Tag Archives: mucus

vomiting blood and yoghurt

Slide04 More alcohol problems this week. Peter came in vomiting blood yesterday afternoon. Vomiting blood is always a bad thing, but this time it was particularly bad. His long-suffering partner Rita came in with him to tell us what had happened. Peter, aged 69 was too drowsy and confused to tell the story himself. He was a retired barman and had always drunk too much alcohol. He recently went to see the liver doctors because his abdomen had filled up with fluid. They told him that he would die soon if he did not give up drinking. Rita said that he had cut down but was still drinking about 3 pints of strong cider every day. Yesterday lunchtime he was about to sit down to eat when he said he felt very sick. He staggered to the bathroom and promptly vomited what Rita estimated to be a pint of bright-red blood down the toilet pan. Rita called the ambulance. He vomited more blood on the way and by the time they arrived he was pale, sweaty and quite drowsy. She was really worried – she thought about what the liver doctor had said about Peter dying soon if he did not give up drinking – he had not given up.Slide05

When patients with liver disease vomit blood it always makes us worry about bleeding varices. Varices are large, distended veins which appear at the junction between the oesophagus (foodpipe) and stomach in people with liver cirrhosis. Cirrhosis often results from liver damage due to alcohol. Ethanol is metabolised to ethanal (acetaldehyde) and causes damage to liver cells as well as the pancreas (see vodka and sweetbreads below). The liver does have a remarkable capacity to regenerate.

Slide06

I’m not sure if the ancient Greeks knew about liver regeneration when they devised the myth about Prometheus. He made the mistake of giving fire to men, and as a punishment was chained to a rock for eternity. Every morning an eagle would fly down and peck out his liver. During the following day his liver would grow back again, to be pecked out again the following morning. He is still there.

ancient Greek vase showing Prometheus having his liver pecked out by eagle wikimedia common user Bibi Saint-pol
ancient Greek vase showing Prometheus having his liver pecked out by eagle –  wikimedia common user Bibi Saint-pol

Although liver does regenerate when damaged by alcohol, it does so to form nodules of liver tissue with bands of fibrosis in between the nodules. This disturbance of normal architecture impairs blood flow through the liver. As a result the pressure in the portal veins carrying blood from the stomach and intestines to the liver increases. Increase in portal venous pressure results in oesophageal varices. When they burst, rapid death from blood loss is common. Another result of increase in portal pressure is ascites – fluid accumulation in the abdominal cavity – the cause of Peter’s abdominal swelling.

all the blood coming from the stomach and small and large intestine goes into the portal venous system and through the liver to be processed - including removal of ammonia and small amines
all the blood coming from the stomach and small and large intestine goes into the portal venous system and through the liver to be processed – including removal of ammonia and small amines – from Grays anatomy 1918

So he was filled up with a blood transfusion, vitamins (see vodka blog below) and given terlipressin – a drug which constricts oesophageal varices and helps to stop bleeding. He was sent as an emergency to have an upper gastrointestinal endoscopy. In fact he did not have significant varices. He had a bleeding duodenal ulcer. The ulcer was cauterised and injected with adrenaline, a biopsy was taken from his duodenum, and he was sent to the admissions unit.  Part of the duodenal biopsy was put into a CLO test kit.

I talked previously about adrenaline causing muscle tremor and relaxation of bronchial smooth muscle by activating adrenergic beta receptors. It is released by the middle (medulla) of adrenal glands in response to severe stress. The reason Peter was so pale was probably more to do with release of adrenaline than blood loss. This hormone has many other actions to help us survive life-threatening situations. It will also act on beta receptors in muscle blood vessels to increase muscle blood flow – good to get away more quickly from the nasty tiger with dripping fangs that likes to eat humans.

Skin blood vessels have few beta receptors – here adrenaline acts on alpha receptors to cause reduction in blood flow. Similarly, in the lining of the duodenum, adrenaline, when injected by the endoscopist, causes blood vessels to constrict and help stop bleeding by acting on their alpha receptors.

When I ask students why adrenaline reduces skin blood flow they usually say it is to redirect blood to the central circulation where it is more needed. The skin only has about 1% of circulating blood. It is more likely that skin blood flow is reduced to limit blood loss when the tiger’s teeth finally sink into that tasty human flesh.

All this preamble is a good excuse to talk about urea. In our hospital normal blood urea levels are between 3.5 and 6 mmol/l. In the US doctors talk about blood urea nitrogen- the same stuff- normal levels are 20-30mg/l. When Peter visited the liver doctor last month his blood results showed that the concentration of urea in his blood was low – only 1.8 mmol/l (5mg/dl BUN). When he arrived in the ED it was elevated at 14 mmol/l (40mg/dl BUN). His haemoglobin was low at 90g/dl and clotting was deranged with an INR of 2.9. Why was his urea low before and now high? To understand this I need to talk about protein metabolism.

Most of us in the West eat lots of protein. More than we need. In the US and UK adults eat about 100grammes of protein/day, although we only need about 50. If we eat 100grammes of protein a day, we need to get rid of the same amount, unless we are growing, body-building or pregnant. Patients who are ill typically break down more protein than they take in – negative nitrogen balance.

I’ve used arguments about in/out balance for fluid in my previous post and will use it for energy in future posts. Not everything in humans can be understood in terms of in/out balance. For instance, with my 11 year-old son we input high grade educational material and all that comes out is poo and fart jokes.

So what happens to this 100grammes of protein? Protein is a polymer of amino acids. You can make useful plastic out of milk protein – see this youtube video:

http://www.youtube.com/watch?v=pIvAl4lu1uA

Casein also used to be used to make plastic items such as buttons. We now have cheaper and better plastics.

Protein that goes into our mouth is mashed up by our teeth and swallowed. The stomach has the first go at breaking up the protein polymer with the enzyme pepsin, secreted by chief cells in the glands of the stomach. It’s a bit tricky making an enzyme that breaks down protein, because all our cells are made of lots of proteins.  There is the obvious danger that the enzyme will destroy the cell that made it. So pepsin is made in an inactive form – pepsinogen that is only activated when it comes into contact with stomach acid. Then the pancreas has a go. It makes trypsin, carboxypeptidase and chymotrypsin which finish the job, to end up with amino acids. The pancreas has to be pretty careful too, making inactive enzymes which become active one secreted – see:

http://www.physiologymodels.info/digestion/proteins.htm

Amino acids are all of the general formula:

general formula for amino acid - the red box stuff can usually be turned into carbon dioxide and water - the blue box stuff is harder to get rid of
general formula for amino acid – the red box stuff can usually be turned into carbon dioxide and water – the blue box stuff is harder to get rid of

The R is mainly made of carbon, hydrogen and oxygen. We have to dispose of 100g daily. The part in the red box is burned up in mitochondria, and like glucose is turned into carbon dioxide, water and energy – 4Kcal/gramme – 400 Kcalories per 100g. The problem is the bit in the blue box. The NH2 group looks like ammonia, and ammonia is toxic. But don’t worry, we have a way of dealing with this – it’s called the urea cycle. This happens mainly in the liver. I could draw a diagram of the urea cycle, but instead will direct you to a 1 minute youtube video showing how it works:

http://www.youtube.com/watch?v=AoBbVu5rnMs

So ammonia is combined with bicarbonate (or carbon dioxide) and via the urea cycle is made into urea, a very non-toxic substance which is excreted in urine.

two molecules of ammonia combine with one of carbon dioxide to make urea and water - its not as simple as that - but that is what the urea cycle does
two molecules of ammonia combine with one of carbon dioxide to make urea and water – its not as simple as that – but that is what the urea cycle does

The reason Peter’s urea was so low when he saw the liver doctor was because he was drinking too much alcohol and not eating enough protein. Now he has had a sudden high protein meal – blood. Blood contains about 70g/l of albumin and globulins in plasma, and about 130g/l of haemoglobin (mostly protein) in red cells – total 200g/l.  If he has bled a litre of blood from his duodenal ulcer he will suddenly have twice the average daily protein intake in a short time – no wonder his urea level has risen.

But Peter’s liver is not working as well as it should, because he has been drinking too much alcohol for a long time and has cirrhosis. A lot of the ammonia from protein metabolism is not being instantly turned into urea, and instead gets into the systemic circulation. When the brain is exposed to ammonia, it does not function too well. It is not only ammonia, but other short-chain amines which the liver has failed to deal with. Bacteria in the colon chop up amino acids and proteins into all sorts of amine-containing molecules which the liver will normally cope with. Peter’s damaged liver is not able to cope with these substances and they get into his circulation and into his brain. Nobody knows how brains work, but we do know that certain chemicals are important in passing messages from one brain cell to another – neurotransmitters. Many neurotransmitters are small amine-containing molecules, such as catecholamines, serotonin (5-hydroxytryptamine), glutamine and dopamine. It is not surprising that when flooded with a smorgisbord of small amines and ammonia the brain does not work too well. Rita told us that Peter was sleeping all day and awake all night recently – a characteristic feature of hepatic encephalopathy. When we examined him when he came back from endoscopy he had a liver flap, or asterixis. That means when he held out his hands they would independently twitch, with a downward flapping movement- another feature of hepatic encephalopathy which was also making him drowsy. There are lots of examples of liver flap on youtube such as:

http://www.youtube.com/watch?v=Rbv-zaVszlk

The reason his INR was raised was because his liver was not producing enough clotting factors. We gave him a concentrate of clotting factors (octiplex) to correct this, and help stop the bleeding.

It took a couple of hours before his CLO test result was available. A small piece of tissue was removed from his duodenum next to the ulcer. The CLO test refers to Campylobacter Like Organism. Helicobacter pylori is one of these which is a major cause of duodenal ulcers. Helicobacter pylori is an amazing germ. It is a bacterium which can survive in a very hostile environment – the human stomach and duodenum. It is the only germ that can normally survive here. The acidity is fierce, often the pH is down to 1 – really strong hydrochloric acid. There is also a high concentration of nitric oxide and proteolytic enzymes. It doesn’t mind.  Helicobacter refers to the shape – a helix or corkscrew.

model of helicobacter showing corkscrew shape and long flagellae
model of helicobacter showing corkscrew shape and long flagellae

I talked before about how bacteria find it difficult to swim in mucus. The stomach lining is covered in mucus, but helicobacter’s corkscrew shape helps it swim in this thick and gloopy layer. Staying in the mucus layer helps protect it from the acid and enzymes. Another protection comes from being able to convert urea into alkaline ammonia – keeping the acidity at bay in its immediate environment. The CLO test simply tests the small bit of duodenum for its ability to convert urea into ammonia – it can only do this if has helicobacter organisms in it. Human cells cannot do this. So, in the test plate, there is an indicator, such as phenolphthalein or phenol red which changes colour with alkali.

this CLO test kit contains phenol red - it is yellow when acid and red when alkaline
this CLO test kit contains phenol red – it is yellow when acid and red when alkaline

The helicobacter turns urea into ammonia, making the environment more alkaline which will change the colour of the indicator. Phenol red changes from yellow to red with alkali.

when a piece of duodenum is put into the CLO test vial it will turn red if there are helicobacter pylori organisms - I just used a bit of soap for this photo as I did not have any infected duodenum to hand
when a piece of duodenum is put into the CLO test vial it will turn red if there are helicobacter pylori organisms – I just used a bit of soap for this photo as I did not have any infected duodenum to hand

We gave Peter intravenous omeprazole, a proton pump inhibitor. This stops the parietal cells of the stomach making acid and helps heal the ulcer. We also gave him lactulose. This is a sugar which helps with hepatic encephalopathy. Lactulose is very similar to lactose – the sugar in milk. Lactose is a disaccharide made of the simple sugars glucose and galactose. Lactulose is made of fructose and galactose. I talked earlier (chest pain) about how most of the world’s population have problems drinking milk when they are adult because they have lost the enzyme which breaks down the bond between the two sugars in lactose. No-one has the enzyme to break down lactulose into its two simple sugars. But bacteria do. In the large intestine, lactulose that we have been unable to break down and absorb in the small intestine is turned into lactic acid, which is also then turned into lots of gas, such as methane and hydrogen. Some patients don’t like lactulose because it gives them stomach cramps and makes them fart a lot. But in patients like Peter it is good because the lactic acid reacts with the alkaline ammonia and small amines to inactivate them and reduce their amount in the circulation affecting his brain, making him confused and drowsy. He went home less confused and more or less OK. I hope he stops drinking.

This is where the yoghurt comes in. The food link at last. In yoghurt the milk sugar lactose is broken down by lactobacilli to form lactic acid. This gives it a nice tangy taste that my daughter likes so much she wears the following tee-shirt.Slide08

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asbestos and black pudding

Some cancers are better than others. Mesothelioma is one of the worst. Alfred was admitted to our ward earlier this week. He is a 78 year old retired shipbuilder. He has mesothelioma in his lung. He spent most of his life in the Naval shipyards welding large plates of steel together to make warships. When he was young, a huge amount of asbestos was used in naval ships. It was packed in thick layers between the compartments of the vessel as it was being constructed. Alfred and his mates played snowballs with lumps of the stuff (of course, no masks were worn then).  Asbestos was used in naval construction because it is a refractory material. That means that it will not burn or melt even at high temperatures, so that it will prevent fire spreading from one part of the ship to another. It is also very cheap – a mineral that needs no further processing once it has been dug out of the ground.

Slide2
chrysotile asbestos
from Ra’ike – wikimedia commons

The reason Alfred came into hospital was because he had suddenly become more breathless and had bad chest pain when he breathed deeply. When we examined him it was clear that he had a large amount of fluid between his lung and chest cavity – a pleural effusion. We were also worried that he may have a pulmonary embolus. Patients with cancer commonly develop blood clots in their veins that travel to the lungs and block up the circulation causing shortness of breath, chest pain and even death if the clots are big enough.

His wife was with him. She knew he had cancer. She did not say it, but clearly she thought he was about to die.

We gave Alfred oxygen, an injection of low-molecular-weight heparin to prevent further blood clot formation and arranged a CT pulmonary angiogram.

Why is asbestos so dangerous?

The common form of asbestos is chrysotile. This is white asbestos. There is also brown, and the even more deadly blue asbestos. Chrysotile is a fairly simple chemical compound – magnesium silicate. Talcum powder is also magnesium silicate, but asbestos has a different crystal structure to talc. The crystals which asbestos is made of are very long, and very thin and break up into tiny, sharp needles. These needles get stuck into the lung and cannot be removed.

Ordinary dust commonly contains silicates. Sand is pure silicate. Silicon and oxygen are by far the two most common elements in the earths crust. Lots of stuff we use every day is made of silicates, including glass, ceramics (the cup you are drinking coffee out of right now), the bricks your house is made of, the cement mortar holding the bricks together, the surface of the paper you put in your printer, toothpaste etc. etc. The reason silicates are so useful is that the silicon-oxygen bond is very strong. This means when you put strong acids, alkalis or solvents in a glass vessel it does not dissolve. It also means that when it is in the wrong place in your body it can cause a problem because it cannot be broken down.

the granite worksurface, the ceramic tiles and grout, the pottery bowl, the glass and surface of the paper are made of silicates.
the granite worksurface, the ceramic tiles and grout, the pottery bowl, the glass and surface of the paper are made of silicates.

Ordinary dust, in reasonable amounts we can cope with. If it gets down into our lungs, it is trapped by the mucus layer on the surface of the tubes, or bronchi. This mucus is continually produced by goblet cells – called that because they have a goblet shape.

Mucus is a very wonderful substance. It is mainly water, but clearly not only water because it is very sticky. It is designed to be sticky to trap dust particles and bacteria. Bacteria don’t like to be trapped in mucus because they find it hard to move around – like us trying to swim in a swimming pool full of treacle.

treacle

Once the bacteria and dust particles are trapped, tiny, beating cilia on the surface of the bronchial epithelial cells move the mucus layer along. These cilia, which look like miniscule hairs, push the mucus, with its cargo of dust and germs, in one direction – upwards. Eventually, it reaches the larynx and then goes down the tunnel of death – the oesophagus – to end up in the acid of the stomach. No germs can survive this apart from helicobacter pylori – the subject of a future blog no doubt. The cilia are easily damaged. One reason smokers cough is because their damaged or absent respiratory cilia do not move mucus up the escalator, so it collects and needs to be coughed up.

Mucus is a wonderful substance made mainly of sugars. Sugars are essentially sticky substances. Lollipops are sticky, honey is very sticky. In earlier times wallpaper was stuck to walls with flour and water paste – wheat flour is composed mainly of starch –  a long polymer of the sugar, glucose.

wallpaper paste

Modern wallpaper paste is made of methylcellulose – a form of cellulose that dissolves in cold water to make something that looks quite like mucus. We use a lot of K-Y jelly in our work. It is also made from methylcellulose. I have read that many litres of K-Y jelly were used to simulate mucus in the Alien films.

The sugars in real mucus are quite special – they are in the form of long sugar chains known as mucopolysaccharides or glycosaminoglycans. I prefer the word mucopolysaccharide. It just means polysaccharide – a sugar chain – derived from mucus. They are special because unlike the common sugar glucose, many of the sugars in mucopolysaccharide chains have an amino group (NH2) and many have sulphate (SO4) groups attached. The sulphate groups make mucus even stickier.

The mucus produced by goblet cells is not just a solution of mucopolysaccharides. It is a complex structure. The goblet cell extrudes a long protein molecule called mucin. The sugar chains are attached to the mucin like bristles on a bottle brush.

Slide1
structure of mucus
the central red shaft is a protein to which many long sugary mucopolysaccharide chains are attached (blue)

So, on average, mucus has more than twice as much sugar as  protein in a large amount of water – rather like wallpaper paste.

Our bodies use mucopolysaccharides for a lot of things apart from making mucus. They are important in lubricating joints and are found in the jelly-like vitreous humor in our eyes. Some bacteria produce these sugars as a slime-coating or capsule which makes them more difficult for phagocytic cells to ingest. (See phlegm and horseradish previously).

Back to the asbestos particles. Being very thin and sharp, they manage to penetrate the mucus layer and get into the lung substance. They would not cause too much of a problem if it were not for the police in the form of macrophages. These officers of the law are very intolerant of foreign invaders and try to destroy them. (I’m not suggesting police are racist by the way). If the foreign invader is a bacterium then fair cop. If it is an organic substance like wood fibre, engulfing it and breaking it down is also a good idea. The problem with asbestos is that it is a silicate, and even though macrophages can make some pretty nasty chemicals, they cannot break down asbestos. It is like glass or ceramic. That does not stop the macrophage trying.

There is a great picture of a macrophage trying to eat an asbestos particle at the end of this imgur gallery:

http://imgur.com/gallery/nBJb6

When trying to dissolve foreign bodies, the nasty chemicals such as hypochlorite can damage DNA. This may be why asbestos exposure causes cancer, although the details are not clear at present.

There is one place in the body where foreign bodies do not cause inflammation – the anterior chamber of the eye. This is because the damage caused by cells such as macrophages would endanger our sight. The eye is known as an immunologically privileged site It means that we can put new plastic lenses in the eyes of patients with cataracts and graft a new cornea from donors without needing immunosuppressive therapy.

And now back to Alfred. He was found to have several large blood clots in his lungs. They had formed in his legs or large veins in the abdomen and travelled upwards and got stuck, reducing the flow of blood in his pulmonary arteries. We treated him with enoxaparin – a low molecular weight heparin. He got better quite quickly and went home with his wife a few days later. She looked much happier than when they arrived. We taught her how to inject her husband with heparin every day.

Heparin is a mucopolysaccharide, made from cow lungs or pig intestines. It is made from the slimy stuff on the surface of the tubes – the mucus. It is separated from the protein it is stuck to using enzymes and chemicals, and purified – the bristles are removed from the brush. We used to use this unfractionated heparin to prevent and treat blood clots.

heparin is a chain of sugars with amino groups and sulphate groups low molecular weight heparin has short chains of five sugars
heparin is a chain of sugars with amino groups and sulphate groups
low molecular weight heparin has short chains of five sugars

Now the long sugar chains are chopped up into five-sugar lengths – low molecular weight heparin. This is easier to give by an injection under the skin rather than into a vein. It is also more reliable in treating and preventing blood clots.

cartoon of fibrin breakdown - from Jfdwolff wikimedia commons
cartoon of fibrin synthesis and  breakdown – from Jfdwolff wikimedia commons

Heparin interferes with the horribly complicated cascade of events that leads to an insoluble protein – fibrin, being formed from the soluble clotting factors circulating in our bloodstream. The system is so complicated because it is vitally important. Stopping blood leaking out of holes in our blood vessels is pretty high up the list of things we have to get right if we are to survive as a species. The clotting cascade is designed to produce large amounts of fibrin clots very quickly when we need it – whether you are being savaged by a wild beast or crushed by a bus, clotting can save your life.  But blood clots in vessels without holes to repair can also be fatal. Alfred could well have died if he had not been treated with heparin.

Fibrin formation is responsible for forming clots in veins. It also strengthens the clots formed by platelets in arteries. The problem is that patients with cancer, or people who have been ill and immobile (or even after a long-haul airplane flight) can develop clots in their veins even when there is not a hole in them.

We suspected Alfred may have a blood clot problem because we found a high concentration of D-dimer in his blood. When a clot forms, say in the wall of an artery which has been damaged, it is remodelled by an enzyme called plasmin which dissolves fibrin. This shaves away the unwanted bits of clot to make them neat and fit for purpose. The fibrin turns into, among other things, D-dimer. Whenever there is a lot of fibrin clot around, the D-dimer level in the blood increases.

Now the food link. I’m particularly pleased with this one – black pudding.

black pudding
black pudding

I went to the butchers yesterday to buy some. I fried it with tomatoes, bacon and sausage for a late breakfast. Black pudding is made in the UK from pigs’ blood. It is cooked, which makes it clot, and mixed with oatmeal and herbs and stuffed into a pig’s intestine from which the inner surface or mucosa has been removed. Drug manufacturers use the mucosa to make heparin. So, black pudding is a large blood clot made in the very organ that gives us a drug for preventing blood clots!