Tag Archives: adrenaline

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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Asthma and pineapple

Asthma can be a horrible disease. I don’t have asthma but a lot of people I know do. I can only imagine what it must be like to not be able to breathe. Patients I see often say that during a bad attack it feels like they are drowning. We admitted a lot of patients with asthma this week – it is one of the common reasons why young people need to come into hospital.

Yesterday we saw Christine, age 26. She has been asthmatic since she was young. Her mother said that it started when she was less than 2 years old. She also had bad eczema – but that is not a problem now. Both Christine’s sisters and her father have asthma, but not bad enough to bring them into hospital. Her 2 year old daughter, Zoe has just started nursery and is getting a new cold every few weeks (normal 2 year olds get, on average, about 8 colds per year) and she is worried that Zoe is getting more wheezy with every one. Christine also caught a cold and just as her runny nose and sore throat were getting better, her breathing started to get worse and she could hardly speak as she was so breathless. At 4 in the morning her husband was really worried about her and called the ambulance.

We’re not very close to understanding why some people get bad asthma. Genes are obviously important as it runs so strongly in families. Everyone thought that with rapid DNA sequencers we would have the answer long before now – surely we just have to look how the genetic code of those who suffer from asthma differs from those who do not and find the gene responsible?

Of course, lots of scientists have been doing just that, but like many other inherited diseases such as hypertension and schizophrenia, we have found that it is not that easy. At least 100 different gene differences have been shown to be associated with asthma, not the two or three originally hoped for. Although I’m not an expert in this area, I don’t think we can say right now that the main genetic cause of asthma is x, y or z.

And then there’s the environment. There seems to be something about living in a modern, industrialised society which makes asthma more likely. Certainly it is much more common in the UK than 50 years ago. Is it television:

A Sherriff et al: Association of Duration of Television Viewing in Early Childhood with the Subsequent Development of Asthma. Thorax 2009;64:321-325.

Or perhaps Simon Cowell, or Barbie dolls? – probably not. The “hygiene hypothesis” is at least superficially attractive. Lack of exposure to nasty germs early in life means that when we are adult we respond to environmental allergens in a different way, provided we have a certain mix of genes.

The fact that eosinophils (closely related to neutrophils I talked about two posts ago*) are found in large numbers in asthmatic lungs, and these cells are thought to be important in protecting us from worm infestation makes the idea that exposure to worms might protect us from asthma. There is some evidence that  that hookworm infection is protective.

Hookworms are small and extremely ugly creatures which are common in some parts of the world – thankfully (?) not in the UK or US – although asthma is more common here than in third world countries.

hookworm

Hookworm from istockphoto (with permission)

Wikipaedia says that 600million people worldwide are infected with this parasite. The way to get hookworm is to tread with bare feet on infected faecal matter.

The hookworm larvae burrow through the skin of your foot and find a vein. They swim up the vein all the way to the heart – they are going with the current so it doesn’t take too much effort. They pass through the right side of the heart into the lungs, and get trapped in the lung capillaries. Then they start burrowing again – this time into the airways of the lung, get coughed up and swallowed into the stomach. Presumably when they are tunnelling through the lung is the point when the immune system is modified by hookworm infection. The worms are tough enough to survive stomach acid, but when they get to the small intestine they use their two pairs of sharp teeth to latch on to the inside of the gut wall. There they live happily, sucking blood from the host, and when mature, lay eggs to be eliminated mixed in with faeces from where their babies hatch, hoping upon hope that another unsuspecting barefoot person will step on them. If you want to know where in the world you need to make sure to have shoes on, and see some even more upsetting pictures of hookworms and this nasty nematode’s questionable lifestyle see:

http://www.infectionlandscapes.org/2012/02/hookworm.html

Whatever the underlying cause of susceptibility to asthma, it is clear that asthmatics respond to certain inhaled particles differently, and in a way that is not helpful to anyone (except pharmaceutical companies). These allergens include

1. house dust mite faeces

2. pollen

3. cat hair

All medical articles about asthma mention these three things, which seem to keep the disease going in those who suffer from asthma. What links them?

House dust mites are everywhere in houses. They are very small, again not particularly attractive creatures.

Slide3

They eat human skin flakes, of which there are plenty in house dust (we each produce and shed ¾ kilo of skin cells every year). Skin is made of keratin, a tough protein polymer which also makes nails and hair. House dust mites love it. The problem is that they have only very tiny intestines and have problems breaking down the tough keratin. So what they do is soak the chewed-up skin flakes in digestive enzymes (one is called Der F 1), pack it into little balls, cover it in a thin membrane and then poo it out in a small (25 micron) faecal particle – about 20 each day. They then wander on their way and wait for the enzyme to do its work. When the faecal particle bag is nice and gooey, with the keratin dissolved, it will come back and eat it. Yum. This coprophagia (eating poo) is also seen in a surprising number of other creatures such as rabbits. Do not read the Wiki article on coprophagia.

Slide2sem of house dust mite

Because house dust mite faecal particles are so small, they stay airborne for a long time when sucked up by a vacuum cleaner and blown out into the room are easily inhaled deep into the lungs. Imagine now that you are one of the cells lining the surface of the lung – a bronchial epithelial cell. This poo-bag, the size of a large bacterium and heavily armed, lands on you. Fully tooled up with digestive enzymes threatening to dissolve you. I’m not surprised that you panic and call the police. The police come in the form of eosinophils, macrophages, basophils and lymphocytes when the alarm (interleukin 8 release, for example) is sounded. They arrive then throw their weight around, releasing all sorts of munitions like hypobromite, leukotrienes, histamine and a range of inflammatory cytokines. There is collateral damage. The effect of this activity is that the smooth muscle surrounding bronchi reacts to these chemicals by constricting. I don’t think anyone knows why bronchial smooth muscle does this – it hardly seems sensible or helpful. It certainly causes a lot of problems. At the same time there is swelling of the small airways because the inflammation caused by infiltration of these cells causes fluid to accumulate in the wall of the small bronchi, and on top of that there is more secretion of mucus than normal. All these things go together to reduce the size of the hole down the middle of the airways and make breathing difficult – asthma.

As well as constricting in response to these inflammatory chemical signals, the bronchial smooth muscle becomes much more “twitchy” – constricting more than usual in response to cold air, exercise, smoke and other triggers such as viral infections. All these cause an imperceptible increase in constriction of airways in non-asthmatics. For people like Christine a simple head cold can mean several days in hospital, a stressed-out husband, a worried daughter, and two weeks off work for both parents.

What about pollen? This is made by the male part of flowering plants – the stamens. When pollen lands on its lady partner (the stigma) that’s just like holding hands – it still has a lot of work to do before it can make babies. It has to burrow down into the gynaecium, using digestive enzymes, so that its male DNA can combine with female DNA. Again imagine the poor bronchial epithelial cell confronted with a randy pollen particle landing on top of it wanting to penetrate with its digestive enzymes – call the cops!

Slide1

Cat hair is also made of keratin. It is finer than dog’s hair and more likely to break up into small particles that can be inhaled. The story I’d like to tell you is that because cats lick themselves their hair is covered with saliva which contains digestive enzymes and therefore provoke a similar reaction from lung cells.

Slide1

I don’t think its quite so simple as that, for it seems that the allergen in cat hair is also produced from sebaceous glands as well as saliva– a protein known as Fel D 4.  Nobody knows what this protein does. Clearly the bronchial epithelial cells of asthmatics are very frightened by it. Maybe it looks like Michael Gove.

So how can we prevent asthma? Can asthmatics avoid inhaling allergens? The problem is that the offending particles are very small and get everywhere. There were some really interesting experiments in the 1980s when asthmatics were kept in special hospital rooms for 2 months or more with fine filters to keep out airborne allergens. Most of them had a remarkable improvement in their asthma, only to get worse again when they returned home. If you want to read more about it see:

Platts-Mills T et al. Reduction of bronchial hyperreactivity during prolonged asthma avoidance. Lancet 1982(2) pp 675-678.

Nobody has yet come up with a way to prevent asthmatics breathing in airborne allergens at the same time as living a normal life.

So, although we give advice about allergen avoidance to our patients, the main effort is in reducing the amount of lung inflammation. Christine is on a course of steroids (prednisolone), which is quite effective, but it takes a few days to work and concerns her, because of its long-term side effects.

Christine also takes salbutamol inhalers. Salbutamol is a drug which is designed to mimic adrenaline (epinephrine), causing relaxation of bronchial smooth muscle and therefore opening up the airways. It is quite effective when inhaled in the lungs but many patients are bothered by tremor with this drug, as some inevitably gets into the rest of the body. Christine says that sometimes she can’t hold a cup of tea without spilling it when she has had a lot of salbutamol nebulizers.  Voluntary muscles – the muscles which moves our arms and legs – respond to salbutamol and epinephrine by becoming unstable and twitchy. Imagine you are being chased by an axe-wielding psychopath. You need to run fast. You need to be strong. In amongst the normal muscle fibres are special devices called muscle spindles. These spindles control the speed and force of contraction. Adrenaline and salbutamol, acting on beta 2 receptors in the muscle spindle, turn up the amplification. This causes instability and loss of precision and results in the tremor caused by fear and salbutamol. Speed and strength are good for getting away from the psychopath, but not good for drinking cups of tea. You can’t have rapid response and fine control. For more info read:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1400891/pdf/brjclinpharm00139-0063.pdf

The food link this week is pineapple. Pineapple contains a digestive enzyme called bromelain, a cysteine protease with the same function to break down protein as the digestive enzyme in house dust mite intestine.

pineapple

Uncooked figs and papaya also have a similar proteolytic enzyme. This means if you try to make jelly (Jell-O in the US) with pineapple it will not set because it breaks down the gelatin protein and stops it working. You can use fresh (not canned) pineapple juice as a marinade to make meat more tender – be careful, or the meat will end up as a sloppy mush.

*eosinophils also have a peroxidase like neutrophils, but eosinophil peroxidase preferentially combines hydrogen peroxide with bromide, to produce hypobromite, which is presumably more effective in killing worms than hypochlorite.