Wednesday, March 31, 2010

Aphorisms 10

Opportunity is missed by most people because it is dressed in overalls and looks like work. - Thomas Edison

If Barbie is so popular, why do you have to buy her friends?

The only substitute for good manners is fast reflexes.

How do you tell when you run out of invisible ink?

OK, so what's the speed of dark?

I couldn't repair your brakes, so I made your horn louder.

How a man lives echoes in eternity (the film Gladiator)

Albert Einstein used to say, “Not everything that can be counted counts, and not everything that counts can be counted.”

While the individual man is an insoluble puzzle, in the aggregate he becomes a mathematical certainty. - Sherlock Holmes

Statistics are no substitute for judgment. - Henry Clay.

Say you were standing with one foot in the oven and one foot in an ice bucket. According to the percentage people, you should be perfectly comfortable.

Sunday, March 28, 2010

Sickle cell anemia

I have committed to teaching the juniors next week on sickle cell disease. In my 35 years at Bournemouth I had only one patient plus some visiting students who had this disease, so I can hardly pose as an expert.

But it is one of the most common genetic diseases worldwide and in America occurs in 1 in 2400 live births. Among African Americans the incidence is 1 in 400. In some places in Britain everybody has a screening test for it at birth, but Bournemouth is not one of them, malaria being quite rare here.

The abnormality is due to the substitution of valine for glutamic acid at position 6 in the beta chain of hemoglobin. Hb S is insoluble and forms crystals when exposed to low oxygen tension. It then polymerizes into long fibers, each consisting of seven intertwined double strands with cross linking.

It is only when the sickle gene is inherited from both parents that the full picture emerges. The features are of a severe hemolytic anemia punctuated by crises. Hb S releases oxygen to tissues more easily than Hb A so the anemia is often more severe than its symptoms. Interestingly some patients live fairly normal lives without incident.

The crises may be painful, visceral, aplastic or hemolytic.

Most common are painful crises caused by the occlusion of small blood vessels. They are precipitated by such factors as infection, acidosis, dehydration or any condition causing low oxygenation (altitude, anesthetic, obstetric delivery or, violent exercise), exposure to cold or vascular stasis. The occlusions may occur in bones (hips, shoulders and vertebrae are most common), the lungs and spleen. The most serious events occur in the brain. In children the hand-foot syndrome is common when occlusions occur in the small bones. It may lead to digits of varying length.

Visceral crises are due to sickling within organs. The most common occurs in the lungs with infiltrates in the lungs causing severe respiratory distress and is the commonest cause of death. Sickling in the liver and spleen can also cause severe illness.

Aplastic crises occur either because parvovirus puts a halt to red cell production or because the body runs out of folic acid.

Hemolytic crises often accompany other types of crisis and are associated with a fall in Hb with a reticulocytosis.

Other clinical features include splenomegaly in infancy, but splenic infarction means that most adults have signs of hyposplenism. Leg ulcers are common.

Treatment is to avoid things that precipitate crises, especially dehydration, anoxia, infections, stasis of the circulation and cooling of the skin surface. Patients should receive folic acid 5mg a day as prophylaxis, they should be vaccinated against pneumococcus as children and adults should receive prophylactic penicillin like other people without a spleen. Good hygiene and nutrition should be practised.

Crises are treated with rehydration, antibiotics, if appropriate, and bicarbonate if there is acidosis. Strong pain relief is often necessary, but some patients do become dependent on opiates. Blood transfusion is only needed for severe symptomatic anemia (normal oxygenation is achieved with hemoglobin lower than in patients with Hb A). Exchange transfusion may be needed if there is neurological damage or visceral crisis, or if painful crises are common. The aim should be to achieve a Hb S level of less than 30%.

Transfusion is often necessary during pregnancy and a Hb S level of less than 30% should be achieved by delivery. Careful anesthetic technique is required to avoid hypoxemia or acidosis

Iron overload may become a problem in patients requiring frequent transfusions.

In carefully selected patients, stem cell transplant may be indicated.

Sicklers in Saudi Arabia often have high Hb F levels and this seems to prevent the worst complications. Drugs have been used to raise Hb F levels, particularly hydroxyurea (called hydroxycarbamide more recently).

Hydroxyurea is a type of chemotherapy used in polycythemia and before Gleevec for CML. It is regarded as very safe, though it can suppress the platelets, Hb and neutrophils, and therefore has to be regularly monitored with a CBC. There has been a randomized clinical trial in patients with sickle cell disease and this showed a 44% reduction in pain episodes, a longer time to the first painful crisis, fewer episodes of acute chest syndrome and fewer transfusions or admission to hospital. In long term follow up, mortality rates were 40% lower.

There have been several less convincing studies which have suggested that Hb F levels can be raised to 20% without significant toxicity, that neurologic function and splenic function improves, and that hydroxyurea does not lead to a higher incidence of second malignancies. This has been a worry since there has been a suggestion of a higher incidence on acute leukemia in patients with polycythemia who take hydroxyurea. It is not clear however whether it is safe to take during pregnancy, and there have been reports of reduced sperm production in men on the drug.

There are a number of experimental treatment being tested. I noticed viagra on the list.

If the sickle cell gene is inherited from only one parent it is completely benign, unless it occurs in association with another hemoglobinopathy. The picture is then that of sickle cell disease, but patients have large spleens. Patients with HbSC disease are particularly prone to thrombosis and pulmonary emboli - especially in pregnancy. and they have a high incidence of retinal problems.

Homozygous Hb C disease, which is common in West Africa, is due to the substitution of lysine for glutamic acid ant position 6 on the beta chain. It tends to form rhomboidal crystals in red cells. It causes a mild hemolytic anemia with many target cells. Splenomegaly is prominent.

Homozygous Hb D disease is a mild hemolytic anemia. Homozygous Hb E disease is the commonest hemoglobinopathy in South East Asia and resembles a mild thalassemia.

Saturday, March 27, 2010

Government jobs secure.

This is a gasoline powered alarm clock which has been given the EnergyStar Label by America's EPA. You can read about it here. It was one of more than a dozen other bogus products submitted for approval since last June by Congressional auditors posing as companies. According to a Congressional report it easily secured the label.

Maria Vargas, an official with the EPA, said the approvals did not pose a problem for consumers because the products never existed. Ms. Vargas emphasized that there was “no fraud,” . She said she doubted that many of the 40,000 genuine products with EnergyStar status had been mislabeled.

I don't think I would be satisfied with that. If it were Toyota that had erred so then every device with a EnergyStar Label would be recalled. One law for the government and one for business.

Thursday, March 25, 2010

Personal matters

It has already been quite a week. I have spent my first night away from home since I returned from hospital. I went to London for the UKCLL Forum Executive Committee Meeting and stayed overnight at the Holiday Inn, Regent's Park. I can't commend it. The lavatory would not flush and a light bulb didn't function. At £136 a night one expects more.

I also attended the Clinical Meeting which was on CLL-like conditions, including SMZL, hairy cell leukemia, LGL leukemia and polyclonal B-cell proliferative disease.. I would name and shame the restaurant that I ate at, but I'm not quite sure which meal was responsible for my tummy upset.

The good news is that I had a CT scan yesterday and there is no progression from last December.

This is the latest photo of our new grandchild. She is beginning to take notice of what is going on now.

Our daughter took the new baby up to see my 90-year old mother so here we have her with her great-grandmother.

We were meant to visit my eldest son and his family at the weekend, but that had to be postponed because they had some plague or other in the house. Happily it seems to have cleared now.

Mr Darling presented his pre-election budget yesterday. It was supposedly a soak the rich to help the poor budget. In a way it was disillusioning since I am no longer rich enough to have been affected by it in any way.

I notice that Obama-care passed in America. NICE is next.

Sunday, March 21, 2010

Sharing in suffering. 1 Peter 3: 17-22.

Someone asked me as I left the church whether I enjoyed my birthday. I tried to remember. It was like any other day. There is no pleasure in birthdays when you get older. I said that my best year was when I was seven and my second best was when I was 43. There was a time when I thought that there would be years of struggling, but eventually I would break through to a time without worries or problems and all would be serene. I now realise that that is never going to happen.

In this world we will have tribulation, says Scripture, and it isn't going to stop until we get to glory.

People sometimes ask why God doesn't stop the trouble. They may conclude that he can't because he doesn't have the power or that he won't because he doesn't care. But the truth is that he will, but because the Day of Judgement will mean the end of the Day of Grace, he is delaying until as many as possible take the salvation that is offered.

I know of a Christian who is tragically dying from cancer at an early age. This person has been taught that with enough faith, healing is possible. Another church member told me that when they were in a similar position they were castigated because they didn't have enough faith for one of their friends to be healed. "How can you expect 'X' to be healed of his cancer, when you have so little faith?"

How sad when Christians are taught so badly! It is the strength of the one we trust that makes the difference, not our strength in holding on to Him; He holds on to us.

The Cross is central to our lives. To this you were called, because Christ suffered for you, leaving you an example, that you should follow in his steps. 1 Peter 2:21.
"I resolved to know nothing," says Paul, "except Jesus Christ and him crucified" 1 Corinthians 2:2 and "May I never boast except in the cross of our Lord Jesus Christ". Galatians 6:14

Some today talk disdainfully of a 'bloody gospel' and want to sideline the cross as an inappropriate analogy for today. I prefer the spirit of the old hymns - Beneath the cross of Jesus I fain would take my stand ('fain' means 'gladly'); I cling to the old rugged cross and When I survey the wondrous cross. This is the context, then, that Peter is speaking in for our next section of his first letter; though we do good; yet we will suffer.

It is better, if it is God's will, to suffer for doing good than for doing evil. For Christ died for sins once for all, the righteous for the unrighteous, to bring you to God. He was put to death in the body but made alive by the Spirit, through whom also he went and preached to the spirits in prison who disobeyed long ago when God waited patiently in the days of Noah while the ark was being built. In it only a few people, eight in all, were saved through water, and this water symbolizes baptism that now saves you also—not the removal of dirt from the body but the pledge of a good conscience toward God. It saves you by the resurrection of Jesus Christ, who has gone into heaven and is at God's right hand—with angels, authorities and powers in submission to him. 1Peter 3:17-22.

This is one of the most difficult passages in the New Testament. What exactly do verses 19 and 20 mean?

Some want to invent some fanciful trip that Jesus took between the crucifixion and resurrection to preach to unbelievers in a Hellish holding cell to give them a second chance or perhaps to crow over them. But we have evidence of where Jesus went after death, "This day you will be with me in paradise," he said to the dying thief.

Doctrinally this is an important passage because it speaks of the Trinity. Jesus was made alive by the Spirit. No problem there, but we are told this about the Holy Spirit: that same Spirit who raised Jesus from the dead was also acting as the agent of Jesus when Noah preached to unbelievers in his day. Noah was a prophet and prophets spoke when filled with the Spirit and what they spoke was the word of God.

Jesus, through the Holy Spirit, speaking via the prophet Noah, spoke to the antediluvian unbelievers offering them a chance to repent. Such was their imprisonment to sin, they refused to hear. As is His wont, God waited patiently for them to repent, but in the end, only eight were saved, through water.

One God in three persons. Churches have fallen out over whether the Son sends the Spirit or if that is just the prerogative of the Father. It sounds like an 'angels on the head of a pin' argument but here is the answer: 'through whom also he went and preached '. Jesus was the preacher through the Holy Spirit.

But the difficulties of this passage don't stop there. What about 'baptism that now saves you '? Again we can go to the thief on the cross. No baptism for him. Baptism is clearly not an essential element of salvation. Baptism is the 'pledge of a good conscience toward God'. It is a symbol of 'the resurrection of Jesus Christ'. Baptists have no problem with this, seeing Baptism as a symbolic representation of going down into the grave and then rising up from it with new life.

Now I admit that this may be pushing the analogy too far, especially as it wasn't Jewish tradition to dig a pit to bury bodies in as we do, but rather to place the remains in a cave to rot and later collect the bones into an ossiary.

But writing a script for the meaning of Baptism is prone to tumbles. According to Peter he is not referring to that other symbolic meaning of baptism either - 'not the removal of dirt from the body ', Peter seems to want baptism to be a symbol of the rescue of Noah from the Flood.

We are saved by 'the resurrection of Jesus Christ'. This same Jesus 'has gone into heaven and is at God's right hand - with angels, authorities and powers in submission to him. '

Do you see Jesus as the babe of Bethlehem, or as the 12-year old child teaching Rabbis in Jerusalem, or as the obedient carpenter's son planing a table, or as the traveling preacher and miracle worker, or the suffering servant on the cross. None of those is an inaccurate picture, but all are incomplete. If you like they are part of his CV. What he is now is the commanding figure of verse 22. All authority and power reside in him. He holds everyone in submission.

Every week or every month, depending on our churchmanship we hold a service to remember his death, but there is a danger in that, that we will see him as a continuing victim. He is the king of the ages, the ruler of the universe, the one in control. When we take up our cross to follow him we are not entering into a speculative enterprise, but a winning formula. Though we share in his suffering we will share in his glory.

Saturday, March 20, 2010

Hemolytic anemias: classification.

I divide up the haemolytic anemias like this:

A] Hemolytic anemias due to intrinsic properties of the red cell.

A red cell consists of three things: hemoglobin, membrane and a few enzymes. Things can go wrong with any of these to cause hemolysis. Mostly they are congenital conditions.

1 Hemoglobin problems. The most important is sickle cell disease, but there are many other polymorphisms that shorten red cell survival.
2 Membrane problems. Hereditary spherocytosis; hereditary elliptocytosis and the one acquired problem, paraoxysmal nocturnal hemoglobinuria.
3 Enzyme pathway problems. Red cells gain their energy by breaking down glucose (glycolysis). They lack the citric acid cycle and have to make do with the Embden-Meyerhof pathway that turns glucose into pyruvate. There are many enzymes on this pathway but only two important ones as far as hemolytic anemia is concerned, and both relate to little by-passes. About 10% of the traffic travels on the first by-pass, which has the purpose of generating hydrogen ions. It is known alternatively as the Hexose Monophosphate Shunt or the Pentose Phosphate Pathway.

The chief enzyme along it is Glucose 6-phosphate dehydrogenase (G-6PD). Around 250 million people in the world have a defect in their G-6PD. Hydrogen ions are needed by the cell to turn NADP to NADPH and thus to reduce glutathione. The normal activity of the cell leaves it susceptible to oxidation and the reduced glutathione prevents this. It is seldom that there is no G-6PD, but commonly there is no enough. Certain environmental agents increase the oxidative stress on a cell. Chief among these are anti-malarials and suphonamides. Dapsone can cause a hemolytic anemia in mormal people, such is the oxidative stress that it produces. In Mediterranean types of G-6PD deficiency Fava beans can cause the oxidative stress (I'm not sure about a good Chianti, though).

The second by-pass is called the Rappaport-Lubering Shuttle, which has the purpose of producing a chemical called 2,3,DPG. This is necessary for hemoglobin to be able to release oxygen to the tissues. The more 2,3,DPG, the easier it is to do this. The important enzyme here is pyruvate kinase. If it is absent then there is more 2,3,DPG and it is easier to get oxygen to muscles. There are only about 200 people in the world with this deficiency.

All the other enzyme deficiencies are so rare that you have to be a super-specialist even to have heard of them. The next commonest has 6 people affected in the world.

B] Hemolytic anemias due to extrinsic factors.

The most important of these are antibodies which come in warm and cold types. I shall discuss these at length at a later time.

Otherwise I tend to think of them under the headings of animal, vegetable and mineral.

There are few animals that cause hemolytic anemia and they are mostly very small, namely the malarial parasite and the bacteria Bartonella spp and Clostridium Welchii. Otherwise there are a few poisonous animals including snakes and spiders.

Vegetables include fava beans that we have mentioned and the poison ricin from the Castor Oil plant.

The mineral causes are mainly drugs, which again I will deal with separately. A special mention goes to water. I remember seeing a man with very severe hemolysis who had been swept through the drainage system of a local lake. He never recovered from his fresh-water drowning. Salt water would not have done the same thing. Finally we have hot and cold to remind us of burns and teh cold antibody symdromes.

Another way of classifying hemolytic anemia is to think about intravascular and extravascular hemolysis. Extravascular hemolysis releases free hemoglobin into the circualtion and causes renal failure accompanied by severe symptoms. The cause are incopatible blood transfusion, paroxysmal cold hemoglobinuria and paroxysmal nocturnal hemoglobinuria, microangiopathic hemolytic anemias, fresh water drowning, some toxins, severe G-6PD deficiency especially after some drugs or beans, severe AIHA, some forms of unstable hemoglobinopathies, and march hemoglobinuria. This last is caused by the squashing of red blood cells in the small vessels of the feet as they slap against the tarmac. It is a problem in long distance runners and schizophrenics who repeatedly slap their heads with the palms of their hands! All the rest are intravascular hemolytic anemias.

Yet another way of classifying hemolytic anemias is by what you see down the microscope. Spherocytes are formed when bits of membrane are chewed off. it happens mostly in the spleen to red cells coated with antibody, or with a membrane lacking the protein spectrin or to cells whose membrane has been damaged by the enzyme lecithinase, produced by the bacterium Clostridium Welchii. The cell assumes the shape with the largest volume and the smallest surface area, namely a sphere. The exit doors from the spleen are only two microns wide, but a sphere cannot squeeze itself through so small a gap, the way that a biconcave disc can, so spherocytes are doomed to a splenic death.

Fragmented cells are seen in anemias where the red cells are mechanically damaged. this can be from fibrin strands in the circulation, such as occur in disseminated intravacular coagulation and microangiopathic hemolytic anemias (thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, malignant hypertension, toxemia of pregnancy, meningococcal septicemia) or by mechanical heart valves or arterial grafts. The anemia can be acute (and usually intravascular) or chronic (also intravascular but without the symptoms) and likely to result in iron deficiency with stainable iron in the urine.

Wednesday, March 17, 2010

What's wrong and what's right about the NHS

A report yesterday suggested that £2 billion was wasted every year by the NHS in treating trivial illness. Most symptoms seen by a GP are self-limiting. If you have a cold or even flu, if you have backache or diarrhea, if you have indigestion, if you're feeling unhappy, if you have cuts or grazes, if you have twisted your ankle, fallen off your bike, or blacked your eye, the doctor has little to contribute to getting you better. Go to the pharmacist and get some ibuprofen or paracetamol. Take magnesium hydroxide if you are constipated, loperamide for diarrhea and proprietary lozenges for a sore throat. You don't need to bother your doctor. It is only when your symptoms persist that he might think of something more serious.

The NHS has lots of benefits, but by it's very nature it has some major drawbacks. If something seems free then it is not valued. When it started people used to line up to get their 'free' hot-water bottles! There is much to be said for a nominal charge to see the doctor to discourage nonsense visits.

The way it is designed the NHS provides what is unnecessary and what is questionable, but fails to provide what can be provided in no other way.

Here is a list of things that I think should be removed from what the NHS provides:

1] IVF. Some people are infertile because of chemotherapy and there is perhaps an argument that the NHS made them infertile and therefore it ought to provide a remedy. But most infertility is caused by pelvic inflammatory disease, often a consequence of an adventurous sex-life before matrimony (by either partner).
2] Termination of pregnancy. There are perhaps 10 occasions a year when continuation of the pregnancy would kill the mother. Most terminations are for inconvenience. I am against them, but if the law allows them I don't see why I have to pay for them. An abortion is not expensive; it probably costs less than the alcohol that made it necessary.
3] Trivial ill health remedies. I know many people who haven't seen a doctor for decades. They get colds and tummy upsets just like everybody else, but symptom control is available over the counter in most instances.
4] Homeopathy. It is astonishing that this mumbo-jumbo is still provided free on the NHS.
5] Mammography screening. For sure breast cancer mortality has come down since mammography began, but it has come down most in women too young to be screened. There are too many false positives and too many unnecessary mastectomies (see my article on cancer screening).

Here are some things that are questionable.

1] Provision of care for self-inflicted illnesses. Although it is seldom enforced, treatment for injuries sustained in a motor car accident should be charged to the motor insurance company. When patients develop lung cancer or chronic obstructive pulmonary disease from smoking cigarettes, perhaps the tobacco companies should be charged, and when they come into the ER having been 'glassed' (smashed in the face with a beer glass) while out on the town, perhaps the purveyor or manufacturer of the alcoholic beverage should pay. Or perhaps a levy towards an insurance policy should be included in the price. Perhaps MacDonalds or Burger King should pay a similar levy towards the cost of managing diabetes.
2] Other forms of screening for illness. PSA testing is not provided on the NHS because the test is not good enough. Far too many false positives. But GPs are paid huge amounts of money to screen for hypertension, diabetes, obesity, cervical cancer, phenylketonuria and goodness knows what. There is obviously a good reason to make an early diagnosis if this will lead to your not having to pick up the bill for expensive treatment when the disease becomes serious, but is there evidence that screening saves money or adds to a patient's wellbeing?
3] Promotion of breast feeding - and all the other 'nanny-state' things associated with pregnancy. On one occasion I had to chase a health visitor away from the house when she brought an attitude that the baby belongs to the state and not to its parents. Where is the evidence base for all these interventions?
4] Setting performance targets for hospitals and GPs. Inevitably any target will be 'gamed'. Trust the professional and hammer him when he errs. Protect whistle blowers and listen to patients.
5] Making post-code prescribing an anathema. If the worst were as good as the best we would save billions. But it's a moving target. Improve the worst and the best would be yet better. Without competition there is no choice and government intervention always means leveling down not leveling up.

Here are some things that should be done but aren't.
1] Pay for all licensed drugs. Expensive cancer drugs are only suitable for small numbers of people. They may stand out as expensive items on a balance sheet, but so few patients need them that they don't affect the the global budget. Indeed NICE probably costs more than it saves (there are hidden costs since the members of committees and those appearing before it do not charge for their time).
2] Treat Alzheimer's disease as an illness instead of the patient's or his family's own responsibility.
3] Pay doctors more to enter unpopular specialties or less attractive areas. Why can Manchester attract footballers but not doctors?
4] Get serious about policing treatments without scientific merit. There is no evidence that using PPIs to treat heartburn is better than antacids or H2 antagonists. Yet £2 billion was spent on this indication one year in the recent past.
5] Don't let pharmaceutical companies run clinical trials. They cheat. If they want to sell their drugs in a particular market, subject their product to trials designed by people who know not people who want to sell.

Tuesday, March 16, 2010

How to detect hemolytic anemia.

A hemolytic anemia is an anemia in which the red cells are being destroyed more rapidly than they can be replenished. Red cells normally last about 120 days in the circulation after which they become rather tatty and are destroyed, mainly in the spleen. However, the bone marrow can make new ones at up to eight times its normal rate, so hemolysis has to be quite severe before the patient becomes anemic.

The symptoms and signs of hemolytic anemia are similar to those of any other anemia except in two circumstances. If the liver is immature and cannot cope with all the red cell breakdown products, the individual may become severely jaundiced; and if the hemolysis is mainly inside the blood vessels when certain severe systemic effects may occur with back pain, shivering attacks, fever, dark urine, collapse and possibly kidney failure.

Otherwise special tests may be necessary to recognise hemolysis. The blood film may show spherocytes (the red cells no longer have a pale central area and a flat shape, but become like little balls with dark centers), elliptocytes (elliptical cells rather than round ones) or fragmented cells. Staining with certain 'supravital' stains will reveal increased numbers of reticulocytes (large young cells with a network of RNA strands showing up) and perhaps 'Heinz' bodies (tiny dark faceted lumps on the surface membrane of the cells). Reticulocytes are a sign of the bone marrow working overtime to replenish the cells that have been destroyed, and are a usual finding in hemolytic anemia unless the marrow has failed (which it sometimes does in a condition known as paroxysmal nocturnal hemoglobinuria) or run out of folate or is stuffed with things that shouldn't be there not allowing room for the red cell precursors to expand (the best example of this is CLL)

Special tests will also reveal signs of increased red cell destruction. When heme is destroyed it gets changed to bilirubin. This is fat soluble, but it gets changed by the liver to a water soluble form and is excreted in the bile. An immature liver cannot do this and so fat soluble bilirubin accumulates in the blood (sometimes called 'indirect bilirubin') causing jaundice. If it gets too much it dissolves in the white matter of the brain thereby damaging it and causing kernicterus or brain damage. This is really only a problem in babies and was once an important disease (hemolytic disease of the newborn) but with the introduction of anti-D prophylaxis for Rhesus negative mothers, it is now seldom seen.

Another heme breakdown product, urobilinogen is excreted in the urine, so a good test for hemolysis is to test for increased urobilinogen in the urine. This a 'sticks' test but if it is raised it should be confirmed by the biochemistry laboratory. Urobilinogen causes dark urine when it is left to stand. When hemoglobin is first released from the red cells it binds to a protein called haptoglobin and the bound hemoglobin is rapidly cleared from the blood, so a low level of haptoglobin is a sensitive test for hemolysis. Hemolysis taking place in the blood vessels overwhelms the haptoglobin and free hemoglobin then binds to albumin as methemalbumin. This is tested for by the Schumm's test. This is a good test for intravascular hemolysis, but the lab doesn't like doing it because it releases a nasty 'bad eggs' smell. Next free hemoglobin can be detected in the plasma and possibly in the urine, but in the kidney tubules it gets destroyed leaving a deposit of iron in the urine which can be tested for with Perl's stain (hemosiderosis).

Detecting hemolytic anemia in CLL is strewn with hazards and it is often missed. The Coombs test is a good indication that the body is thinking about destroying red cells, but often it stops there. You can't rely on finding reticulocytes because the marrow often has no space to make abundant erythrocytes. Nor is measuring bilirubin a good indication of red cell breakdown since any increase may be very short-lived as the liver metabolises the indirect bilirubin. Reduction in haptoglobin levels is the most useful test along with urinary urobilinogen levels. In teh days when hematologists looked at blood films they would often find spherocytes to clinch the diagnosis. Alas radioactive Chromium-labelled red cell survival studies are no longer done except in specialized laboratories, and sometimes the diagnosis depends on a therapeutic trial of steroids.

Persecution in Jos: walk the walk. 1 Peter 3:15-16

Terrible news from Jos. Jos in Nigeria is a Christian town and the capital of Nigeria's Plateau state. It is the center for the Evangelical Church of West Africa which supports a theological seminary and a major teaching hospital there. Two incidents of large-scale violence have occurred, first in the city of Jos itself on Sunday 17 January 2010, and then in three mainly Christian villages to the south of Jos on Sunday 7 March. In the latter incident men from the Muslim Fulani tribe, armed with swords and machetes, arrived at the villages in the early hours of the morning. The residents of Zot, Dogo Nahauwa and Rastat were woken by the sound of gunshots and ran terrified into the streets, where the attackers were waiting for them. A horrendous massacre followed. Local police say 109 people were killed, mainly women and children, but other sources suggest this figure could be much higher, perhaps up to 500.

Some media sources have reported that this atrocity was in retaliation for an attack by Christians on Muslims in Jos in January, where up to 300 people died. It is clear, however, that this earlier violence was started by Muslims who attacked a church. Christian leaders in Nigeria acknowledge that some Christians retaliated and do not condone their actions, but there is no evidence to suggest that their response was on the size or scale reported in the media. There are conflicting reports about how many of the dead in January were Christians and how many Muslims. Baroness Caroline Cox of Britain's House of Lords notes that “In the violent attacks, not only in Plateau state but also in neighbouring Bauchi and other northern states, a consistent pattern has emerged ... the Muslim militants take Christian corpses to mosques, where they are photographed and released to the media, creating the impression that these are Muslim victims.”

In January, a church leader in Jos expressed his belief that Muslims had carried false reports about the conflict to the international media in order to discredit the Church. Confirmation of this view may be found in a video report produced by the Aljazeera news channel in co-operation with a powerful Nigerian Muslim organisation called Jama’atu Nasril Islam and later posted on YouTube via various Muslim websites. Not only does this video erroneously suggest that the January violence was simply a massacre of Muslims by Christians; it also appears to use footage from other contexts altogether, spliced in to give bogus support to its story.

It is in this context that the violence on 7 March has been reported as “retaliation” by Muslims against Christians, but this has been denied by the governor of Plateau State, Jonah Jang, who said that it cannot plausibly be seen as a reprisal for the earlier outbreak. He has also criticised another Aljazeera report on the January violence, saying, “Some people moved Aljazeera there and then covered dead bodies and started labelling them. When you cover dead bodies and start labelling them, who knows who you are covering?”

An eyewitness account from 7 March describes how “attackers were shooting to herd fleeing villagers toward another group of attackers carrying machetes ... The attackers asked people, ‘Who are you?’ in Fulani, a language used mostly by Muslims, and killed those who did not answer back in Fulani.” By Sunday afternoon the bodies of the dead were lining the dusty streets. Many of the victims were among the most defenceless – elderly people, women and children, including a four-day-old baby. All the churches in Dogo Nahawa had been burned down, and many homes had been torched. The next day Christians wailed in the street and sang hymns to Jesus as a truck carried dozens of bodies to a mass grave. Hundreds of Christians have fled their homes, fearing further attacks. Significantly, Ben Kwashi, the Anglican Archbishop of Jos, has called the attacks “systematic and quite well organised”, indicating that they were pre-planned.

Incidents of large-scale anti-Christian violence have occurred periodically in Nigeria’s Middle Belt (where Christians and Muslims are roughly equal in number), and sometimes in the Muslim-majority North, for many years. But recently these have become more frequent and severe, with major outbreaks in Jos (November 2008), Bauchi State (February 2009), Borno State (July 2009) and Jigawa State (February 2010), in addition to those described above.

Peter wrote the third chapter of his letter in the context of suffering. He writes in verse 14 "Even if you should suffer for what is right, you are blessed." Then he gives this challenge:

Always be prepared to give an answer to everyone who asks you to give the reason for the hope that you have. But do this with gentleness and respect, 16keeping a clear conscience, so that those who speak maliciously against your good behavior in Christ may be ashamed of their slander.

Many Christians are intimidated by this challenge. I am not gifted as an Evangelist, they will say. But we are not being asked to stand in the street in a soapbox or even to preach from a pulpit, but merely to be able to answer when asked, "Why are you a Christian?"

The answer is not difficult. At the beginning of this letter, Peter tells us: Praise be to the God and Father of our Lord Jesus Christ! In his great mercy he has given us new birth into a living hope through the resurrection of Jesus Christ from the dead,

I don't know about you, but if Jesus was not raised from the dead, then he is just another dead philosopher like Socrates or the Buddha. But the resurrection of Jesus is a historical fact, attested to by many witnesses. In I Corinthians 15:3-8 Paul gives us a list of witnesses: For what I received I passed on to you as of first importance: that Christ died for our sins according to the Scriptures, that he was buried, that he was raised on the third day according to the Scriptures, and that he appeared to Peter, and then to the Twelve. After that, he appeared to more than five hundred of the brothers at the same time, most of whom are still living, though some have fallen asleep. Then he appeared to James, then to all the apostles, and last of all he appeared to me also, as to one abnormally born.

Dead men aren't seen walking around cooking food, eating, speaking and having their hands and feet probed. Ask this of anyone who claims to have the truth, "Get yourself killed and then rise from the dead three days later." It ain't going to happen. Jesus is unique. His crucifixion illustrates his words; his resurrection authenticates them.

But secondly, tell the truth about yourself. On Sunday we baptized four people in our church. All were able succinctly to tell how they became Christians. All were different but all were the same. I tried to be good but I failed. I realized that I would never be good enough for God. God revealed himself to me (in many and wonderful ways) and I put my trust in the risen Savior to have dealt with my shortcomings so that when God, the Father, looks at me He sees only his Son whom He loves. I know that I both died with him and was raised with him and I share with him eternal life. Even now I have His Spirit with me, a deposit of what is to come.

There are lots more arguments and I recommend that you read Michael Ots's little book What kind of God? to answer all those difficult questions that are thrown at us.

But don't be aggressive. Peter tells us to witness with gentleness and respect. We are not to harangue people. I know they are wrong, misled and perverse. I know they are vexatious, irritating and obtuse. But don't get angry. Be polite and self effacing. Remember you are witnessing for God and before God. Show respect, for you tread on Holy ground. Don't lose your temper at their waywardness. God shows patience with them and so should you.

And as we talk the talk we should walk the walk. Heaping coals on them comes not from any violent act, but from their shame when people see that any unwholesomeness that they accuse you of is a slander. Some have been saved without a word when they see how Christians behave. So I am sad for Jos. Sad for the retaliation since it gives an opportunity for the Devil to besmirch the reputation of the church. But Scripture tells us to rejoice when people insult us, persecute us and falsely say all manner of evil against us because of Jesus.

Saturday, March 13, 2010

Anemia with large red cells: 3 Non-megaloblastic causes

This will be final essay on anemias with large red cells. To complete the two previous essays, I should add that it is dangerous to treat B12 deficiency with folic acid, since although the anemia will improve, the neurological problems will not.

But today I want to deal with macrocytosis that is not due to megaloblastic anemia since megaloblastic anemia accounts for less than 10% of all cases of macrocytosis seen in a hematology lab.

Large red cells are not necessarily associated with anemia and the best example of this is in the newborn where the cells are large and the hemoglobin is high. Why this is so is not clear, but in view of what I shall say later, it should be noted that baby red cells have fetal (HbF) rather than adult (HbA) hemoglobin in them.

When I say baby red cells I mean the red cells of babies rather than freshly produced red cells, although these too are larger than normal. Freshly produced red cells (or reticulocytes) are larger than normal too, probably because they contain extra things like strands of RNA and some nuclear remnants. These are removed as the red cell goes through the spleen so patients who have had a splenectomy also have large red cells. The commonest cause for an increase in reticulocytes is hemolytic anemia, but that is a subject for another day. Response to hematinics or hemorrhage can also cause a reticulocytosis.

In many populations the commonest cause of a raised MCV is alcohol (in Finland it is the cause in 65% of cases!). Alcohol causes a macrocytosis in a number of ways. It can be malnutrition and therefore folate deficiency, but this is relatively rare. Also rare is a severe hemolytic anemia. Most cases are believed to be caused by a direct toxic effect on the bone marrow. In acute alcoholic poisoning the bone marrow shows a characteristic pattern of abnormalities. In terminal alcoholic abuse the red cells are large because of liver failure. A confirmatory test of alcoholism is the serum gamma-GT.

Smokers as well as drinkers may also have a macrocytosis. I used to think that this was because most smokers are also drinkers or perhaps a toxic effect of cigarette smoke, but I now know that it is because smokers frequently have chronic obstructive pulmonary disease (COPD). As many as 50% of patients with COPD have a raised MCV. It has been suggested that this is related to the frequent finding that such patients also have numbers of HbF cells.

Liver disease per se causes a raised MCV, again, often with a normal hemoglobin. It is thought to be caused by increased cholesterol in the cell membrane, a feature of a disordered fat metabolism. The same cause has been attributed to the macrocytosis of hypothyroidism. Hypercholesterolemia is a feature of this and the red cells on the blood film have characteristically wavy edges.

In my practice one of the commonest causes of macrocytosis was myelodysplastic syndrome (MDS). All types of MDS are associated with macrocytosis including sideroblastic anemia, which in the older text-books was said to be a cause of small red cells. This is not completely untrue, since the very rare sex-linked congenital sideroblastic anemia does have small cells, and the MDS-type of sideroblastic anemia does have some small red cells on the blood film, even though the MCV is usually raised.

Anything that is in the bone marrow that shouldn't be there can cause a macrocytosis, be it lymphoma, myeloma, myelofibrosis or secondary cancer. We should not forget drugs as a cause. We have mentioned cytotoxic drugs like hydroxyurea (hydroxycarbamide), 6-mercaptopurine and azathiaprine that produce a pseudo-megaloblastic picture or interfere with folate metabolism like methotrexate, 5-fluorouracil and phenytoin, or its absorption, like metformin and cholestyramine, but we should also mention the anti-AIDS medications, stavudine, lamivudine and zidovudine.

Megaloblastic anemia is one of the less common causes of macrocytosis, so a full history needs to be taken to exclude the other causes. Paradoxically, a history of hypothyroidism should alert the physician to pernicious anemia, since both are autoimmune diseases and there is a considerable overlap between the two.

The order of investigation should be blood film first, followed by a reticulocyte count. The blood film should pick up most cases of megaloblastic anemia and a serum B12 should follow if they are there. A low B12 should send you on a hunt for the cause, but PA is the most likely. Borderline B12 levels are best incestigated by methylmalonic acid and homocysteine levels if the lab does them, as well as a red cell folate level. Serum folates should no longer be done. The main purpose of a bone marrow is to diagnose primary or secondary malignancy (including MDS).

Gaming the system

A report on the British post Office in today's Telegraph is a remarkable example of gaming the system. The Post Office has been set a target meant to ensure that almost all First-Class letters arrive the day after posting. A system has been set up to monitor this. 22,000 anonymous volunteers send a letter by First Class Post and the time of arrival is noted. However, these envelopes contain a microchip that can be felt. Managers at sorting offices then compiled computer spreadsheets of the addresses on the envelopes so that “key customers” could be given priority treatment, ensuring their mail arrived on time. These letters were prioritized them at the expense of letters that you or I send.

Investigators found evidence of this technique being used nationwide from as long ago as 2002. The report said attempts to manipulate the performance figures had become “entrenched” in some areas, and “culturally ingrained” in others. Staff from different parts of the country were found to have swapped notes on how to beat the system or discussed ways of manipulating the market research in Internet chat rooms.

Customers were likely to question whether the figures had been massaged or manipulated to ensure that the maximum bonuses were paid to the hierarchy of Royal Mail.

This story is reminiscent of similar stories about the NHS where targets were met, yet the service deteriorated and it reveals an inherent problem in any target oriented business. The targets often represent a surrogate end-point which in normal circumstances represents what is actually desired. For example: the government required that patients in accident and emergency rooms were dealt with and admitted to a ward within 4 hours of attending a hospital ER. With the resources available this was an impossible outcome, so managers redesignated corridors as 'wards' and trolleys as 'beds'. Thus the target was met without any improvement for the patient. Hence a target-culture is much decried. What is needed are smart-targets that cannot be gamed.

During the second word war in the UK there were two factories competing with each other. One made tank armor and the other anti-tank weapons. Each type of stronger armor was sent down the road to the weapons factory and each new shell was sent up the road to the armor factory. I fear things are a bit like that in government owned industries. Regulators invent rules and businesses invent ways to get round them. The same things happen in finance. It is said that the only people who pay tax are those with sub-standard accountants. It would be better if somebody tried to run a business for the benefit of the customer.

Friday, March 12, 2010

Screening for cancer.

The American Cancer Society is urging a more cautious approach to screening for prostate cancer. Among its recommendations is the advice that men with a life expectancy of less than 10 years should not be offered screening. The chairman of the committee said that two decades into the the PSA era of prostate cancer screening, the overall value of early detection in reducing the morbidity and mortality from prostate cancer remains unclear. One interesting statistic was that for each man who experienced the presumed benefit of screening, more than 20 had to be diagnosed with prostate cancer. This represents the most optimistic view assuming that the entire decline in prostate cancer mortality is due to screening. In fact the benefit ratio could be as poor as 1 in 50.

Raised PSA levels are frequently caused by benign prostatic hypertrophy or by a low grade malignancy that is unlikely to cause problems during the lifetime of the indidividuals. These people still have to undergo prostatic biopsy (which can be painful) and if it indicative of a low grade cancer they have the worry of deciding whether or not they should be treated. If they decide not to be treated then the horrors of watchful waiting beset them.

If it is deemed necessary to try and treat the prostate cancer surgically, the patient does not have a smooth passage. Apart from the immediate complications of bleeding and urinary stricture, the two primary longer term adverse effects of surgery are urinary and sexual. Data would suggest that long-term incontinence rates after surgery are from 12% to 16%. Long-term rates of erectile dysfunction after surgery in contemporary series ranged from 19% to 27%. It has been recently reported that, as with urinary incontinence, there is a higher rate of erectile dysfunction with minimally invasive radical prostatectomy compared with radical retropubic prostatectomy.

Radiation therapy is also not without toxicity. Acute toxicities that can present during treatment in up to 50% of men include urgency, dysuria, and nocturia, loose bowel movements or diarrhea, and hemorrhoidal and anal irritation. As with surgery, the most commonly encountered late toxicity is erectile dysfunction, which affects up to 50% of men.

Prostate cancer is very sensitive to the removal of a testosterone drive. Among the most common types of side effects of hormonal therapy are increased risk for weight gain, obesity, and diabetes; cardiovascular disease; breast enlargement and tenderness; sexual problems, including diminished sex drive and erectile dysfunction; emotional changes, including anger, sadness, and, in many, a generalized sense of fatigue; osteoporosis; loss of muscle strength and mass, which also increases the risk of falls in older men, predisposing them to bony fractures; anemia, which also contributes to fatigue; and cognitive changes, such as impaired thought processes and memory loss.

Similar fears have been raised about breast cancer screening. The authors of this report come from the Nordic Cochrane Center (the word 'Cochrane' usually implies a sensible approach to the statistics of health care). The report is in response to a report from the UK NHS Breast Cancer Screening Program which celebrates the 20th anniversary of cancer screening in the UK with the statement that the program saves 1400 lives a year

The authors regard this as propaganda, and since it is in line with the British government's expectation I would say that it just plain lying. No other breast screening program makes such claims. For example the Swedish mammography service claims to save 1 woman in 1000 screened, not the 2.8 per 1000 claimed here. It is easy to prove that the claim is nonsense. The decline in breast cancer mortality since 1989 in women who were screened (ie aged between 50 and 64) was 35%. But for women aged 40-49 (who weren't screened) the decline was 41% and for those aged 65-69 (who weren't screened until 2001) the decline was 38%. It would be special pleading to suggest that some other factor was responsible for the better outcome in those women who weren't screened, while the slightly smaller improvement in those who were screened was because they were screened. Moreover the improvement in survival began a couple of years before screening began. It is more likely that treatment has improved, most likely because of tamoxifen.

The most serious hazard of mammography is the overdiagnosis and overtreatment of healthy women who would not have acquired breast cancer in their lifetime had they not attended screening. It has been estimated that as many as a third of breast cancers picked up by screening are unnecessary diagnoses. That amounts to about 7000 breast cancer diagnoses a year in the UK.

In 2007 there were 83,728 recalls after initial screening in the UK. Of these, 14,753 were eventually found to have cancer - in other words 70,000 women were worried unnecessarily. About 40% of those recalled (about 34,000) undergo needle biopsy. There are about 2500 excision biopsies every year of which nearly 1700 will show a benign lesion. It has been estimated that screening leads to an extra 20% mastectomies each year, but some of these will be for carcinoma-in-situ (this is the breast cancer version of monoclonal B-cell lymphocytosis). 29% of carcinoma-in-situ cases were treated by mastectomy. Now perhaps 40% of cases of carcinoma-in-situ cases will progress to full blown carcinoma, but which 40%? There is no knowing whether they will include any of the 29% operated on.

Many of my readers will know what it is like to walk around with a cancer diagnosis, even if the doctors tell you that no treatment is necessary. The problem with screening is that it assumes that 'cancers' picked up by screening will behave in the same way as cancers picked up when they present in the normal way. There is quite a lot of evidence that they do not. Nor should it be assumed that a cancer patient who survives 12 years after diagnosis following screening has done any better than the patient who dies 8 years after diagnosis is a conventional way. Both might have died exactly the same length of time after the first cancer cell appeared; it's just that the first patient has known about it longer.

Last year the diagnostic criteria for CLL changed. No longer do 5000 lymphocytes define the disease; you have to have 5000 B-lymphocytes. B-lymphocytes normally comprise 10-18% of all lymphocytes, so you see that the threshold has been raised considerably. Patients who last year thought they had leukemia have now been told that they have a benign condition. Unlike other forms of leukemia, CLL is very similar to other cancers that occur predominately in older people. It may well be true that there are other cancers for which a relatively benign form exists. If we have very sensitive forms of diagnosis we may well end up diagnosing all sorts of cancer that never needed diagnosis.

It is now a year since I was diagnosed with cancer. In retrospect six months previously a small enlarged lymph node was detected on CT scan. It was known from colonoscopy to be situated somewhere near the junction of small and large bowel. At operation no primary tumor was found, but the lymph node was found to contain well-differentiated adenocarcinoma. I was given 9 course of chemotherapy on an intense schedule. At the end of this a residual and inoperable was 75% smaller than before the chemotherapy. Three months on the node was unchanged on CT scan and I am due another scan shortly. My CEA test gave an answer of 3 at the time of the operation, which does not indicate a large amount of cancer, but now it is <1. I have nothing to suggest that my disease has recurred.

Even though my cancer had spread at diagnosis, this clearly does not mean that it was an advanced disease. With breast cancer we know it to be a systemic disease even at an early stage of diagnosis. Bowel cancer may well be the same. Now I begin to ask myself the question as to whether my screening test was wise. I certainly had no symptoms prior to diagnosis and I have suffered quite a lot in the ensuing year. Perhaps I should have had the disease for many years before it drew attention to itself; perhaps it never would have done and I would have had my coronary in bed at the age of 90. On the other hand, perhaps it has behaved so well because I had a hefty dose of chemo while it was still small. I guess I will never know.

Wednesday, March 10, 2010

Clinical Trials

One of the things that I do is oversee clinical trials. I no longer participate by entering patients into trials but I assess whether a trial should take place on grounds of both ethics and funding, I monitor the data produced and make judgements on how the trial has been conducted and I assess the results.

I sit on the Gene Therapy Advisory Committee, which is the Ethical Review Committee for all trials conducted in the UK involving either gene therapy or stem cells.

The science involved in these studies is challenging, but it is necessary for the committee to understand it in order to assess how likely it is to succeed and how dangerous it is likely to be. Of around 160 studies that we have looked at over the past 10 years, the majority have been ineffective and did no harm, but of late there have been trials that have been both effective and very toxic. There has been a steep learning curve for us members.

Some of the more arcane elements of gene therapy are outside my field of expertise, but it does help to have a good understanding of general medicine and of the nature of cancer. One of our most pressing concerns is the quality of the patient information leaflet. We insist that it is written in terms that a lay person can understand. It is important that the information does not give an over optimistic outlook for the treatment. Remember that what is taking place is an experiment. The likelihood is that it will not benefit those taking part, though information gathered from the trial might benefit later patients. It is easy to attract patients to trials of treatments for hopeless diseases. Whatever you say to them they believe that they will be the one to benefit.

I also sit on CTAP which is the grant awarding part of the Leukemia Research Fund. It funds phase 2 trials, which look at efficacy of a new drug or combination of drugs in a small number of patients. It is not a wealthy organization so we only want to fund the best. Our concern is not to fund trials that are already taking place elsewhere, and to ensure that the maximum amount of information is obtained from the trials we do fund. The major LRF funded trial in recent years is the one that demonstrated clearly that FC is better than either single agent F or single agent chlorambucil for CLL.

In addition I sit on a number of Data Monitoring Committees and Independent Review Panels for CLL trials. Here we have to monitor how the trial is being conducted, whether unforeseen complications occur and to recommend protocol variations if they do, and to assess whether a trial should move on to the next phase.

I am in the middle of a succession of such meetings at the moment, which I why I have been a rather silent blogger.

I am, of course, sworn to silence about individual trials, but I have some observations about trials in general, which may be of interest to my readers.

First, clinical trials are essential. Without them we have only a series of anecdotes and opinions. Trials should be designed so as to find out if the hoped for conclusion is unlikely to happen. For example, if you believe that all swans are white and there are stories that black swans exist in Australia, then there is no point in only looking at swans in America or Europe. Your theory must be tested under conditions most likely to prove it wrong.

The ultimate test of a new treatment is the randomized controlled trial in which the new treatment is compared with the best of the old in a population randomly allocated to either treatment. Ideally, both patients and their medical teams should be unaware which treatment the patient is given and the success or otherwise should be assessed independently by someone unconcerned with the trial who also does not know which treatment the patient received. Sometimes it is impossible to meet these conditions. For example if a new treatment makes you sick and the old one doesn't then it is pretty plain who is having what.

It is noticeable that some people, such as homeopaths, don't buy into RCTs. All I can say is that any assertion that such an untested treatment works is likely to be spurious. I am quite willing to believe that many patients feel better when they purchase the whole package, with the time it takes, the sweet talking and the impressive procedures, but such packages are impressive placebos.

Any substance put forward as a treatment will already have demonstrated activity in a test tube and should have been given to at least two species of animals to demonstrate its safety. The first type of trial that is done is a phase 1 trial to determine a safe dose. Such trials are often done of normal volunteers, but they can go disastrously wrong as happened at Northwick Park. Six young men reacted disastrously to minute doses of an antibody the first time it was administered at a much lower dose than had apparently been safe in monkeys. Who would volunteer to take part in such a study? Many young men earn a sizable living from such studies, getting up to $5000 a time.

But most phase 1 studies are pretty safe. Cancer drugs are almost always tested in cancer patients, often in patients who have reached the end of the line, having exhausted all the licensed drugs. They are hoping for another Gleevec, for it was in a phase 1 trial that Gleevec first showed its superiority in CML. The idea of a phase 1 trial is to find the highest dose that is safe. Usually cohorts of three patients are treated with a single escalating dose. Eventually a dose will be found that causes toxicity and the last dose below this is chosen.

1. 2. 3. 5. 8. 13. 21. 34 ... is known as the Fibonacci sequence and the rate of escalation is a modified Fibonacci sequence.

A phase 2 study is looking to see whether the chosen dose has any activity. Fourteen patients need to be treated without benefit before concluding that the drug has no effect. After that more may be treated to determine exactly how great the effect is. However, around 40 patients is usually enough. Randomized phase 2 studies enable us to compare an immediate effect with the standard treatment. For example, drug A might cause 40% remissions against only 25% with the standard therapy. This doesn't tell us that drug A is better. Remission rate often correlates with survival, but not always. If drug A puts 40% into remission but kills 60% it is not such a good treatment as drug B which only puts 25% into remission yet only kills 5%, the remaining 70% living for more than 2 years.

What we are usually looking for is length of overall survival, and if that is the same for both treatments then the quality of life during that period of survival comes into it. To determine whether a given treatment is better than a competitor, then we need to do a randomized phase 3 trial. The endpoint is overall survival and the number of patients required is determined by how much better than standard treatment the new treatment is suspected of being. A small difference requires a big trial; a big difference only a small trial. When improvements in outcomes are only nibbling at the problem then very large trials are needed.

For diseases like CLL where current treatments are associated with very long survivals in most patients you have a problem. You can either pick out some characteristics associated with very poor survival (like del 17p) and do your trials on this group, or you can find a characteristic associated with very long survival (like MRD negativity) and use that as a surrogate end point.

One of the problems with CLL is that as time passes we know more about the disease, so that ongoing trials become superfluous. Take the definition of a complete remission. Only about 15 years ago, all you needed to have a complete remission was no symptoms, a normal blood count, no lymph nodes to feel in armpits groins or neck, no liver or spleen to feel, and a bone marrow with fewer than 30% small lymphocytes in it. Today that is not sufficient. CT scanning has shown that enlarged lymph nodes may be present in the abdomen in many patients with what would previously have been called a CR. The spleen has to be three times the normal size before you can feel it and livers can be felt even though they may be a normal size. You can't make livers and spleens disappear completely so who knows whether a liver or spleen is of normal size or slightly enlarged? CT scans are so sensitive that a normal lymph node may be seen and called as pathological.

To get round this problem, a new standard is emerging. Tiny numbers of CLL cells can be detected in the blood using idiotypic PCR or 4-color flow cytometry. Increasingly, trials are being designed with negative minimal residual disease as an endpoint, and in my opinion this is to be encouraged.

Finally, when a patient volunteers to take part in a clinical trial, the doctor conducting that trial has been given a great gift and it behoves him to conduct the trial properly. I have seen too many occasions when the recording of observations is frankly slapdash. I think that some centers enter patients into trials for pecuniary reasons or just to get their names on a paper, without any curiosity about the outcomes. Improperly conducted trials are unethical and should not be allowed. When a pharmaceutical company finds that a particular center does not comply with the protocol the center should be excluded from future trials. For a patient to quit a trial midway is also an affront to all the other patients involved. I understand that the toxicity may enforce abandonment, but there will be follow-up blood tests and examinations that ought to be done. For a pharmaceutical company not to publish the results of a trial (even if it is offensive to their shareholders) is an insult to the professionals and the patients who took part.

Friday, March 05, 2010

Could Hitler get to heaven?

Can you imagine a heaven that admits Adolf Hitler and excludes Mother Teresa? The Christian heaven might be like that. Where do I get that idea? From Jesus.

Jesus told a parable. You can read about it in Luke chapter 18 verses 9-14. It is the story of the Pharisee and the Tax Collector.

To some who were confident of their own righteousness and looked down on everybody else, Jesus told this parable: "Two men went up to the temple to pray, one a Pharisee and the other a tax collector. The Pharisee stood up and prayed about himself: 'God, I thank you that I am not like other men—robbers, evildoers, adulterers—or even like this tax collector. I fast twice a week and give a tenth of all I get.'
"But the tax collector stood at a distance. He would not even look up to heaven, but beat his breast and said, 'God, have mercy on me, a sinner.'

"I tell you that this man, rather than the other, went home justified before God. For everyone who exalts himself will be humbled, and he who humbles himself will be exalted."

There is no doubt that the story doesn't carry the weight it did in Jesus' time. Pharisees have a reputation as hypocrites and a tax collector, though feared and despised, is just a bloke with a job that has to be done. For a present-day audience we ought to talk about the parable of the church-goer and the chancer.

In Jesus' day a Pharisee was a member of a group that was fastidious about church attendance. The Temple Courts were full of them. They were those who studied the Bible. They kept the Mosaic Law. They wore a phylactery on their heads. They were very careful about tithing. They liked nothing better than a religious discussion. In First Century Jerusalem they were respected figures who took their religion seriously - even St Paul called himself a Pharisee of Pharisees.

Tax Collectors on the other hand weren't just hated because they collected taxes. None of us likes paying taxes, but this wasn't just a case of 'shoot the messenger'. Tax collectors were collaborators with the occupying power. It wasn't just collaborating, either. This was a case of knowing which side your bread was buttered; seizing the main chance and taking advantage of the financial situation. Tax collectors were rich men. We know from the story of Zacchaeus that they used to defraud the public and salt up treasure for their own benefit. They were traitors, they were crooks and they were rich. No wonder they were hated.

The Pharisees were fastidious. Not content with keeping all those food laws, laws about sacrifices and laws about relationships, they used to use the book of Leviticus for bed-time reading. Fasting is commended, but where does it say in Scripture that you should fast twice a week? For fear of falling short in any respect, they made up rules to supplement the Law of Moses.

They missed out on the purpose of the Law. It wasn't there so that we could boast about how well we could keep it, but to show us the impossibility of being good enough for God by our own actions.

We can be like the Pharisees. I go to church twice on Sundays. I never miss the midweek meeting. I'm always there for weddings and funerals - not like some who only put in a token appearance and never give the church the support it deserves. I'm always the first one they call on when something needs doing, whether it is painting the porch or replacing light bulbs. If someone needs picking up from the airport, I'm the first to volunteer. I serve in the soup kitchen and offer hospitality to students.

Now all these are good things; I'm not decrying them. They are good works. But who is the comparator? The Pharisee thanked God he was not like other men. My imaginary churchgoer boasted that he was 'not like some...'. When we get like this we choose whom we compare ourselves with. Have you heard people say, "I may not be perfect, but I..." That's the problem, if we are trying to be good enough for God by our own actions then the standard we should compare ourselves is perfection. We need to compare ourselves with Jesus.

Before I was converted I tried to be good. It was only when I realized that I couldn't even live up to my own standards that I saw that I needed a savior.

Some people venerate the Virgin Mary. She was a blessed woman. She was obedient to God when it was shaming and terrifying. There is a lot to praise her for, but listen to Mary's song: "My soul glorifies the Lord and my spirit rejoices in God my Savior." Some Christians regard Mary as being without sin. If that were so, why should she address God as 'my savior'? Jesus was without sin, yet he never calls God his savior. He addresses him as 'Abba' or in English, 'Daddy'.

The truth is that Mary like all mankind was steeped in sin. She needed a savior just as much as the next person. There is no-one so good that their own righteousness can get them to heaven, save only the Lord Jesus Christ - God incarnate. Our righteousness is decried as 'dirty rags' - a polite translation of the Hebrew.

The tax collector knew he was a sinner. He didn't push himself to the front; he stood at a distance. He wouldn't even look up to heaven. Instead he asked for mercy. The Greek word for 'mercy' is elsewhere translated 'propitiation'. In other words, he asking for someone else to deal with his sins because he knows that he can't be good enough.

Let me tell you the story of Manasseh (which is found in 2 Chronicles chapter 33). He was the young son of Hezekiah who was one of Judah's good kings. Manasseh come to the throne at the age of 12 and reigned for 55 years. He was perhaps the worst king of Judah. He did evil in the sight of the LORD, following the detestable practices of the nations the LORD had driven out before the Israelites. He even had his own sons made into human sacrifices. We read that the LORD brought an army from Assyria against him and that they took him prisoner, putting a hook through his nose and binding him with bronze shackles. But later, in his distress he sought the favor of God and humbled himself greatly before the LORD. We read that the LORD was moved by his entreaty and listened to his plea.

The story of Manasseh tells us that no-one is so bad that he can't be saved, just as the story of Mary tells us that no-one is so good as not to need saving.

Will Hitler be in heaven? I think it unlikely, but if Hitler realized the magnitude of his sins and cried to God for mercy through the propitiating blood of Jesus Christ, then there is hope even for Hitler. Will Mother Teresa be excluded from heaven. Again I doubt it, but if she was relying on her own good works, however good they were, and not on the sacrifice of the Lord Jesus, then, yes, she might be denied heaven.

What about you, my friend? Are your good works the fruit of the Holy Spirit in your life, the consequence of your salvation, acts of gratitude to God for your wonderful salvation, or are they what you think will win him over? If it's the latter, how would you ever know that you had done enough? Are you relying on a dustbin full of dirty rags? Do you think that two dustbins full would be better?

Fludarabine versus chlorambucil (again)

In 2000, the CALGB 9011 trial demonstrated the apparent superiority of fludarabine over chlorambucil in previously untreated, symptomatic CLL. With a median follow-up of 5 years there was a higher overall response rate with fludarabine (63% vs 37%; P < .001), a longer median progression-free survival with fludarabine (20 vs 14 months; P < .001), but median overall survival was statistically similar with fludarabine vs chlorambucil (66 vs 56 months, respectively; P = .21).

At ASH 2009 a further 10 years follow-up was presented. Overall survival is now significantly significantly longer with fludarabine (63 months) than with chlorambucil (59 months) Or is it? Although the unadjusted p value was 0.04, after adjusted for co-variables (the fact that there were minor differences between the two groups) the p value was 0.07 - that is, not statistically significant or there was a 7% chance of such a result occuring by chance.

When one takes into consideration that the dose of chlorambucil used in this trial was 40 mg per sq m (as opposed to the 70 mg per sq m used in the Catovsky trial) one is rather driven to the conclusion that there is not much to choose between the two drugs.

In this trial there was another arm that combined fludarabine and chlorambucil that was terminated early because of toxicity. Long term follow-up of those receiving this arm demonstrated that 6/137 developed a myeloid malignancy (acute leukemia or MDS) compare to only 1 receiving fludarabine and zero receiving chlorambucil.

Tuesday, March 02, 2010

Anemia with large red cells 2 Folic acid

I hesitate to put up a diagram of folate metabolism because it is so complicated. The correct name for folic acid is pteroylglutamic acid. Humans cannot synthesize it so we must take it in as a vitamin. Bacteria do synthesize it from pteridine, p-amino benzoic acid and glutamic acid, but this is inhibited by suphonamides which are therefore toxic to bacteria but harmless to humans.

I don't know whether the second diagram is more understandable, but if you focus on the top right hand corner, this is the bit that is relevant for megaloblastic anemia. The rest of the diagram is all about how various forms of chemotherapy interact with folate metabolism and we may come back to that. The part I am referring to is the change from dUMP to dTMP.

DNA and RNA differ in a number of ways. DNA is where the information for the genes is stored. Its structure is well known by now; the famous double helix where a chain of sugar molecules forms the banisters and interlocking purine and pyrimidine bases form the steps of the spiral staircase.
The bases are Guanine that always mates with Cytosine and Adenine that always mates with Thymine. The order of the bases is the basis of the code. RNA is single stranded and acts as both the messenger and the template for protein production; three bases representing a single amino acid. But the bases for RNA are different: instead of Thymine we have Uracil.

These molecules are very similar but thymine has an extra methyl (CH3) group hanging on one of the benzene rings. In Man thymine can only be made from uracil and there is a special enzyme that does it called thymidilate synthetase. One form of folic acid, 5, 10-methylene tetrahydrofolate, acts as the donor of the CH3 group to make thymine.

So although a patient without enough folic acid or who can't get it into the right form because of an absence of B12, although such a patient can make RNA, he can't make DNA properly. I was once buttonholed by a cytologist who told me that she had just diagnosed pernicious anemia from a cervical smear; a timely reminder that the megaloblastic process is not confined to blood cells, but is found in any tissue that is making new cells and therefore new DNA. Again it should be emphasized that B12 deficiency and folate deficiency both end up with identical blood pictures - megaloblastic anemia.

Diagnosis of folate deficiency is made by measuring the red cell folate, having first ascertained that the serum B12 is normal (red cell folate may be low in B12 deficiency). The serum folate is not a useful investigation - it merely tells you what sort of diet the patient has been having recently.

How can you get folate deficient? Folic acid is present in green vegetables so it is possible for those who live on tea and jam and bread to become deficient because of a poor diet, but it is unusual. Alcoholics are among those most likely to have a poor diet. More commonly there is an overuse of folic acid leading to a relative shortage. Typically, any condition where there is increased cell turnover puts the patient at risk. Pregnancy used to be one of the commonest causes, but most pregnant mums get folate supplements. Hemolytic anemia, any severe skin condition like eczema or psoriasis and any rapidly growing cancer or leukemia can cause a shortage of folate. Patients in intensive care may also develop folate deficiency.

Then there is malabsorption. Folate is absorbed from the small bowel and the condition most commonly associated with folate deficiency is celiac disease. Tropical sprue may be a problem in the Tropics (its why the ex-pats used to take Marmite with them), and Crohns disease, sclerodema of the gut and surgical resections may all be a cause. Some drugs interfere with folate absortion, notably phenytoin and sulphasalazine.

Folate deficiency is not associated with neurological syndromes apart from neural tube defeccts for which pregnant women should receive 400 micrograms a day as prophylaxis. This is thought to act through the methionine to homocysteine interaction. Eaised levels of homocytsteine are also associated with thrombotic lesions, for which folic acid is also a remedy.

Megaloblastic anemia generally has a low red cell count and a high red cell distribution width (RDW). Thrombocytopenia and neutropenia are also common and sometimes the presentation is of severe pancytopenia.

There are rare enzyme deficiencies like orotic aciuria and Lesch-Nyan syndrome that cause megaloblastic anemia, and certain drugs have an antifolate activity like methotrexate. Other drugs that interfere with DNA synthesis can cause megloblastosis with normal B12 and folate levels incude hydroxocarbamide, 5-fluorouracil, cytosine arabinoside, 6-mercaptopurine, azathiaprine, and anti-retroviral drugs. Megaloblastic changes may also be seen in some myelodysplastic syndromes.

Monday, March 01, 2010

Anemia with large red cells. 1 Vitamin B12

I learned my hematology 40 years ago. I have just started teaching some new trainees, and rather than rely on what I remembered, I have perused the journals to ensure that I am up-to-date in what I am teaching them. Having done microcytic anemias last week, my subject for today is macrocytic anemias. Macrocytosis for the purpose of this essay is an MCV of more than 100 fl.

Macrocytes, or large red cells, occur quite commonly in a hematologist's experience and he/she must have a plan of how to cope with them. The first thing that one has to decide is whether this is a megaloblastic process or not and this is done by looking at the blood film.

For the megaloblastic anemias you expect to find oval macrocytes rather than round ones and neutrophil polymorphs with 5 or more lobes. Finding those immediately sends you down the road of investigating for a megaloblastic process. In any case probably everyone who doesn't have an explanation for his large red cells should have a serum B12 measured.

The method for measuring vitamin B12 has changed over the years that I have been practising hematology. originally the patient's serum was used as a source of B12 to make a bacterium grow, then there was a radio-assay, but more recently radioactive isotopes have been banned from routine laboratories, but the method we use now has a large grey area where we are not sure whether the result is low or normal. Levels less than 100 pg per ml (74 pmol/L) mean definite B12 deficiency, but levels between 100-400 pg per ml (75-295 pmol/L) are borderline. It is clear what to do with definite low levels, but if the level is borderline then clinical judgement is required. If available (but usually they are not) measurements of methylmalonic acid and homocysteine may be helpful. Sometimes it is wise to exclude deficiency of folic acid (about which more next time).

Most people who have a low B12 level have pernicious anemia, but there are other causes. Pernicious anemia is an autoimmune disease where the immune system attacks the stomach, preventing the secretion of intrinsic factor (IF). We used to diagnose with with a Schilling test which measure the absorption of B12 with and without IF, but the inordinate fear of radioactivity has also driven this test from the menu. Instead we look for evidence of autoimmunity, looking for antibodies to gastric parietal cells (GPC) and IF. These tests are very poor with 40% false positives for GPC and 50% false negatives for IF. Even doing both tests mistakes are easily made.

It is therefore important to check for other causes of B12 deficiency such as carcinoma of the stomach, Crohn's disease affecting the terminal ileum, previous operations on either the stomach or the terminal ileum, chronic infection with H. pylori and if you have been eating raw fish in Finland, infestation with the fish tapeworm, Diphillobothrium latum, which actually eats B12 as it passes and any form of blind loop in the intestines (incuding jejunal diverticulae) that can become infected with B12-eating bacteria. Rare causes include some very uncommon congenital conditions like Immerslund syndrome and transcobalamin II defeiciency, Zollinger Ellison syndrome, nitrous oxide abuse, and some sorts of medicines including PPI drugs like omeprazole (because IF production in the stomach is linked to acid production), and the anti-diabetic drug, metformin.

This is new. You can treat B12 deficiency with oral vitamin B12.

The absorption of B12 is complex. We get all our vitamin B12 from meat of one sort or another - we can't manufacture it from a substrate. Absorption takes place in the last 18 inches of the small bowel, and nowhere else. To get into this bit of small bowel (known as the terminal ileum) you need intrinsic factor which is made in the stomach. B12 is excreted in the bile, but on re-entering the small bowel it binds to IF and gets re-absorbed. If your diet is deficient in B12 it can take 20 years before it shows, but if you lack IF or a terminal ileum you become anemic within a year or five at the most. Even so, most people who are B12 deficient are not yet anemic.

Some people find it hard to believe that you can't survive on a diet without meat and they point to the Hindus of India who are Vegans. What they don't realize is that you can also get B12 from bacteria. That's why cows have 4 stomachs and chew the cud, and rabbits eat their own feces (called coprophagia). Vegans in India get their B12 from bacterially contaminated food. B12 is stable even when cooked to destroy the bacteria.

However, contrary to what I was taught, it appears that 1-2% of B12 can be absorbed by simple diffusion, so that if a large enough dose is given orally, enough will be absorbed to treat pernicious anemia. This is not just a whim; it has been the subject of a Cochrane review, and that is about as Kosher as you can get. The dose is 1-2mg daily for a week then 1-2mg weekly for a month and thereafter 2mg monthly. From the randomized controlled trials that have been performed it seems that B12 deficiency from any cause will respond to oral B12. In Sweden three-quarters of all B12 prescriptions are for the oral medication and it is becoming popular in Canada. It is estimated that switching to oral B12 would save millions of dollars every year. Of course, the placebo effect is less, and B12 intramuscularly is the favorite placebo of some doctors.

What does vitamin B12 do? Several things. It is heavily involved in the metabolism of folic acid which is necessary for the manufacture of DNA, and which I shall write about next time. But it is also involved in some complex biochemical reactions such as those involved with homocysteine and methylmalonic acid. It is also necessary for the correct functioning of the nervous system. How it affects the nervous system is not known, though it has been suggested that homocysteine metabolism may be involved. However, it is important to recognize that the neurological problems are those of B12 deficiency alone and do not involve folic acid. There is a peripheral neuropathy caused by degeneration of the posterior and lateral columns of the spinal cord. This shows itself as numbness, loss of positional sense, absent ankle jerks and brisk knee jerks. In severe cases there may be atrophy of the optic nerves and dementia.