Russell Farris and Per Marin MD PhDThe potbelly syndrome: how common germs cause obesity, diabetes and heart disease.Basic Health Publications Inc, Laguna Beach, CAPp 246 ~ Paperback $17.95 (US) $23.95 (Canada)Reviewed by David Wheldon MB FRCPathThis book explains how common, non-resolving intracellular infections can, over long periods of time, subvert the body's defences by causing chronic elevation of cortisol while provoking chronic activation of pro-inflammatory cytokines; this has serious repercussions, including type II diabetes, atheroma and heart disease. Much of what we put down to ageing is caused by chronic infection.When I started as a clinical medical student in Bristol, England, I joined my colleagues and went to the appointed ward. We were still known as 'clerks' then. The ward was in a huge and antiquated eighteenth century building. We democratically elected a 'Head Clerk' who allocated patients to us. We then 'clerked' our patients, in our naïve way, stumbling though primers of examination technique. So much had to be learned in so short a time. One of the consultants was known to be pleasant and a good teacher; the other was feared for his mordant sarcasm. My first patient was a small man of 42; he smiled at me with amazingly friendly eyes. 'They've given me you, have they?' He lay propped on pillows; he couldn't find the breath to sit up. The slightest exertion exhausted him. Finding the energy for bodily functions, even with the help of several nurses, was an agony of breathlessness. Over the years he had become a cardiac cripple; a series of myocardial infarctions had removed most of the muscle of his heart; the lost muscle had been replaced by a fibrous sac which blew in and out with each beat, effectively reducing his cardiac function even further. He had the stigmata of hyperlipidaemia, including yellowish streaks on both upper eyelids. He had uncontrollable diabetes. He was unfailingly friendly even when I made a botch of drawing blood from his veins. His intravenous lines never lasted very long before they clotted. We got on together very well. I never heard him complain once about his predicament. He was a family man, and his wife and children were frequent visitors. One night he had his last heart attack. His death took place in the confusion of a pointless resuscitation attempt. Post-mortem examinations were routine in those days. Our post-mortem room was an ancient theatre-like barn of a place with high, narrow windows. Attendance at the post-mortem was mandatory for the student who had clerked the patient. He or she would take up his or her place on the other side of the slab from the pathologist. The clerk would begin a clinical resume, and the pathologist would ask questions on the clinical course. It was perhaps a brutal way of teaching but it was more effective than any textbook or slide-show. The appropriate organs, dissected to show the pathology to best advantage, were put on dark green cloths in enamel trays, all ready for the midday demonstration. The moment arrived. The tiers of seats were filling. Midday tolled from the clocktower in the fog outside. What was demonstrated? The strained heart with thrombus in the left anterior descending coronary artery, the lumen reduced and irregularly crescent-shaped; the aorta with the rough walls and the disorganised plaques into which there had been haemorrhage. The coeliac, the renal and the carotid arteries were all badly affected, as were the arteries which form the circle of Willis at the base of the brain. The pathologist was a good teacher; the students were eager to listen to him as he demonstrated the arterial lesions and how the site of each might have presented as clinical disease - cardiac infarction, renal insufficiency, infarction of the bowel, stroke, anoxic cord damage, dissecting aneurysm. He was a man before his time in many ways; in an era when a high diastolic blood-pressure was considered the indicator of coronary heart disease he believed that a widening pulse pressure was an ill omen. 'I am amazed how long a body can function with arteries like these. When did the disease begin? In childhood. What causes it? I believe infection. With what organism? I wish I knew the answer. I know no more than you.' Then we washed our hands and went for lunch, probably at the Homoeopathic Hospital: we didn't believe in homoeopathy, but we knew that homoeopaths liked to eat well. The Homoeopathic Hospital dining room was pleasant and friendly, with table-cloths, unlike the dingy spartan canteen at the Royal Infirmary. We were the ignorant amongst the ignorant: we did not know that five years earlier, in a distant part of the world, a new intracellular organism had been isolated. It was considered an 'orphan'; an innocent non-pathogen. It was later to be called Chlamydophila (Chlamydia) pneumoniae. Forty years after its discovery this little microbe with its tiny genome and its biphasic life-cycle is slowly being recognized as the cause of the profoundest pain, morbidity and chronic suffering experienced by humanity. The name chlamydia means a cloak: it was originally given this name because it was thought (erroneously) that it cloaked the nucleus of the cell it invaded. But it's an appropriate name still; the germ lives a cloaked and secret life, hidden from the host defences; and, cloaked, it causes multisystem disorders which are hard to elucidate and considered by some impossible to treat. The fact of infection is cloaked behind words such as autoimmunity and degeneration which do little except mask a lack of understanding.As I began to read the present book all those events came back before me with a clarity not felt since they occurred. We can now explain many mechanisms which caused that man's tragic end - at 42 - in the muddle of a failed resuscitation.Russ Farris has the right kind of brain for a task like this. He spent much of his life in the world of artificial intelligence. The multifactorial and multisystem nature of these diseases as they change in time and site need the application of a wide-ranging mind. His basic premise is that the mammalian host defence system is directed towards acute infections; it is very effective (generally) in dealing with these. The mechanisms are complex, but Farris has a way of explaining complexities by breaking them down into component systems which interact one with another. One such system he considers is the hypothalamo-pituitary-adrenal axis, which is normally kept under very close control. It regulates stress-hormones like cortisol. With the onset of infection, however, cortisol secretion is increased; this has the effect of raising blood sugar to feed the brain and to replace that used by the defence system. This usually works well. With chronic unresolved infections, though, chronic and subtle hypercortisolaemia occurs, and this does damage. There is a natural understanding of the interaction of systems in the book, dealing with the notoriously difficult concept of the cytokine system. I once know a clinical biochemist who said 'when I hear the word cytokine I reach for my gun!' The reason for his cynicism is not hard to understand. Cytokines are cell messengers which have very complex interactions, and are certainly far from being understood. Cytokine A (CA) may stimulate production of CB but only if CD is also present in small but not large amounts, whereas CE blocks the effect of CD but only in the absence of CF. In health all should work as smoothly as the interlock mechanism in an old-fashioned railway signal-box (and, indeed, there are broad similarities of purpose.) Infections activate a set of protein messengers called pro-inflammatory cytokines. One of these, Tumour Necrosis Factor-alpha, is produced in response to bacterial endotoxin. Cortisol, as one of its many functions, acts as a damper on the pro-inflammatory cytokines, preventing them getting out of hand. This is a a two edged sword: in chronic infections you get raised cortisol levels and raised proinflammatory cytokines together. This is seen in many chronic inflammatory processes. It is found in diseases as diverse as Multiple Sclerosis (during relapses and as the disease becomes progressive) and coronary artery disease; it is found in Alzheimer's disease. Symptoms of raised cortisol levels and raised proinflammatory cytokines should warn you: look for an infection. And if the CRP is raised, look hard for an infection. And for years people have looked for infections in these chronic illnesses without success. It is forty years since Chl pneumoniae was discovered, and, as the author says, hospital consultants do, by and large, have little understanding of this organism. I can vouch for this. I was speaking to a colleague, a consultant medical microbiologist, who politely asked me my interest within the subject. 'The treatment of chronic infections with Chl pneumoniae.' 'Oh, I never see infections with that!' To which the answer is 'You don't look.' Charles Stratton, a medical microbiologist at Vanderbilt University, and a member of the team who first discovered the presence - by culture as well as the detection of specific gene-sequences - of Chl pneumoniae in the CSF of people with MS, believes that method is all important, with fastidious attention to detail and, in the case of culture, repeated centrifugation and prolonged incubation. Doctors are inclined to show undue credulity when it comes to negative laboratory findings. Saying 'we didn't find it so it's not there' is, after all, not that much different from saying 'you claim there is a needle in that haystack; I've spent a whole ten minutes looking for it without finding it so it's not there.'Farris comments on the need to draw doctors into the art of looking for chronic infections. With some it is easy; with others its difficult. Some doctors feel that their body of personal knowledge has some existential attribute: 'I am what I know.' This has a slightly paranoid subtext: '. . . and I don't want to be what you know.' It's only a step from that to refuse consideration of any kind of examination of the evidence. You have to choose your doctor wisely.The chapters in this book are very sensibly arranged in order to unravel a complex pathology. Pathology is complex because it is a response to a very individual set of circumstances: the pathology of infection is particularly complex because it involves the interaction of two organisms. Small genetic differences in host and parasite can decide the whole outcome of the situation. And, at the species level, the outcome depends on how the organism has been equipped to play the game. Does it, like Human Herpes Virus-6, infect you in early childhood, cause a minor rash, and, afterwards, sleep in your cells for the rest of your life, waking up only if you get something like an HIV infection? If that's the way its operational metier is coded into its genome. Does it, like Bacillus anthracis, want to kill you as quickly as possible, multiplying until it fills your blood and then sporulating into seeds which can survive as dust for centuries? Two very different modi operandi.The book gives a description of classic Cushing's disease and how raised cortisol levels shrink muscle and increase visceral fat. In chronic infection the tendency to a Cushingoid state is secondary; it almost seems like a microbial strategy to calm the host down. The mechanism of atherosclerosis causation is very well described. Chl pneumoniae is found in atheroma. Is it causative, or is it making use of a niche caused by altered anatomy? Farris finds very convincing evidence for a causal connection.The controversy over cholesterol levels is well argued. Chapters on hypertension, diabetes and insulin resistance are very good. As you read them you can see how the argument is being pulled together. The stages of chronic hypercortisolism are described with great clarity.The chapter 'Diagnosing chronic subtle hypercortisolism' is written by Dr Per Marin, a Swedish scientist who has spent much of his life studying the relationship between cortisol and health. His writing is very much complementary to Farris's and the two authors are concordant. Marin lays perhaps less stress on the role of chronic infections in subtle hypercortisolism; in his view the causes are likely to be: small adrenal tumours, environmental stressors, psychological disorders, sleep disturbances, physical ailments such as ischaemic lesions and arthritis, infections and feedback errors in the HPA axis. Perhaps it's because I'm a microbiologist, but I'd put infections higher in that list. Atherosclerosis is so common a disorder - one might say almost universal - and it's accompanied by lipid peroxydation, hyperhomocysteinemia, disorders of haem synthesis and mitochondriopathy, all of which fit with an intracellular infection. The host defence mechanism has various arms; one of them is the ability to detect bacterial components which bacteria alone possess. Lipopolysaccharide is one such component; it's like a red and white striped barber-pole: the body recognizes it at once - and takes action. There are a number of sources of lipopolysaccharide in the body; intracellular infection is one; another is translocated lipopolysaccharide from the gut. The stresses of life impinge on the autonomic nervous system, preventing efficient absorption of essential nutrients but permitting exit of lipopolysaccharide, which is present in large amounts there. Liver disease or heart failure will allow endotoxin or even whole-germ translocation.'Taking charge of your own health' is the chapter that begins to talk about therapeutics. Here Farris discusses the need to tutor your doctor, who will probably be very unfamiliar with these ideas; he goes on to discuss life-style and treatment; he details the need for searching the medical Internet resources like PubMed. He talks about the recognition an avoidance of stressors which exacerbate infections. The penultimate chapter is an intriguing one; it is about strategies for reversing the stress-hypercortisolaemia loop.Would I buy this book? Yes. I recommend it warmly. It is written with great intelligence and versatility by authors who have the ability to make a difficult and complex subject available to an educated layman. It will also be very useful to medical practitioners who wish to learn understand the body's response to chronic unresolving infection and how this leads to disease. We are about to witness a sea-change, and this is a timely book: the medical establishment is on the verge of accepting persistent and unresolved intracellular infection as a cause of much chronic morbidity. But it isn't yet doing much about it. The information is present - as Farris says, if you spend some time on PubMed you will learn that it is indeed present. Only, this information is not being efficiently collated. This book goes a long way to rectifying that need, and I wish it and its authors well.