immune system of the body attacks the liver; primary biliary cholangitis (PBC); primary sclerosing cholangitis (PSC); infectious diseases with complications such as hepatitis B and hepatitis C; and liver cancer.
Earlier this month, hepatologists (liver specialists) from around Israel convened in Eilat for a conference discussing new research and treatments involving liver diseases. One of the guest speakers was Prof. Gideon Hirschfield, a senior lecturer and specialist at the Center for Liver Research at the University of Birmingham, which has one of the largest liver departments in Europe that performs some 200 transplants a year. He has been cited more than 100 times on PubMed and delivers keynote presentations on liver disease around the world.
Born in South Africa, Hirschfield studied medicine in the United Kingdom, and then became an assistant professor at the University of Toronto.
At the University of Oxford, he received the Wronker Prize for the most outstanding performance in the final honor school, and went on to Cambridge University, where he completed his clinical studies with distinction. He undertook junior medical posts at the Hammersmith and Royal Brompton hospitals before moving to a MRC clinical research fellowship at University College London. There he worked within the uniquely translational National Amyloidosis Center.
His doctoral dissertation focused on the development of inhibitors of C-reactive protein. He completed his advanced gastroenterology and hepatology training at Cambridge, and he was awarded specialist status in 2007.
Until January 2012 he worked in Toronto, where he was a staff physician and assistant professor of medicine at the University Health Network and University of Toronto. During this period, he managed one of the largest autoimmune liver disease groups in North America. He spent nearly five years working in Toronto, where he gained global recognition for his specialist liver practice. HIRSCHFIELD MADE his latest visit to Israel as the guest of Neopharm Israel, the country’s second-largest distributor in the Israeli healthcare and life-science market. He spoke about an important new “orphan drug” (aimed at treating rare diseases) called Ocaliva (obeticholic acid) for the treatment of primary biliary cholangitis (PBC).
The designation of orphan-drug status provides pharmaceutical companies in the US with incentives such as tax credits and eligibility for exclusivity as a manufacturer of orphan drugs. This is aimed at promoting the development of pharmaceuticals for rare diseases with few patients to take the drugs.
The US Food and Drug Administration only last month granted fast-track approval for Ocaliva for patients who have not improved after taking ursodeoxycholic acid (UDCA or Ursofalk), which is very effective for mild and early cases of PBC.
In an interview with The Jerusalem Post, Hirschfield said that the new drug was a “breakthrough” and the first drug in 20 years to be approved for PBC. The oral pill, he said, binds to the farnesoid X receptor – a key regulator of bile acid metabolic pathways in the liver and intestines. The new drug has been found to increase bile flow from the liver and suppress the production of bile acid in the liver, thus reducing the exposure of the liver to toxic levels of bile acids. ALTHOUGH LIVER diseases, especially autoimmune disorders of the organ, are increasing in number, they are not well known to the public. Some are due to genetics or environmental influences, and some to both. Liver disease can result from excessive consumption of alcohol (cirrhosis, or irreversible scarring of the liver), unprotected sex or poor nutrition and obesity (leading to potentially reversible fatty liver disease).
According to Hirschfield, there are both genetic and environmental factors in PBC. Nine out of 10 patients are women around the age of 50. There are some 1,500 sufferers in Israel. For one-fifth to a quarter of them, Ursofalk will not offer adequate relief; for them, Ocaliva is a welcome blessing (used with Ursofalk or alone if the patient cannot take it), he continued. The new orphan drug is made by Intercept Pharmaceuticals in New York. Neopharm will apply for adding it to the official 2018 basket of medical technologies (provided by the health funds at state expense) in the coming months.
The new drug is not for everybody. It is only for those with high-risk disease that is likely to turn into cirrhosis and liver cancer.
“We want hepatologists to think of their patients’ risk, so if they need the drug, they can avoid a liver transplant. There is a great shortage of transplant organs around the world, and there’s also an age barrier. Usually, if you’re in your 70s, there’s an unofficial limit for getting a donor liver,” he said. PBC BEGINS without symptoms. About a quarter of patients, according to Hirschfield, are diagnosed by chance as the result of irregular liver enzymes in a conventional blood test. As time passes, he said, there may be chronic tiredness, itching, abdominal pain and dryness in the eyes and mouth. Liver hormones become irregular. The chronic disease causes the liver’s small bile ducts to become inflamed, damaged and eventually destroyed. Bile remains in the liver, causing scarring and reducing the amount of functional tissue. If not treated early, it can lead to cirrhosis, ascites (accumulation of liquid), bleeding in the esophagus and liver cancer. Fatal liver cancer is often the result.
Liver cancer can also result from chronic hepatitis B or C virus infection, he continued. “We have cracked hepatitis C, but we’ve been losing patients to PBC.” Fortunately, for a few decades there has been a vaccination to protect children from hepatitis B; this has significantly reduced the number of liver transplants around the world. In the last few years, highly effective drugs to treat – and cure – hepatitis C infections have come on the market, thus there has been less incentive for developing a protective vaccine, Hirschfield said.
Children with autoimmune liver disease are first admitted to Birmingham Children’s Hospital in his city. When they reach 16 or 18, they are transferred for care and follow-up to the hospital of the University of Birmingham. “The children present with symptoms different from those in adults,” he noted.
“At least half of the people with liver disease would not have contracted if they’d had a better lifestyle. This is true of those related to unsafe sexual relations and alcoholism, but not with autoimmune diseases,” he said. “They have not done anything wrong.”
As a result of this connection, there is some stigma associated with liver diseases, and patients don’t like to talk about it, he added. “There is less media discussion of liver diseases, so patients are reluctant to tell their friends and even relatives about it.”
Patients whose immune system attacks the liver may also suffer from other autoimmune conditions such as thyroid disease, celiac disease, Sjogren’s, scleroderma and rheumatoid arthritis.
No one knows what environmental risks trigger PBC and other liver diseases, said the UK expert.
“A large variety of things, even nail polish and hair dye, have been mentioned, but there is no scientific evidence to back this up. The immune system of every person is slightly different from that of others,” he said.
It is possible that the risk of getting PBC is related to where you live or were raised, just as multiple sclerosis poses a higher risk if you live in the northern hemisphere without much light.
“We did a study that we will present in the US about the risks of getting PBC depending on where you live. It is an interaction between genes and environment; if you move to a place like Israel, with more sunlight, we don’t know at what age moving is important to cut your risks,” said Hirschfield, who has been to Israel many times.
PBC patients also often have thin bones and osteoporosis, said Hirschfield. “I recommend to them that they take vitamin D for improving bone health.” FATTY LIVER disease is become increasingly widespread in the developed world, and the general public are being aware of it.
“It is a syndrome, not really a disease,” he said. “Understanding environment and disease is very complicated and a challenge. The syndrome affects not only the obese but even some thin people. Treating lifestyle diseases is very hard.”
But it is clear that people with fatty livers who exercise regularly, change their diet to include more vegetables, nutritious fibers and fish and less meat can reverse their condition.
There are not enough liver specialists in the world, said Hirschfield. “Education is vital. New drugs that can help with liver disease galvanize hospitals to get more specialists. There are more women in the field; in 25 years’ time, their share will be even higher.”
Other changes in medical practice regarding his specialty include remote monitoring via smartphone sensors. “And doctors will have to show more compassion. The question is whether the health services will allow the doctors to slow down and show more compassion for patients,” he said.
Hepatology “is an evolving specialty. I spend a lot of time educating doctors around world about liver disease, and this takes time and money and a partnership with a lot of stakeholders,” he added.
There are about a dozen liver specialists in his Birmingham center and hundreds of hepatologists in England.
An American association for the study of liver disease met recently in Washington, DC, and 10,000 doctors and researchers attended. There is also a large European association. A few hundred attended the Eilat hepatologists conference that Hirschfield attended.
“The field is definitely developing as the prevalence of autoimmune disease rises along with liver cancer. We don’t know why, but we are trying to find out,” he concluded.