COVID-19 and Gilbert’s Syndrome

So you have lots of bits of information about COVID-19, but what do they add up to if you have Gilbert’s Syndrome? Well, there are a number of things I can tell you which should help join the dots and give you the big picture of where you stand when faced with COVID-19, if you have Gilbert’s Syndrome.

First of all, we have to understand what type of virus COVID-19 is.

It’s a virus similar to the flu and colds. Because it’s new no-one had it before and so no-one is immune and can catch it easily. You can catch it the same way you catch any cold or flu – the virus travels in tiny droplets pushed out from the infected person’s nose and mouth when they cough or sneeze. It either goes straight into your mouth or nose, or sits around for a while waiting to catch a ride on your body. The virus hijacks your cells in your nose, throat and lungs and multiplies. Your body then responds with the usual attack mechanisms, and depending on how healthy your immune system is, and how much of the virus you have been exposed to, you can see it off or have a more severe, possibly fatal reaction. The severe reaction is partly because the body’s immune system response goes into overdrive and the lung tissues become blocked because they become inflamed – which is why people have difficulty breathing. 

Okay, so far, it’s pretty straightforward – but there are differences in how viruses can affect people. This one is pretty different where children are concerned (see below). Others can also affect the liver more – recently the pandemic of 2009, H1N1, was shown to cause liver damage: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941665/

So far, studies show that COVID-19 doesn’t seem to cause permanent liver damage, although there can be some impact on the liver initially, which doesn’t appear related to the medication given to patients, as this extract from The Hindu, and the Lancet journal text extract below show: 

Liver damage in mild cases of COVID-19 is often temporary and the organ can return to normal without any special treatment. This could be due to the state of direct infection of liver cells or could as well be due to liver cells getting caught up in the immune war between body’s immune system and the virus with chemicals produced by our body, namely cytokines. The Hindu

https://www.thelancet.com/journals/langas/article/PIIS2468-1253(20)30084-4/fulltext :

‘mild liver test derangement is present at baseline in many patients with COVID-19 before significant medication use. Ie. the liver is impacted before medication is given’

‘It has been proposed that COVID-19 causes direct liver injury via a viral hepatitis, but we believe that there are alternative explanations. First, the derangement of liver function is clearly mild. Second, when liver function tests for patients with different durations of symptoms are examined, there is no evidence that later presentation is associated with greater liver function derangement.’

What’s also great to hear is that: ‘worse outcomes were not seen in the 42 patients with chronic liver disease and COVID-19 who had outcome data’

The greatest problem that people will face when fighting off COVID-19 are underlying health problems which impact the immune system:

https://patient.info/news-and-features/covid-19-coronavirus-what-is-an-underlying-health-condition

In which case you must take special care!

Paracetamol, ibuprofen and COVID-19 – originally it was thought that ibuprofen might cause problems for people with COVID-19, and for those of us with Gilbert’s Syndrome this was bad news. Paracetamol has been shown to impact the liver more in people with Gilbert’s Syndrome (it makes me feel VERY ill),https://www.ncbi.nlm.nih.gov/pubmed/10412886 , so ibuprofen might by your painkiller of choice. Fortunately the WHO and governments have given it the all clear https://www.gov.uk/government/news/commission-on-human-medicines-advice-on-ibuprofen-and-coronavirus-covid-19

So, you should not worry more if you have Gilbert’s Syndrome as COVID-19 doesn’t appear to have an especial impact on the liver. However, just on flu and colds generally – the stress on your body can make you feel really unwell and trigger your Gilbert’s Syndrome symptoms. This is important to tell clinicians if they are treating you so that they can understand what’s happening to your body and why. 

Check out this leaflet from an NHS trust and its recommendations to get the flu vaccine if you have a liver disease, including GIlbert’s Syndrome. https://psnc.org.uk/avon-lpc/wp-content/uploads/sites/23/2015/07/Liver-Disease-and-Flu-Vaccine-Importance.pdf

There may be other questions that we can’t answer such as – is there a link between low white blood cell counts, Gilbert’s Syndrome and fighting infection; what if some of the medication used in the treatment of COVID-19 is processed in the pathways of the liver affected by our enzyme deficiency. As it appears there is a link between high levels of bilirubin and reduced white cell count https://journals.sagepub.com/doi/10.1177/0004563214541969 (topic for another post!), you could potentially hypothesize that this is a good thing – as the overproduction of white cells is part of the excessive inflammatory response I talked about that can actually harm not heal. As mentioned above – do let your clinicians know you have Gilbert’s Syndrome and that some medication, processed in the Phase II pathways, isn’t dealt with as well. 

If you want to know more about how COVID-19 virus works and how the body responds (knowledge is power after all), check out this video from Yale: https://www.youtube.com/watch?v=vvKhT9tAhig

And if you’d just like to feel like you know a bit more about how the liver works check this out: https://www.healthline.com/health/what-does-the-liver-do

But wait – why doesn’t it affect children more, like other flu and colds? How is it different? 

https://time.com/5816239/children-coronavirus/

Why are children less affected when their immune system is still developing? It’s theorized it is BECAUSE their immune system is developing that the life threatening response to COVID doesn’t occur as much in children – the adult body’s immune response includes a ‘cytokine storm’ which results in an inflammatory response in the lungs, making it hard for adults to breathe. Children’s bodies don’t yet respond as aggressively to the virus. 

https://royalsocietypublishing.org/doi/pdf/10.1098/rspb.2014.3085

As age advances, the immune system undergoes profound remodelling and decline, with major impact on health and survival [81,82]. This immune senescence predisposes older adults to a higher risk of acute viral and bacterial infections. Moreover, the mortality rates of these infections are three times higher among elderly patients compared with younger adult patients [83]. Infectious diseases are still the fourth most common cause of death among the elderly in the developed world. Furthermore, aberrant immune responses in the aged can exacerbate inflammation, possibly contributing to other scourges of old age: cancer, cardiovascular disease, stroke, Alzheimer’s disease and dementia [84]. During a regular influenza season, about 90% of the excess deaths occur in people aged over 65.

I hope this information helps you live better with Gilbert’s Syndrome!

Jaundice

WHAT IS JAUNDICE?

The word “jaundice” comes from the French word jaune, which means yellow.

Jaundice is a yellowish staining of the skin, the whites of the eyes, and mucous membranes by bilirubin, a yellow-orange bile pigment. Bilirubin (read more about it here!) comes mainly from the breakdown of red blood cells, and is basically a waste product that your liver gets rid of.

Jaundice usually appears when the bilirubin in your blood is more than 3 mg per dL (51.3 µmol per L). The classic definition of jaundice is a serum bilirubin level greater than 2.5 to 3 mg per dL (42.8 to 51.3 µmol per L) as well as having yellow skin and eyes.

Your body processes bilirubin in 3 phases: prehepatic (before it gets to the liver), intrahepatic(whilst in the liver), and posthepatic(after leaving the liver). If any of these aren’t working properly you can become jaundiced.

PREHEPATIC

The human body produces about 4 mg per kg of bilirubin per day, from the breakdown of blood cells. Bilirubin is then transported from to the liver for conjugation (where it needs to link up with other enzymes and chemicals so that it can be removed from the body) .

INTRAHEPATIC

Unconjugated bilirubin (the bilirubin that hasn’t been removed by linking up with an enzyme) doesn’t dissolve in water but is soluble in fats. That means it can easily cross the blood-brain barrier or enter the placenta. The unconjugated bilirubin is conjugated (linked up with) with a sugar via the enzyme glucuronosyltransferase (the enzyme that people with GS don’t have enough of) and is then soluble in the bile.

POSTHEPATIC

Once soluble in bile, bilirubin is transported through to the gallbladder, where it is stored, or passed on to the duodenam. Inside the intestines, some bilirubin is excreted in the stool, while the rest is dealt with by the bacteria in your gut.

JAUNDICE AND OTHER SYMPTOMS

Some people with jaundice have no symptoms at all.  But some may have an acute illness, which is frequently caused by infection, may seek medical care because of fever, chills, abdominal pain, and flu-like symptoms. For these patients, the change in skin color may not be their greatest concern!

Patients with noninfectious jaundice may complain of weight loss or itching / skin discomfort. Abdominal pain is the most common symptom in patients with pancreatic or biliary tract cancers.Even something as nonspecific as depression may be a symptom in patients with chronic infectious hepatitis and in those with a history of alcoholism.

‘False’ jaundice can happen if you eat foods rich in beta-carotene (e.g., squash, melons, and carrots). Unlike true jaundice, you don’t get yellow eyes, or changes in bilirubin level.

CAUSES OF JAUNDICE:

PREHEPATIC CAUSES

Unconjugated hyperbilirubinemia (this is when you’ve too much bilirubin in your bloodstream because it’s not been processed in the liver, as in Gilbert’s Syndrome) might happen before bilirubin has entered the liver cells or within the liver cell. If you’ve had an unusual breakdown in your red blood cells then there may be too much of the waste product, bilirubin, for your liver to process as normal.

This will usually result in mild bilirubin elevation, to about 5 mg per dL (85.5 µmol per L), with or without clinical jaundice. The blood might be breaking down because of a number of causes in the blood cells or your enzymes which mean your red cells have stayed alive longer than normal, and built up.  Other causes include autoimmune disorders, drugs, and defects in hemoglobin structure such as sickle cell disease and the thalassemias.

INTRAHEPATIC CAUSES

Un-Conjugated Hyperbilirubinemia Gilbert syndrome is a common, benign, hereditary disorder that affects approximately 5 percent of the U.S. population. It usually results in a mild decrease in the activity of the enzyme glucuronosyltransferase. Gilbert syndrome is typically an incidental finding on routine liver function tests, when the bilirubin level is slightly increased and all other liver function values are within normal limits. Jaundice and further elevation of the bilirubin level may occur during periods of stress, fasting, or illness.

Conjugated Hyperbilirubinemia. Main causes are when there’s a blockage preventing bilirubin from moving into the intestines. Viruses, alcohol, and autoimmune disorders are the most common causes of hepatitis. Inflammation also disrupts transport of the bilirubin and causes jaundice.

Hepatitis A can cause acute onset of jaundice. Hepatitis B and C infections often do not cause jaundice straight away, but can lead to jaundice when chronic infection has led to liver cirrhosis. Epstein-Barr virus infection occasionally causes hepatitis and jaundice that resolve as the illness clears.

Alcohol has been shown to affect bile acid uptake and secretion, stopping the normal flow through the liver. Chronic alcohol use may result in fatty liver (steatosis), hepatitis, and cirrhosis, with varying levels of jaundice. Fatty liver, the most common liver problem, usually results in mild symptoms without jaundice but occasionally progresses to cirrhosis. Hepatitis secondary to alcohol use typically presents with acute onset of jaundice and more severe symptoms.

More rare conditions that can cause jaundice: Autoimmune hepatitis traditionally has been considered a disease that affects younger persons, especially women. Two serious autoimmune diseases that directly affect the biliary system without causing much hepatitis are primary biliary cirrhosis and primary sclerosing cholangitis. Primary biliary cirrhosis is a rare progressive liver disease that typically presents in middle-aged women. Fatigue and itching / skin discomfort are common initial complaints, while jaundice happens later. Primary sclerosing cholangitis, which is also rare, is more common in men; nearly 70 percent of patients also have inflammatory bowel disease. Dubin-Johnson syndrome and Rotor’s syndrome are rare hereditary metabolic defects that disrupt transport of conjugated bilirubin.

Common drugs can also cause problems, such as acetaminophen, penicillins, oral contraceptives, anti-psychotic medication, and steroids. Cholestasis can develop during the first few months of oral contraceptive use and may result in jaundice.

POSTHEPATIC CAUSES

Gallstones in the gallbladder are fairly common in adults. Obstruction within the biliary duct system can inflame the gallbladder, and can lead to infection. Cholangitis is diagnosed clinically by the classic symptoms of fever, pain, and jaundice, known as Charcot’s triad. Cholangitis most commonly occurs because of an impacted gallstone, which might then be removed.

Biliary tract tumors are uncommon but serious causes of posthepatic jaundice. Gallbladder cancer classically presents with jaundice, enlarged liver, and a mass in the right upper quadrant (Courvoisier’s sign). Another biliary system cancer, cholangiocarcinoma, typically manifests as jaundice, itching / skin discomfort, weight loss, and abdominal pain. It accounts for roughly 25 percent of hepatobiliary cancers.

Jaundice also may arise with pancreatitis. The most common causes of pancreatitis are gallstones and alcohol use. Gallstones are responsible for more than one half of cases of acute pancreatitis, which is caused by obstruction of the duct that drains the biliary and pancreatic systems.

Evaluation

The initial work-up of the patient with jaundice depends on whether the hyperbilirubinemia is conjugated (direct) or unconjugated (indirect). A urine anlysis that is positive for bilirubin indicates the presence of conjugated bilirubinemia. Conjugated bilirubin is water soluble and so passed through urine.

SO IF YOU’RE JAUNDICED WHAT DO THEY DO TO WORK OUT WHAT’S CAUSING IT? Here’s the clinical information :

BLOOD TESTING

First-line serum testing in a patient presenting with jaundice should include a complete blood count (CBC) and determination of bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transpeptidase, and alkaline phosphatase levels.

Depending on the results of the initial tests, further serum tests or imaging studies may be warranted. The second-line serum investigations may include tests for hepatitis A IgM antibody, hepatitis B surface antigen and core antibody, hepatitis C antibody, and autoimmune markers such as antinuclear, smooth muscle, and liver-kidney microsomal antibodies. An elevated amylase level would corroborate the presence of pancreatitis when this condition is suspected based on the history or physical examination.

IMAGING

Ultrasonography and computed tomographic (CT) scanning are useful in distinguishing an obstructing lesion from hepatocellular disease in the evaluation of a jaundiced patient. Ultrasonography is typically the first test ordered, because of its lower cost, wide availability, and lack of radiation exposure, which may be particularly important in pregnant patients. While ultrasonography is the most sensitive imaging technique for detecting biliary stones, CT scanning can provide more information about liver and pancreatic parenchymal disease. Neither is good at finding stones inside the ducts.

Further imaging that may be done by a gastroenterologist or interventional radiologist includes endoscopic retrograde cholangiopancreatography and percutaneous transhepatic cholangiography.

LIVER BIOPSY

A liver biopsy provides information on the architecture of the liver and is used mostly for determining prognosis. It also may be useful for diagnosis if serum and imaging studies do not lead to a firm diagnosis. Liver biopsy can be particularly helpful in diagnosing autoimmune hepatitis or biliary tract disorders (e.g., primary biliary cirrhosis, primary sclerosing cholangitis).

Bilirubin explained

Bilirubin explained

All about Bilirubin.

If you’ve been diagnosed with Gilbert’s Syndrome, then you’ve most probably been told that your bilirubin levels were high.  It’s one of the most common ways of determining that a patient has Gilbert’s Syndrome, and usually happens after general blood tests.

But what is Bilirubin, what does it do and will it harm us? 

Bilirubin comes from the blood when blood cells become old, and die.  Hemaglobin, the substance in blood that carries oxygen, is broken down to heme and globin and is passed onto the liver. Bilirubin is formed from the heme part of hemaglobin, and is a bright greenish yellow colour.

The bilirubin is not water soluble when it gets to the liver, and needs an enzyme to become so, then it can be easily passed out of the body.  The water soluble substance now passes through the gall bladder as bile and into the small intestine where it continues to be processed by bacteria in the intestines, and is passed out through the faeces and urination.

This enzyme that makes the bilirubin water soluble is called glucuronyl transferease, known as UGT for short, and is what people with Gilbert’s Syndrome are genetically lacking.  This means that the bilirubin is not ‘conjugated’ or converted so that it can easily leave the body.

The enzyme also uses blood sugar to help in processing bilirubin, which is one reason why missing meals can affect you.  It’s best to ensure you have regular small meals, and cut down on unrefined sugar and carbohydrates like white bread and pasta, so that the amount of enzyme you have can always have a stable supply of blood sugar to do its job.

There is always some bilirubin that is in the blood but this is chemically different from the ‘conjugated’ bilirubin.  GS sufferers however, have a lot more of this ‘unconjugated’ bilirubin because it hasn’t been disposed of as it should through the usual process. It’s the difference between the 2 types that tips off those conducting the lab tests on your blood that you have GS.

When bilirubin builds up in the blood at more than around 2.5mg/dl, then the skin and eyes become discoloured with yellow, otherwise know as jaundice. There are a number of reasons bilirubin builds up in the blood other than the lack of the enzyme, and it’s important to rule those out before diagnosing Gilbert’s Syndrome.  For example the patient’s bile duct could be blocked, or they could have a type of anaemia, or hepatitis.

Drugs can also affect the measurements of bilirubin, and many can increase it such as  steroids, some antibiotics, antimalarials, codeine, diuretics, MAO inhibitors, nicotinic acid, oral contraceptives, and others.  Drugs that decrease bilirubin measurements include barbiturates, caffeine, penicillin and high dose salicylates.

You’re likely to be diagnosed between the age of 10 and 30.  Males are more likely to have Gilbert’s Syndrome than females, and there are some slight differences in the gene depending on racial background.  Many people will not even notice they have it.

Diagnosing Gilbert’s Syndrome

People with Gilbert’s Syndrome are often diagnosed after a blood test shows a high level of bilirubin in their blood. You may have gone to the Dr with an unrelated problem, or have presented with a number of symptoms such as feeling tired all the time, feeling sick, jaundice (yellow skin or eyes), abdominal pain, IBS, lack of concentration, and generally feeling unwell. At least 30% of people with Gilbert’s Syndrome may have no symptoms at all.

The Dr will first rule out other liver problems, usually through liver function tests on your blood which will show if the liver is damaged as well as checking the level of bilirubin, and provided you have no other easily identifiable problem you may be diagnosed with Gilbert’s Syndrome.

Sometimes tests are conducted before and after a 48 hour fast as this seems to really raise the bilirubin levels in people with Gilbert’s Syndrome. Bilirubin levels in people with Gilbert’s Syndrome can change over time, and so may be missed if they happen not to be raised at the time of the blood test. Bilirubin is measured in millimoles per litre (umol/L). Total serum bilirubin higher than 17 umol/L is outside the normal range.  The bilirubin typically fluctuates in the range of 20 – 40 mmol/L although normal values may occur, and results as high as 80 mmol/L may be seen in patients who have not consumed food for several days. Gilbert’s Syndrome is the most common cause of raised bilirubin levels, however there are rare and more serious conditions such as Criglar-Najjar Syndrome which is inherited from the same gene.

Very rarely a liver biopsy may be performed to rule out other liver conditions, and you may also be offered genetic testing.

Unfortunately, after diagnosis you are likely to be offered little help to deal with your symptoms. However, if you are experiencing nausea, IBS, or other problems you may be prescribed medication that can help.  For other symptoms, well, we’re here to help and hopefully some of the information on this website will help you live better with Gilbert’s Syndrome.