First, Do No Harm

'Primum non nocere' - first, do no harm - is a classic axiom of physicians. Easy to say and remember, correct to the point of truism, it may be hard to observe always in practice.

Prophylactic therapy is especially likely to challenge the axiom. Treatment is prescribed to reduce the risks of future illness, although the person is well at the time. The risks of treatment now are justified if much greater future risks can be mitigated or averted.

Treatment of high blood pressure is a common example. The intention is to reduce the chance of future cerebral haemorrhage [stroke], kidney damage, and heart failure. The general and specific side-effects of therapy are judged less significant than the risks of devastating future disease.

Anti-hypertensives commonly dull the enjoyment of life. Tiredness, lack of energy, low mood, loss of libido and similar symptoms seem to accompany significant lowering of blood pressure, whatever the regimen. I used to teach, half in jest, that telling a patient the blood pressure is high and tablets should be taken indefinitely will change a person in robust health into a complaining neurotic.

And there are also the complications specific to the particular drugs prescribed.

In my experience stopping blood-pressure treatment guarantees a grateful patient.

Anti-coagulant therapy is an especially difficult type of prophylaxis. Abnormal blood clotting may cause serious or fatal embolism: clot which is dislodged from its point of origin, to be carried in the blood-stream until finally it impacts and obstructs an artery; the tissue supplied by that artery loses its blood supply and is damaged or dies - the process of infarction.

Pulmonary embolism is a dreaded complication of surgery to the abdomen, pelvis, hips or legs. Clot forms in pelvic or leg veins, usually with no warning signs. Eventually clot breaks loose, is swept by the blood to the right heart and then into the pulmonary artery. Sometimes the clot is big enough to obstruct the main pulmonary artery, causing sudden death. Smaller clots may obstruct a major branch of the pulmonary artery, causing shock and collapse.

Routine post-operative use of heparin greatly reduces the risk of pulmonary embolism. Modern preparations of heparin make this prophylaxis safe, but the drug must be given by subcutaneous injection.

But heparin use is not without risk.

A 30 year old woman in her first pregnancy gave a family history which was not fully understood. Consequent testing of her blood-clotting system showed a minor abnormality, which in theory might predispose to thrombosis. The doctor prescribed heparin, despite the lack of a history of thrombosis, and her pregnancy.

I was alarmed. I worried about the hazards of heparin in a pregnant woman, especially during labour and delivery. I know that in pregnancy strange things happen to sophisticated blood tests; I doubted the reliability of the abnormal result.

But I was only a relative: I had no clinical responsibility.

In the event she delivered a healthy baby, but had a postpartum haemorrhage estimated at more than 1 litre. She recovered well without transfusion, but she came close to it.

Repeat blood tests gave normal values.

Primum non nocere: and, I might add, leave well alone.

Atrial fibrillation is another condition with a risk of embolism. This disorder of the heart-beat may complicate other heart diseases, and is more common in older patients. The electrical signal triggering the heart-beat fails to stimulate and propagate across the atria - the small chambers which sit above the ventricles. Contraction of the atrial muscle ceases to be co-ordinated and controlled; instead chaotic contractions are triggered by abnormal electrical activities in the atrial muscles.

The atria fail to contract. Blood flow through the atria is slow and abnormal. Clot may form, and then break off into the ventricle, and so into the arterial blood. Clot may then impact in branch arteries anywhere in the body, but obstruction of arteries to brain, intestines, kidney and leg is especially dangerous.

Repeated minor embolism over a long time causes progressive organ damage, notably to brain and kidney.

The risks of embolism are judged sufficient to warrant long-term anticoagulation in atrial fibrillation. Warfarin tablets are the usual prescription. Warfarin has few side-effects, but the dose has to be carefully controlled: too much and the patient bleeds, too little and clots may form. Unfortunately control requires regular hospital visits for a blood test and review, which is a burden for patients, and expensive for the health service, especially if the patient is old, infirm, or disabled.

Effective Warfarin therapy also demands intelligent patient compliance.

Serious bleeding can still occur even in apparently well controlled patients. Accidents happen, unforeseen consequences occur. I will quote two examples from many.

I had an urgent call to theatres. A middle aged man was in surgery for acute appendicitis. The incision was bleeding badly and control was difficult. An urgent blood test suggested he was anti-coagulated. Plasma infusion and other measures resolved the crisis.

We later learned he had been unwell with abdominal pain for several days. A neighbour had given him some tablets which she had been prescribed after an operation. Those tablets were Warfarin.

A woman in her 50's came with thrombophlebitis in the right calf. I prescribed warfarin, as recommended to prevent pulmonary embolism. She attended the clinic and all seemed well. After 5 weeks she came back as an emergency with a severe stroke. Her clotting tests were as expected. She died, and necropsy showed intracerebral haemorrhage.

The coroner recorded a verdict of death by misadventure.

The problem is that it is hard to identify patients who have certainly benefited from prophylactic anticoagulation, but any experienced physician remembers cases where Warfarin has caused crisis or even disaster.

I don't like anti-coagulants, I prescribe them with misgivings, but the prevailing opinion is that the benefits justify the risks, and I must comply.

But always in my mind echoes the advice of an eminent physician, a former mentor: "Warfarin is rat-poison - and that is its proper use".

Primum non nocere. Leave well alone.

The Eleventh Hour of the Eleventh Day of the Eleventh Month

I hate the weasel words of the Whitehall Cenotaph - "The Glorious Dead". 

There's nothing glorious about being dead, especially those slaughtered for nothing in the hell of the trenches.

Rudyard Kipling chose the words, stricken with grief and guilt after the death of his only son.

But he was wrong, no doubt trying to make atonement: understandable, pitiable, but wrong.

Siegfried Sassoon knew from bitter personal experience. He spoke the truth.

On Passing the New Menin Gate

Who will remember, passing through this Gate,

The unheroic Dead who fed the guns?

Who shall absolve the foulness of their fate,—

Those doomed, conscripted, unvictorious ones?

Crudely renewed, the Salient holds its own.

Paid are its dim defenders by this pomp;

Paid, with a pile of peace-complacent stone,

The armies who endured that sullen swamp.

Here was the world’s worst wound. And here with pride

‘Their name liveth for ever,’ the Gateway claims.

Was ever an immolation so belied

As these intolerably nameless names?

Well might the Dead who struggled in the slime

Rise and deride this sepulchre of crime.

John Kipling was killed during the Battle of Loos, in September 1915. Massed infantry were ordered forward in parade-ground formations, towards barbed wire and machine guns. British losses after 3 weeks were 16,000 dead and 25,000 wounded; a short section of the front had been pushed forward 2 miles.

"The Corpse-Field of Loos", the Germans called it, sickened by the slaughter, holding fire as British survivors retreated.

Many of those gunned down were malnourished, poorly educated, conscripted young men from the impoverished slums of London and the big cities. Many wounded suffered hours in the mud before dying.

The loss of young officers was especially grievous: the brightest and the best of their generation, so important in the seed-corn of the future.

"The Glorious Dead."

The story is told that some months later Winston Churchill attended a conference on the Battle of Loos. Afterwards he was asked what he had learned. "Never try such a damn-fool thing again", he growled.

But the generals had learned nothing. They went back to their chateaux and planned the Battle of the Somme.

Remembrance

We approach again the anniversary of the eleventh hour of the eleventh day of the eleventh month; the time we dedicate to remembrance of the numberless casualties of the terrible wars of the twentieth century; in particular the catastrophic European civil wars.

Europe may never recover from the industrialised slaughter of its sons in the Great War, or from the horrific destruction accompanying a second slaughter between 1939 and 1945.

I make no apology for posting again this poem by Wilfred Owen, killed during some senseless attack ordered in the last days of the Great War of 1914-18.

Parable of the Old Man and the Young

So Abram rose, and clave the wood, and went,

And took the fire with him, and a knife.

And as they sojourned both of them together,

Isaac the first-born spake and said, My Father,

Behold the preparations, fire and iron,

But where the lamb for this burnt-offering?

Then Abram bound the youth with belts and straps,

And builded parapets and trenches there,

And stretchèd forth the knife to slay his son.

When lo! an angel called him out of heaven,

Saying, Lay not thy hand upon the lad,

Neither do anything to him. Behold,

A ram caught in a thicket by its horns;

Offer the Ram of Pride instead of him.

But the old man would not so, but slew his son,

And half the seed of Europe, one by one.

This poem was set to music by Benjamin Britten. It is the centre of the War Requiem: music we should recreate every Remembrance day, and which should be played only in live performance.

A Second Chance To Get It Right

This happened in Muscat, in 'Oman.

He was a student in the university. He had just returned from his native village to the campus after a vacation.

He was referred urgently because he had developed jaundice.

He told me he had felt hot and unwell for maybe 10 days. He had diarrhoea, not severe. He had rather vague abdominal discomfort.

He had noticed his eyes were yellow the previous evening; today he was worse.

Unexpectedly he said he had continued to eat, and smoke cigarettes.

There was no significant past history. He had taken no drugs.

Examination showed a well-nourished young man, obviously jaundiced, with a low fever, 38.4 degrees.

The liver was a little enlarged and tender; the spleen could just be felt.

This looked like acute hepatitis, most likely acute hepatitis B. His continued appetite for tobacco was puzzling; aversion to smoking is an important sign in hepatitis. Also I expected him to be more unwell with hepatitis, perhaps with a story of feeling better as the jaundice came out.

Still, everything else fitted.

I arranged some blood tests, and he was admitted to the ward.

Next morning I came to do a ward round, accompanied by a junior doctor and several students.

There was a commotion around a bed at the end of the ward. Several nurses were there, and another was hurrying up the ward carrying several hospital blankets.

It was my 'hepatitis' patient. He was shivering violently, shaking the bed, complaining of feeling cold.

This was a rigor, a sudden severe fever. His body temperature was rising rapidly. He felt cold because the body's thermostat had reset to a value hotter than normal, and had activated the mechanisms to increase heat production.

The clinical thermometer read 40.4 degrees. The penny dropped.

Hepatitis does not cause rigors. Acute malaria does - and malaria can occasionally present with jaundice. After all, the parasites destroy red blood cells, liberating haemoglobin, which is broken done in the spleen to produce the yellow pigment of jaundice, bilirubin.

I took another blood sample to the lab. My colleague quickly made the stained smear, and we looked using the oil-immersion microscope objective.

There they were: tiny parasites of Plasmodium falciparum in 1% of red cells.

Acute falciparum malaria.

An important experience for the students - and indeed, for their teacher.

Back to the ward, to prescribe quinine tablets, 600 mg. 8-hourly for 1 week.

The response was dramatic. His temperature was normal that afternoon; the jaundice disappeared in 2 days. He stayed in hospital until the treatment was finished - he could hardly go back to the student hostel where he had a room, and it was important to complete the treatment as prescribed.

Later I asked about his home village. It was in a wadi I knew well, with extensive palm groves and gardens attesting abundant water. Almost certainly it was a hot-spot for malaria.

"Where have you been recently" is a question to remember while taking a medical history.

A Painful Lesson

This happened 8 years ago. I have changed details where necessary.

I was working in the north of England. We had been on 'take-in' for 24 hours. I met my team of junior doctors at 0745 to do the 'post-take' ward round which ended our duty period, after which the juniors would be free until 0900 the following morning.

Some 2 hours later we had seen and made management decisions for the new admissions, maybe 12 or 14 in number. I thought we had finished.

But there proved to be one more to see, in a side-room, usually used to isolate cases where infection was feared.

Before we went in the registrar warned me the patient was a man who had undergone surgery for 'gender reassignment'. The patient had wanted admission to the female ward, but had to go in the side ward, for obvious reasons.

A warning bell should have sounded in my head, but it didn't.

The name on the bed-notice was 'Barbie' - no surname. The cover of the notes had 'Barbra' written in marker pen across the top.

The patient was heavily built, plump faced, with broad shoulders and big hands. The hair was long, platinum blonde, loose, but carefully combed and clipped. Heavy make-up did not completely conceal a dark beard area. Large filigree gold rings hung from each ear-lobe. There was a whiff of perfume, which did not disguise a smell of tobacco.

Barbra was wearing a white cotton sleeved bed-gown: breast development could be seen. Nearly every finger had a ring; the nails were painted purple, and manicured.

Barbra was taking daily doses of an oestrogen preparation, and several other preparations of vitamins, minerals and tonics.

Barbra was unemployed, living with a male partner in social housing.

The clinical problem was chest pain, and suspicion of angina pectoris. The pain had lasted several hours the previous afternoon, but had resolved after admission. There was a previous history of hospital attendance for similar pains, but no heart or chest disease had been identified.

On this occasion ECG's taken on admission and 16 hours later had shown no abnormality. Blood values on admission had been in the normal ranges; the results of a second set of blood tests were awaited. Chest X-ray was unremarkable.

Examination revealed a normal pulse, blood pressure a little increased, normal heart sounds, and no other significant signs.

The clinical evaluation was that this was unlikely to be heart disease. Barbra could go home that evening, provided there were normal results from the third set of tests and ECG at 24 hours after admission, as the hospital protocol required.

I discussed the findings with Barbra. It is difficult to be totally confident that such chest pain is not angina, so I asked for an appointment for out-patient review in a week's time. The atmosphere was friendly, reassuring and good-humoured, or so I thought.

Barbie failed to attend follow-up.

Instead the hospital received a furious letter of complaint ten days letter. Both sides of a foolscap sheet, written by hand in small neat capital letters. While discussing Barbra's chest pain I had used male personal pronouns - he, not she; his, not hers.

There were complaints of severe emotional distress in consequence, threats of litigation, and of a complaint to the General Medical Council. There was a demand that I should attend counselling for my attitude problem to transsexual people.

I was horrified. This torrent of anger was totally unexpected, and unreasonable.

I spent several days - and nights - worrying. The threats caused little anxiety. but the ferocious personal accusations did. How could an unintended impoliteness cause such fury, especially as it went unremarked at the time?

In the end I sent a bouquet of flowers with a brief note of apology: I heard no more.

I subsequently learned there had been a previous, similar incident. Barbra came before with chest pain, and had made a scene in the ward when a colleague had used the wrong personal pronoun. "I think", said my colleague, "Barbra gets a kick out of aggrievement and outrage. You walked into a trap".  

Maybe: maybe people like Barbra have powerful psychological stresses relieved by an outburst of anger. Victim status brings rewards, too.

But there remains a difficult issue for the physician. Male sex is in the Y chromosome in every cell in a man's body. Genitalia can be amputated and some simulation of female parts created by plastic surgeons; female sex hormones can be taken; womens' dress can be worn, and womens' behaviour emulated: still the genetic reality remains. The white cells in the blood will lack the Barr bodies which identify a blood specimen as female.

Does the male pattern of disease prevalence persist when female hormones are taken for years? Do oestrogens protect men against coronary heart disease, as they do women? I don't know.

What is the chance of cancer in an oestrogen-stimulated male breast? I don't know.

If Barbra came complaining of difficulty passing urine would I be wrong to suspect prostate problems?

I'm glad I'm retired.

British Democracy 1649-2009

Democracy was born in Britain on the 4th. January 1649. On that day the House of Commons enacted itself as the final authority in England, in words which have echoed down the centuries.

Resolved, &c. That the Commons of England, in Parliament assembled, do Declare, That the People are, under God, the Original of all just Power:

And do also Declare, that the Commons of England, in Parliament assembled, being chosen by, and representing the People, have the Supreme Power in this Nation:

And do also Declare, That whatsoever is enacted, or declared for Law, by the Commons, in Parliament assembled, hath the Force of Law; and all the People of this Nation are concluded thereby, although the Consent and Concurrence of King, or House of Peers, be not had thereunto.

The people are the original of all just Power; the Commons, representing and chosen by the people, have Supreme Power. This is the fundamental principle of democracy.

Others enacted the same principle for themselves, notably the Americans. It is the root of all constitutions written at the independence of the countries of the British Empire.

Through the centuries the British people kept faith with this fundamental democratic principle, when necessary fighting devastating wars in its defence.

Today, 4th. November 2009, this principle is formally abandoned. Yesterday the Czech president signed the Constitution of Europe, the Lisbon Treaty, devised and written by the unelected Eurocracy.

The Eurocracy has taken to itself the power to over-rule national governments, including our House of Commons. The new unelected President of Europe will have precedent over our Prime Minister. Britain is to be an off-shore island in a European federation, a German-French hegemony.

All this has come about by stealth, small step by small step. Politicians have lied to their electorates and betrayed solemn undertakings to bring us to this.

Let New Labour be remembered as the government which ended 360 years of sturdy democratic  independence of my country.

Let Gordon Brown be remembered as the unelected Prime Minister who sneakily signed the Lisbon Treaty without the authorisation of the British people.

From now on I shall give financial and electoral support to politicians pledged to repatriate the Supreme Power which a generation of politicians have ceded to the Eurocracy. This will over-ride all other issues. If it means supporting people to whom previously I would not give time of day, so be it.

The Endgame.

Today the High Court in Prague gives its verdict on the legality of the Lisbon Treaty in the context of the constitution of the Czech Republic. It is expected to declare no serious problems.

President Havel will thereby have to end his stand against the ambitions of the Eurocracy. The last obstacle to the Lisbon Treaty has failed; Havel must sign; a Federal Europe will be established in all but name.

Who will get the new top jobs, especially who will be the first president? I suspect we are seeing the endgame of the Blair Retirement Plan.

Slowly we are understanding the final objectives of the european policies of Prime Minister Blair. As always, the good reasons were trumpeted, the real reasons were suppressed or denied.

The good reasons are so familiar: Europe as a world superpower to balance American hegemony; wonderful commercial opportunities in an ever expanding market; Britain at the heart of Europe, a wise, experienced, senior member of this union of high ideals, punching above its weight; Europe as a great force for peace, reconciliation, and human rights. Yesterday we heard it all again from David Miliband.

I will be generous and allow that the Eurocracy probably believes its own rhetoric: the good and the real reasons are complementary, the public and private ambitions co-exist.

The real reasons can only be surmised, but I think the following is more likely to be reality than cynicism.

As the consummation of a political career, an EU appointment is devoutly to be wished.

The Aristeurocracy - the cabal of senior eurocrats - enjoys power with little democratic accountability, a most tempting prospect for those wearied by the tribulations inflicted by an electorate.

They believe the hand of history is on their shoulders - if I may borrow a phrase.

Better to walk with destiny than cope with the problems of little people in a weekly constituency surgery; better to present your case to a sympathetic EU committee than have to argue it forcefully against an opposition in the House of Commons.

And much better not to be subject to proper audit of your expenditure decisions.

No-one mentions money, of course. Only the vulgar raise the issue. Called to public service, our masters are indifferent to the high salaries the Eurocracy awards itself, they reluctantly accept the multitude of expenses and other perks, and the wonderfully generous pensions are no more than their just rewards.

After 5 years even a simple MEP can expect a pension and maybe a million pounds saved, while an EU commissioner can expect a very comfortable future.

We remember that Tony Blair promised that the British rebate was safe in his hands. Mrs. Thatcher had negotiated a substantial relief of Britain's net contributions to the EU. In the event he conceded the rebate in return for a verbal assurance that agricultural subsidies would be reviewed sometime soon, and maybe other unspoken concessions and understandings.  

At the same time he was discussing with other leaders the job description of the President of Europe to be created by the new constitution - which mutated into the Lisbon Treaty after rejection in referenda in France and the Netherlands. It is reported that he showed great interest in the presidency, arguing for detailed changes in the initial description.

Yes, I know I should be ashamed even to think that Mr. Blair may have allowed considerations of personal opportunity to influence him in such dealings: perish the thought!

But there is no doubt about the consequences of the Blair concessions. Over the next 5 years Britain's increasing obligations to the EU will leave little change from 40 billion pounds - and that's just net contributions to the EU budget, our serious trade deficit with Europe will continue. That huge sum will be borrowed. This is the 'elephant in the room' in all discussions of Britain's financial crisis.

The Blair Retirement Plan has had a difficult ride so far. First the delays caused by referenda results. Then the risk of collapse of the Brown government, and a new Tory government promising a referendum in Britain. Mandelson was shipped back to London to buttress Brown until the Lisbon Treaty could finally be ratified. The irish were bought out, and the Czech nuisance may soon be over.

Blair's mate Silvio backs him for President, and Sarkozy is open to persuasion. Others lower in the EU pecking order are variously for, against or indifferent. In the end Blair's ambitions will be decided by Die Bundeskanzlerin, Frau Angela Merkel.

But nothing is for nothing in the EU. Blair's budget concessions were years ago. Is there any other card the British eurocracy could play for Blair?

What if Frau Merkel makes her support conditional on Britain joining the euro? Could Brown be persuaded his conditions are fulfilled, and the time is right to bounce Britain in? He too must be wondering about his future opportunities. He has nothing to lose, a chance to prove he can be decisive, and bid for a place in history. Influential people would praise him as a statesman, and at the least he would deeply embarrass the Tories.

Ridiculous!

The DROLLS 1-3

DROLL: the Doctor's Record Of Lessons from Life.

Wise aphorisms learned in the school of experience. My first three are here.

DROLL 1: The best apples on the tree are always just out of reach.

DROLL 2: The ripest apple is the one that falls as you try carefully to gather its neighbour.

DROLL 3: The better the apple, the more it attracts pests and parasites.

Read, mark and learn from one who knows!

Liver Failure - Last Words [ for now ... ]

There exists no reliable system of artificial liver support, despite a half century of expensive research.

There are kidney machines, heart machines, lung machines; there are well established methods to manage loss of intestines, pancreas, endocrine glands, skin, even reproductive organs.

There is no liver machine, and less radical management of liver failure is reactive. We lack the fundamental understanding of liver function necessary for confident, precise management. We have no medical means to reactivate brain and kidney function in liver failure; only liver recovery or transplant does that.

Livers for transplant are hard to obtain. In liver failure the need is urgent: the patient will die in a few days without the transplant. Perfusion techniques mean a liver taken for transplant can now be kept in reasonable condition for a day or two, buying time to bring liver and patient together, in a prepared theatre, with experienced staff. Even so, the opportunities for transplant in liver failure are few. There is no prospect of a 'liver bank', like a blood bank.

In all surgery the best results are from routine, planned procedures. Liver transplantation is major surgery demanding specialised facilities and meticulous preparation.

Animal livers have not proved useful. They cannot be transplanted. In artificial systems they produce plasma for the animal species of origin, which is likely to have serious differences from human plasma.

Liver failure is an unsolved clinical problem. We may appreciate the magnitude and complexity of the abnormalities in liver failure, but so far there is no full understanding of what happens when the liver goes down. Without that strategic understanding management has to be based on trial and error, experience, even guesswork.

Liver medicine awaits a breakthrough in research into the basic physiology of the liver.

Liver, Brain and Kidney

In my last posting but one I described the clinical features of liver failure. It is interesting that many problems in the management of liver failure are caused by the secondary failure of other organs, especially the brain and kidney. The direct consequences of liver failure - jaundice, blood clotting defects, low blood glucose and low body temperature - are less threatening or are easily treated.

Secondary brain and kidney failure occur together, though one may more severe. If the liver goes down it takes brain and kidney down with it.

Perhaps brain and kidney functions are impaired by the same abnormality, caused by loss of liver function.

If liver function recovers, naturally or after transplant, brain and kidney recover too. The problems are functional, not structural.

I have seen a woman in liver coma for five days recover consciousness in less than twelve hours after a successful liver transplant.

What do brain and kidney have in common? How might liver, brain and kidney interact?

Liver function is central to these questions: kidney failure from other causes does not affect liver or brain function; similarly, coma from other causes does not affect liver or kidney.

High blood flow is a common feature of these three organs. Each takes about a quarter of cardiac output at rest - over a litre per minute in each case. Reduced blood flow may be a factor in the secondary failure of the kidney, but not for the brain.

Brain and kidney also share a dependency on the sodium-potassium pumps in their cell membranes. These produce the chemical and osmotic gradients fundamental to kidney function, and the electrical potentials on which the brain depends.

The conventional wisdom is that liver failure is an intoxication, Substances accumulate in the blood which poison brain and kidney.

Ammonia is the traditional culprit. The problem is that clinical severity does not correlate with blood ammonium values, and washing out ammonium by dialysis does not improve the patient.

The ammonium ion is physically similar to the potassium ion: it is conceivable that ammonium could interfere with sodium-potassium pumps.

There is a long list of other candidate toxins, including methionine and tyrosine or derivatives, diazepam-like substances, and bacterial endotoxins. The same problems apply: poor correlation of biochemical values and clinical state, and failure to improve on dialysis.

These objections weaken if the toxin binds to plasma proteins, or is itself a protein or other macromolecule. But exchange transfusion is no benefit either.

The intoxication hypothesis is strengthened by the undoubted improvement after emptying the colon: patients in stupor or early coma may be aroused by purging or enema. 'Bowel sterilisation' using antibiotics may also be beneficial. Unfortunately these manoeuvres fail if the liver failure is severe.

[A doctor prescribing an enema for a patient in liver coma should do it himself.]

Deficiency is the alternative to intoxication. The liver produces substances essential for brain and kidney function: loss of these essentials causes the secondary organ failures.

Glucose is an obvious example. Reduced blood glucose content will certainly impair and eventually damage the brain, but most patients in liver coma have adequate blood glucose, naturally or by infusion.

The rapid start-up of brain and kidney after transplant does suggest the restoration of something vital for brain and kidney cell function, either a substrate or an activator of a metabolic process.

Poor activity of membrane sodium-potassium pumps can be demonstrated in white blood cells from patients in liver failure. Incubating the cells in normal plasma rapidly restores full activity.

Such depressed pump activity resembles the effect of digoxin on normal cells. Patients in liver failure do not show the ECG changes familiar after digoxin dosage.

But, it is legitimate to ask, why do membrane sodium-potassium pumps have a receptor for digoxin? The same question asked of the brain and morphine led to the discovery of endorphins.

Digoxin and bile acids share the unusual 5-beta steroid nucleus. So far as I know, this type of steroid is produced only by the liver in humans. Bile acids accumulate in the blood if the bile duct is obstructed. They cause intense itching, and may affect the ECG, but brain and kidney functions are maintained.

So this is my hypothesis. The liver produces a regulating activator of the sodium-potassium pumping enzymes in cell membranes, especially in brain and kidney. Perhaps other ion transporting enzymes are similarly regulated. Function of these enzymes is impaired if supply of the liver activator fails, with consequent encephalopathy and nephropathy.

The activator may be a 5-beta steroid molecule, similar to a bile acid. It may be short lived in the body, so constant synthesis is necessary. The activator binds to the digoxin receptor on the enzyme, and increases its activity. Digoxin binds but does not activate, and blocks access of the activator.

Cerebral oedema is a lethal complication of liver coma. It must happen because the pumping of salt and water out of brain cells has collapsed. This is a hint that membrane pumps are failing, but of course other causes must be considered.

And. of course, the putative activator might not be a 5-beta steroid, but some other substance produced by the liver, maybe a peptide, maybe an active vitamin such as adenosyl-cobalamin, or something else entirely.

May be it is another metabolic pathway which is activated, such as ATP production. Ion pumps need ATP.

I have studied liver failure for many years. I have seen theories and treatments come and go. I perceive that there is a fatigue in liver research at present, especially in the mechanisms and management of liver failure. I suspect the subject needs a breakthrough in understanding of liver function, especially its interactions with other organs.

If I had a research facility, my priority would be liver-kidney interactions - much easier to study than the liver-brain axis. Membrane ion pumps would be my first focus.

The Death of Stephen Gately

What can reliably be concluded about the cause of death of Stephen Gately? Sudden death does occur in apparently fit 33 year old men, but the list of diseases which can do this is short.

Conditions which might cause sudden death in a young man without previous diagnosis include:

- aortic coarctation;

- hypertrophic cardiomyopathy;

- aortic valve stenosis;

- coronary thrombosis;

- pulmonary embolism;

- subarachnoid haemorrhage.

All these would be identified with confidence at necropsy.

Some infections can rarely cause acute death - death within hours of onset. Two might be listed:

- meningococcal septicaemia;

- influenzal pneumonia.

These have a notoriety in this respect, but of course other infections might just do it.

A patient would feel ill, and raise alarm, probably even if sedated.

The authorities have reported that Stephen Gately was found in a kneeling position by a sofa, his head on a pillow. He had vomited, but had not inhaled vomit. At necropsy he had pulmonary oedema.

Pulmonary oedema is fluid accumulation in the tissues and alveoli of the lungs. It can be rapidly fatal if untreated. An erect posture relieves the severe breathing difficulties of pulmonary oedema, so his position when found is consistent.

Pulmonary oedema is not the same as fluid obstructing airflow in the trachea and bronchi, as would be found if vomit were inhaled, or in drowning.

The fluid in pulmonary oedema comes from the blood, not from outside.

I can imagine him asleep on the sofa, awakening in severe respiratory distress, weakened and confused by lack of oxygen, and managing to struggle to a kneeling position before final collapse and death.

The problem is that pulmonary oedema is not a complete diagnosis. In Britain a death certificate citing pulmonary oedema alone would be returned by the registrar. Pulmonary oedema is due to a primary condition, most commonly affecting the left ventricle of the heart and causing it to fail.

The first four conditions listed above could do this, but none is mentioned by the authorities. Perhaps more information will be released eventually.

Speculation is always dangerous, especially where there is celebrity and controversy. However I can think of one further cause of sudden death from pulmonary oedema, and that is the drug Ecstacy, MDMA.

Acute heart failure and pulmonary oedema are recognised complications of high doses of MDMA. This cause of death might not be evident at necropsy.

I understand samples are in the toxicology laboratory, so this hypothesis will be tested.

In the meantime we can only reflect again on the fragility of life, especially when acutely challenged, and mourn the death of a man in his prime.

Cirrhosis: Foul and Fatal

Cirrhosis: cirrhosis of the liver. It is an untreatable, lethal disease. Any study of the prognosis of cirrhosis in Britain is likely to find that, from the time of diagnosis, half are dead within one year, and very few will survive five years. Many cancers have similar prognoses.

The incidence of liver cirrhosis is increasing, especially among women. Epidemic alcoholism is the most important cause, but demographic change is increasing the number of cases of imported liver disease, notably chronic hepatitis B and C.

Cirrhosis should be an active subject of public and political concern, but there is lack of understanding about the disease, and a popular tendency to dismiss warnings about alcohol.

Make no mistake. Cirrhosis is deadly, and a foul way to go. The occasional patient can be rescued by liver transplant, but the opportunities for this dramatic intervention are few.

Cirrhosis is a process which destroys normal liver structure and function. Sustained or repeated injury to the liver lights up a chronic inflammation, which progressively damages and destroys liver cells. Fibrous scars develop in the liver substance. The injury also damages the liver's normal regeneration and repair mechanisms, so that abnormal nodules of liver cells begin to replace surviving normal liver tissues.

These nodules fail to link properly into liver blood and bile systems: the nodular cells cannot provide normal liver function.

Eventually the smooth normal liver is replaced by a nodular scarred mass, essentially a fibrous conglomerate of benign liver tumours.

Cirrhosis, once started, tends to progress remorselessly: stopping drinking has little effect.

The blood supply of the liver is unusual. Blood coming from the intestines, spleen and pancreas is intercepted by the liver, for processing before release into the general circulation. The veins from intestines, spleen and the pancreas join to form the portal vein, which then branches into the liver. There is an arterial supply, the hepatic artery, but this is relatively small.

Total blood flow through the liver at rest is about one quarter of cardiac output, approximately equal to blood flow through the brain.

What is the function of the liver? This was a favourite question to students, and few indeed were the occasions when the answer was satisfactory.

The liver is a gland secreting two fluids.

Bile is the first: a liquid secreted through the bile duct into the duodenum. It is the pathway for the excretion of bilirubin, a breakdown product of haemoglobin. Bile also assists digestion, providing the detergent bile acids, phospholipids and cholesterol needed, especially for the absorption of fats.

Blood plasma is the second secretion of the liver, and by far the most important.

Blood is the product of three organs: bone marrow and lymphatics supply the cellular components; the kidney regulates water and mineral balance; the liver synthesises and controls the complex array of organic molecules which make up the plasma - glucose, albumin, blood clotting factors and so on.

The liver is the custodian of the constancy of the internal environment, the condition for free life, independent of the environment.

If the body is an engine, the liver is the carburettor.

Liver function ensures that the blood has a constant composition: the concentrations of plasma components are controlled within strict limits. It synthesises as necessary, stores and releases glucose and other nutrients, and removes wastes and foreign substances.

Liver function maintains the plasma volume, by regulating the synthesis and plasma concentration of albumin.

The liver is the main source of body heat at rest: its intense metabolism produces heat. It is notably hot to the touch, and blood leaving the liver is the hottest in the body, commonly at least one centigrade degree above the body temperature.

The liver has defence functions too - trapping and destroying bacteria and foreign materials in the blood from the intestines.

Liver, kidney and bone marrow function must be closely co-ordinated. These interactions are poorly understood, but their failure in liver disease has important clinical consequences.

The liver has a huge functional reserve: probably 90% of liver function may be lost before clinical problems begin.

The syndrome of liver failure has three main parts.

Jaundice is the first: accumulation of bilirubin in the blood. This is disfiguring, but does little to impair health otherwise.

The second is nephropathy: impaired kidney function. The patient cannot excrete salt and water adequately. Daily urine volume falls, and sodium excretion may be less than a tenth of normal. The normal urinary excess of sodium over potassium is reversed.

Oedema develops, especially of the lower parts - feet, legs, abdomen. There is likely also to be fluid accumulating in the abdomen - ascites.

This retention of water dilutes the plasma: thus the concentration of albumin falls, but the total body albumin pool is normal or even increased.

In some way the liver drives kidney water and salt excretion. The mechanism of this interaction is not clear.

The third is encephalopathy - disturbance of brain function. In the early stages this causes apathy, loss or reversal of diurnal rhythms, loss of social inhibitions, poor spatial discrimination, and other neuro-psychiatric changes. 'Flapping tremor' is a transient, abrupt loss of posture of the out-stretched hands, with instant recovery. It occurs in other metabolic brain diseases.

Stupor leading to coma is the final state of liver failure. Once established, coma is difficult to reverse and the prognosis is poor.

Fetor is common in liver failure - an unpleasant smell to the breath, like bad meat. It is caused by the excretion of methylated sulphur compounds into the inspired air.

Liver failure is one mode of death in cirrhosis. There are at least two more.

Blood flow through a cirrhotic liver is impeded. Pressure increases in the portal vein, and venous pathways bypassing the liver open up. Eventually varicose veins develop, notably in the lower oesophagus, but also in the rectum and round the umbilicus. These are points where the portal and systemic circulations meet.

Oesophageal varices are large, thin-walled veins, carrying a big flow of blood. They rupture easily, causing severe bleeding into the oesophagus, and so massive vomiting of blood. This dangerous catastrophe is difficult to manage. Varices can be blocked by endoscopic injections of sclerosing substances, when they are not bleeding. Occasionally other interventions are possible.

No one who has witnessed a patient dying in a bed-full of blood will ever doubt the dreadful consequences of cirrhosis.

Finally, malignancy may develop in a cirrhotic liver. Usually a sudden deterioration raises suspicion. Sometimes a blood test can confirm the diagnosis, but the diagnosis may be made only at post-mortem. Malignant change is untreatable and likely to be rapidly fatal.

Never risk cirrhosis. Heed warnings about safe drinking; immunise against hepatitis; practise safe sex - hepatitis is transmitted venereally.

Cirrhosis is as lethal as cancer.