Pathology excellence for clinical confidence.

Dr Pierre M. Durand · May 2024

Obesity has emerged as one of the most pressing health problems globally, especially over the last 50 years. It is set to have an even more significant impact on human health and economics in the coming decades. In this newsletter, I will cover some of the main topics in obesity like epidemiology, aetiology, energy balance and metabolism, complications, and finally some notes about management strategies. But first, why has obesity emerged as such a significant health issue?

The origins of obesity

Obesity is really a problem of the 20th and 21st centuries. It’s usually said to have started in the 1970s, but that’s only because the WHO declared it so based upon the data at the time. But in reality, most non-communicable diseases don’t have a ‘point of origin’. Some recent data from a Danish study (SCIENCE ADVANCES, 2023, 9:37) push the epidemic back to before WW II when it was noted that the heaviest people were already getting heavier. Whatever the timing, there are two main reasons for a rise on obesity. These are not the only reasons, but they certainly seem to be the most important. First, the dietary influence and second, the increase in sedentary lifestyles. In the former the problem is greater consumption of energy dense, processed foods. In the latter it is the kinds of occupations and leisure activities that require less activity, and many of the social ills that accompanied lifestyle changes, e.g., stress, television, insomnia, mental health problems, etc. The two main factors (diet and lifestyle) form a positive feedback loop. The time constraints of a ‘modern’ lifestyle promote the consumption of convenience foods, and poor diets cause further lifestyle problems like inactivity, mental health issues and insomnia. If we trace the origins of the rapid rise in obesity it correlates with these two primary factors: diet and lifestyle.

Epidemiology

Obesity is, well, a massive problem. WHO labels it a pandemic. Obesity is defined as an excess of body adiposity, but of course this is problematic. What does that mean for different groups of people? And then by quantifying the definition (usually in terms of BMI), one soon realises that these are simply best guesses. Still, they do have some uses, except that one must remember that the thresholds for obesity are not biologically the same for everyone. It is sometimes considered more helpful to look at the epidemiology of diseases that may be caused by obesity e.g., type II DM. But that is also not ideal. Either way, the evidence that obesity is a global issue is uncontroversial. In addition, the problem is worse in some communities than others. That is of course, due to both genetic and lifestyle/dietary factors.

If we use the definition of obesity as a BMI≥30 then according to the WHO one in eight people was obese in 2022. And worldwide adult obesity has more than doubled since 1990. Adolescent obesity has quadrupled. These statistics vary enormously. Consider that American Somoa has the highest prevalence (>70% of the population is defined as obese) and it seems Ethiopia has the lowest (1%). Of course one must treat these numbers with great scepticism. There was/is a famine in Ethiopia so trying to measure obesity in ‘normal’ circumstances sounds a bit silly. In South Africa, it is claimed by WHO that roughly 31% of men and 68% of women are obese. According to the definitions used they are likely close to the mark. But it does highlight two points. First, there is a tendency for poorer countries and groupings within populations to have higher rates of obesity. This relates to the causes of obesity being closely associated with poor diet and nutrition. And second, there are major differences in ethnicities that aren’t usually taken into account. East Asians (Japanese for example) have lower BMIs based on genetics. Polynesians have some of the highest.

Aetiology

The most important clinical decision to make is whether the cause of the obesity is primary (organic) or secondary. There are numerous primary causes, where the leading cause is something other than diet/lifestyle. Examples include:

1. Non-syndromic genetic causes, e.g., mutations and polymorphisms in leptin, melanocortin and other genes (see Int J Mol Sci. 2022, 23) and syndromic genetic causes, e.g., Prader–Willi, fragile X, etc.

2. Endocrine/metabolic conditions, e.g., hypothyroidism, Cushing’s etc.

3, Iatrogenic causes, especially medications like corticosteroids, psychiatric drugs, antiepileptics.

5. Psychiatric conditions especially mood and eating disorders.

6. Musculoskeletal conditions that lead to chronic inactivity and associated dietary problems.

Secondary causes are sometimes divided into various contributing factors, but broadly speaking they usually related to the two main components of diet and lifestyle (Figure 1). It is worth pointing out that the genetics associated with secondary causes refers to how individuals respond to particular diets and lifestyles. This is different from the genetics that is causally related to the physiological abnormalities leading to obesity.

Figure 1. Causes and Effects of Obesity

Energy Balance and Metabolism

Obesity is a disruption of metabolic homeostasis. The molecular pathology of obesity is exceedingly complex and to reduce it to one or two metabolic or endocrine pathways is hugely misleading (except of course for the well described genetic causes). On some level the dysregulation of most metabolic pathways can be associated with obesity, from protein metabolism to neuropeptides, from the hypothalamic-pituitary-adrenal/gonadal axes to the urea cycle. The point is that there is seldom, if ever, a single metabolic cause of secondary obesity and certainly the effects of obesity permeate through the individual’s entire physiology. It is well established that obesity affects multiple systems, including endocrine, liver, musculoskeletal, cardiorespiratory, neurological (centrally and peripherally), reproductive, etc.

In many discussions of energy balance and obesity, it is often said that obesity is caused by an imbalance in energy intake versus energy output. Well, that is only partially true. And I find that an unhelpful approach for two reasons. First, it focusses the management approach on decreasing intake and increasing output. Doing so is notoriously problematic. It will eventually work assuming the calculations are updated over the course of management, but patients almost all say that doing so only works in the short term. Long term this seldom works. And that brings the second reason to the fore. One kJ of energy doesn’t have a set equivalent body mass value. It depends on what is being weighed. One kilogram of muscle, one kilogram of adipose, and one kilogram of glycogen all have different chemical energy values. And the tissues also all have different resting metabolic rates. So, the input-output approach depends on what kind of energy is being consumed, which tissues are used to burn energy, and how the energy is stored in the body (protein, fat, or glycogen). This is something that the vast majority of non-obesity specialists are either unaware of or ignore. It is possible that one might have a small energy deficit but gain weight. This is unlikely to happen at morbidly obese levels, but most patients using this energy balance strategy are in the overweight, mildly obese range.

Associated with the two problems above is the issue of changing metabolism. Human physiology has built in homeostatic, compensatory mechanisms. When diet suddenly changes or the energy balance shifts, physiological compensatory mechanisms are activated. This means that the weight being shed has a changing energy value because there is a change in the tissue type being catabolised. The upshot is that the original calculation of energy intake versus energy output is no longer valid.

There are other problems associated with this approach because the kind of energy that is being consumed influences the storage tissue that it is converted into. Covering all the problems associated with the energy input-energy output strategy is beyond the scope of this newsletter. The point I wish to make is that one doesn’t have to ignore this metric, but don’t make it the primary focus of weight loss.

Complications of Obesity

Obesity is truly a whole-body problem. Any of the physiological systems can be compromised. The managing healthcare worker should consider problems beyond the obvious cardiorespiratory complications of hypercholesterolaemia, cardiac overload, hypertension, and respiratory difficulties. And the higher the BMI, the more apparent the other complications in non-cardiorespiratory systems will be. Other systems affected may include:

1. Musculoskeletal: osteoarthritis, muscle atrophy, osteopaenia, increased likelihood of injury.

2. Endocrine: Diabetes mellitus type 2, hypothyroidism, elevated cortisol.

3. Neurological: peripheral nerve damage, cognitive decline including dementias like Alzheimer’s disease, mood disorders, insomnia, CVAs

4. Dermatological: skin infections and fragility, hyperpigmentation, psoriasis.

5. GIT: dysregulation of bowel activity, haemorrhoids, cholecystitis, fatty liver, pancreatic disease.

6. Neoplasia: obesity is associated with numerous cancers some of which indicate a markedly increased risk e.g., endometrial (5-7x). Others have a much smaller risk e.g., gallbladder (1.6x) with many in between.

6. Psychosocial: social relationships are frequently compromised and obese people report greater loneliness.

The most common organ systems impacted by obesity and their complications are summarised in Figure 2.

Figure 2. Common complications associated with diabetes (Credit: The Lancet, 2002; 360:475).

Obesity management

The correct management of obesity if far more complex that most healthcare workers realise. The first decision to make is whether the obesity is primary. Is there a primary syndromic or non-syndromic cause? Is it helpful to do genetic testing? Or assessing for endocrine causes e.g., a primary Cushing’s disease, Polycystic Ovarian Syndrome, etc. Specific pharmacological intervention may be required.

Assuming the obesity is secondary, the first point to be clear about is that it is a multifaceted physiological disorder that requires lifestyle changes. Labelling the problem as excessive energy intake and thus focussing purely on counting calories is almost certainly doomed to fail for the reasons discussed earlier. This may be helpful at a later stage but at the beginning appropriate dietary change is only one of many arms of the management strategy. It is just as important to focus on psychosocial factors, physical activity, endocrine dysregulation (thyroid, insulin, cortisol, and the hypothalamic-pituitary-gonadal axis), eating patterns, alcohol consumption, mood, sleeping, and much more. Certainly, it will not be able to pinpoint in most cases whether one of the system dysfunctions, say DM type 2, is a contributing cause or a consequence of the obesity. By acknowledging that it is both, one is reminded that treating obesity as a multifaceted physiological disorder is the most appropriate strategy.

For the general practitioner, I would suggest the following basic pathology assay: U and E, Hb, CRP, LFTs, HbA1c, lipogram, TSH, fasting insulin, screen for PCOS (female), cortisol, and an ANF as a screen for an autoimmune condition. Depending on the clinical presentation, others may be required (e.g., co-existing suspicion of a urinary tract infection or something else), but these are the ones one may suggest at the outset. One may also consider severe disruption of the hypothalamic-pituitary-adrenal/gonadal axis and investigate appropriately.

Finally, it is worth noting that obesity management is a lifelong commitment. There will always be setbacks, which can be disheartening. But educating both healthcare workers on the nature of obesity as a lifelong condition with long-term objectives via small steps is a sensible approach. Furthermore, patients should actively be discouraged from falling prey to misinformation and fad diets. Misinformtiaon is a huge problem in this field. Including the skills of a respected nutritionist/dietician will likely be money well spent.

Reference

The following provides the most up to date review of obesity by the American Heart Association.

Clark JM, et al. Obesity and Overweight: Probing Causes, Consequences, and Novel Therapeutic Approaches Through the American Heart Association's Strategically Focused Research Network. J Am Heart Assoc. 2023 12:e027693.

Dr PM Durand · June 2023

Platelets: clinical interpretation of abnormal counts in general practice

In general practice, one is sometimes faced with the (often unexpected) finding of a high or low platelet count. The finding may be accompanied by comments on platelet morphology. A decision needs to be made about what, if anything, needs to be done about the abnormal platelet count. In this newsletter, I outline a very brief approach to the differential diagnosis (DD) of abnormal platelet counts and some clinical ‘pointer’ questions I have used to refine the (DD). But first, a note about their structure and function.

PART 1: Platelet biogenesis, structure and function

Platelet biogenesis

Myelopoiesis comprises three broad cell lineages. These are erythropoiesis (red cells), granulopoiesis (neutrophils, eosinophils, and basophils) and megakaryopoiesis, which ultimately gives rise to the platelets observed in the peripheral blood.

Megakaryocytes are produced (primarily) in bone marrow tissue by differentiating from haemopoietic myeloid stem cells and under the control of thrombopoietin. As megakaryocytes mature, they migrate to the perivascular environment where the interactions with endothelial cells lead to pseudopodial extensions and fragments of proplatelets. Although the turbulence and shearing of blood flow cause some platelet formation, most of the megakaryocyte fragments embolize to the lungs where they interact with the pulmonary vasculature. Pulmonary tissue and vasculature are intimately associated with platelet shedding. Occasionally whole megakaryocytes may migrate to the lungs, but there is also mounting evidence that the megakaryocytes observed in lung interstitium may in fact originate from stem cells in the lungs themselves. Dissecting the origins of megakaryocytes and platelets is an ongoing research project.

Platelet structure and function

Platelets are small (1-3μm diameter), anucleate, and deceptively simple in appearance (Fig. 1). In addition to mitochondria, alpha-granules and dense granules are abundant intracellularly. Alpha granules contain high molecular weight molecules like factor V, von Willebrands Factor (vWF), and fibrinogen, while dense granules harbour low molecular weight compounds like serotonin, ADP, and calcium ions. Platelet bilayer membranes are convoluted with canalicular systems penetrating the cellular interior. Embedded in the membrane are two distinct functional receptor types: agonist and adhesion molecules. Agonist receptors recognize ligands like collagen or thrombin, while the adhesion receptors bind adhesins like vWF and fibrinogen.

Platelets play an active role in a range of physiological responses. In addition to haemostasis and thrombosis, platelets are involved in immunity and wound healing. I will focus on the coagulation functions only.

Platelets circulate close to the vessel walls and following a vascular insult or dysfunction in haemostasis cells adhere to the vessel wall matrix via receptors like GP1b/V/IX binding to vWF and GPVI binding to collagen. This binding activates platelets (they are also activated by thrombin, ADP, etc., which are released by granules or are present in the circulation) and they flatten out leading to a core thrombus, which rapidly incorporates additional platelets from the circulation.

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PART 2: Abnormalities in platelet count

In humans, 150–450 billion platelets are found in one litre of whole blood. Platelet lifespan is 8–10 days, which means a daily turnover of 100 billion platelets to maintain a count within the ‘normal’ reference range of 2 SDs from the mean. Normal for some patients (2.5% above and 2.5% below) may be slightly outside the standard reference range.

Abnormalities is platelet count are common in general practice, however, it should be borne in mind that normal platelet counts can be associated with abnormal platelet function. Abnormalities in function (with a normal platelet count) may be inherited or acquired and are not discussed below. If there is a suspicion of platelet functional abnormality, patients should be referred to a specialist haematologist.

Causes of thrombocytopaenia

Platelets are sometimes activated in the process of drawing blood into EDTA coated vacutainers because EDTA affects the GPIIb/IIIa receptor conformation facilitating its binding to fibrinogen. Small clots, fibrin strands and platelet clumps on the peripheral smear alert the haematologist that this has occurred, which means that the platelet count is artificially low. This cause of pseudo-thrombocytopaenia is first excluded before interpreting the cause of the low count.

As with all low cell counts, the causes of true thrombocytopaenia are divided into those with a central or peripheral origin. Central causes are due to either (A) ineffective megakaryopoiesis, or (B) displacement of the bone marrow and can be summarised, briefly, thus:

(A) Ineffective megakaryopoiesis

1. Medications: antibiotics, psychiatric medications, anti-inflammatories, antivirals, chemotherapy, quinine, etc.

2. Nutritional deficiencies: especially Vit B12 and folate.

3. Infections: herpesviruses, enteroviruses, retroviruses, hepatoviruses are commonly associated with decreased platelet production.

4. Autoimmune conditions: especially SLE and RA.

5. Poisons: alcohol, benzene, pesticides, heavy metals, etc.

6. Inherited / genetic conditions: More than 40 genetic conditions lead to thrombocytopaenia. Occasionally a diagnosis can be made based on the platelet morphology and associated features in other myeloid cells. Many conditions are asymptomatic, but in some cases a genetic diagnosis may be helpful for therapeutic and prognostic reasons. The more common inherited thrombocytopaenias are Bernard-Soulier, Glanzmann’s, von Willebrand’s type IIb, Gray platelet syndrome,

(B) Marrow displacement

1. Marrow fibrosis: Myelofibrosis and chemical insults that lead to fibrosis of the marrow architecture.

2. Neoplastic infiltrates: many solid tumours metastasize to the bone marrow.

3. Haemopoietic malignancies: malignancies of myeloid and lymphoid origins infiltrate and displace bone marrow. Acute promyelocytic leukaemia is not only a cause of marrow displacement, but is also associated with DIC, which is one of the peripheral causes of a low platelet count. Acute megakaryocytic leukaemia also results in a low platelet count because megakaryocytes fail to mature normally.

4. Granulomatous conditions: TB and sarcoidosis are the commonest causes of granulomata in the bone marrow, but, of course, there are others, e.g., leprosy, brucellosis, histoplasmosis etc.

5. Marrow necrosis: necrosis is relatively rare but may occur in a wide range of conditions including malignant infiltrates, medications and chemotherapy, poisons etc. Sickle cell disease is a common cause of necrosis in parts of Africa.

Peripheral causes of thrombocytopaenia result from the (1) consumption, (2) destruction, or (3) sequestration of platelets.

(1) Platelet consumption is due to the formation of clot. This may be normal, of course, but pathologically low numbers of platelets are typically due to the consumption of cells in thromboembolic conditions or in thrombotic microangiopathies (formation of microclots). Activation of the coagulation system and the production of microclots are potentially a very dangerous situation and can be associated with a range of conditions. The most common, and potentially most serious are TTP (thrombotic thrombocytopaenic purpura), DIC, HELLP syndrome, preeclampsia, and HUS (haemolytic ureamic syndrome). The clinical condition, patient history, and associated pathology results (U and E, FBC, LFTs, d-dimers, LDH, haptoglobin, peripheral smear, etc.) are essential for the differential diagnosis.

(2) The immune destruction of platelets is most commonly associated with viruses, although many medications may also bind to the surface of platelets and stimulate an immune response (heparin-induced thrombocytopaenia is well known, but other drugs may cause a similar picture). In South Africa, the common viruses associated with ITP (immune thrombocytopaenia purpura) are HIV, hepatitis, herpes viruses, and respiratory viruses. However, may others have been documented in IPT, e.g., SARS-CoV2.

(3) Platelet pooling (sequestration) typically occurs in the spleen. Any condition, therefore, that causes an enlarged spleen is often associated with a low platelet count. And the larger the spleen, the more platelets are sequestered. Massive splenomegaly occurs with MPDs (myeloproliferative conditions) and malaria with thrombocytopaenia a common complication. Of course, in malaria, platelet consumption (e.g., DIC) is also a concern.

Causes of thrombocytosis

Platelets are acute phase reactants. Conditions, therefore, that cause an inflammatory response or that activate the coagulation cascade stimulate megakaryopoiesis. Common conditions are infections, autoimmune diseases, iron deficiency, malignancies, trauma, etc. Such instances of thrombocytosis are secondary and are labelled as such. Primary causes refer to the haemopoietic clonal conditions.

As indicated above, megakaryopoiesis is one of the lineages in the myelopoiesis, the others being erythropoiesis and granulopoiesis. Clonal disorders of any components of the myeloid line may therefore spill over into megakaryopoiesis and cause dysplastic megakaryopoiesis and (sometimes) an elevated platelet count. Essential thrombocytopaenia is one of the myeloproliferaive conditions that primarily affects megakaryopoiesis, but occasionally one notices a high platelet count (or more commonly a normal platelet count with abnormal morphology) in other MPDs.

Because myeloproliferative conditions affect all the myeloid lineages, an elevated basophil count is often an associated feature. This is used as a useful clinical marker of potential MPDs. Of course, basophilia may also be reactive (allergies, medications, autoimmune conditions, etc.), but in the presence of splenomegaly or the suspicion of a clonal condition an elevated basophil count is a helpful marker.

PART 3: Clinical pointers / suggestions

Abnormalities in platelet counts are a common and often bewildering finding in general practice. If there is no obvious clinical cause, the question usually faced is: what, if anything, should be done about it? Below, I have listed some key questions to ask oneself that may guide one? These are only ‘pointer’ questions, but are often useful.

In the absence of any helpful further information from pathology results or from the questions below, it is suggested that cases are discussed with a pathologist. Further investigations and management can then be advised.

Some key ‘pointer’ questions to ask oneself on cases of thrombocytopaenia:

1. Is the low platelet count real? In other words, there is no platelet clumping reported.

2. Is there evidence of clotting (consumption of cells)?

3. Is there an enlarged spleen?

4. Has the patient had an infection? If so, consider immune-mediated destruction.

5. Are there petechiae, purpura?

6. Are the LFTs, Hb, WCC, U and E abnormal?

7. Is the patient taking a medication that could cause immune-destruction of platelets?

8. Is there possibly an inherited cause?

Some key ‘pointer’ questions to ask oneself on cases of thrombocytosis:

1. Is this reactive or a primary clonal problem?

2. Is the spleen enlarged?

3. Is there a basophilia?

4. Is the red cell count and granulocyte count abnormal?

5. Are the other pathology results abnormal? Iron studies, LFTs, U and E, etc.

Figure 1: Platelet structure with key agonist and adhesion receptors.

Dr PM Durand · June 2023

ALCOHOL

There is perhaps no other recreational drug that has had such a profound effect on human societies as alcohol. It is imbibed, in some form or another, by almost all societies. In this newsletter I will provide a biopsychosocial commentary on its usage, effects, metabolism, complications, and on breathalyzers. When the word alcohol is used here, it refers specifically to ethanol, because ethanol is usually the fermentation product in alcoholic beverages. But first some preliminaries.

The history of alcohol and the disingenuous claims of its medical and social benefits

Alcohol, usually in the form of ethanol (C2H5OH), is produced as a fermentation product by bacteria and fungi. A wide range of carbon-based compounds from most parts of plants are used as the primary energy source. These include grapes and other berries, fruits (apples, pears, etc.), roots and tubers (e.g., potatoes), grains and grasses, stems, and leaves. Some of the earliest evidence for human production of alcohol can be found in clay pots dating to 7000-6600 BCE and discovered in the Yellow River Valley. Rice, honey, and fruits were fermented, and the alcohol products were likely used in social, religious, or medical practices. Alcohol fermentation was introduced independently by many other cultures, but it seems that these occurred later.

Besides the obvious medical uses (e.g., as an antiseptic), alcohol has previously been touted as having medical and social benefits. Recent meta-analyses of the putative medical benefits have been highly critical of previous reports that claimed alcohol, especially when associated with red wines, can protect against cardiovascular and other diseases when imbibed in limited quantities, of the order of one standard glass every other day. While this is an appealing claim, the benefits appear to be entirely overstated, something that astute medical practitioners were always wary about. The most recent reviews lead to the conclusion that no amount of alcohol consumption, in any beverage, is beneficial, although minimal consumption may not have any adverse long-term sequelae. This is another reminder that clinical research must always be subjected to the most stringent review. Discerning researchers always have a healthy dose of skepticism, and the motivations of funders should be considered.

One can also ask: are there any social benefits to alcohol consumption? As advertising agencies are keen to illustrate, alcohol is, in some circumstances, a social lubricant. Whether this represents a benefit is really a question for sociologists and those in the mental health professions. And, of course, the conviviality that may accompany alcohol consumption must always be weighed up against the much more obvious social costs. The association between alcohol abuse and societal problems in South Africa like domestic and other violence, social disintegration, mental health problems, road traffic accidents, and so much more makes for horrendous reading. It would be wholly disingenuous to tout the benefits of alcohol consumption in social settings without contrasting them with the far greater costs to society and the economy.

The acute effects of alcohol consumption and measuring blood alcohol concentration in expired air

The absorption of alcohol begins immediately after ingestion, first through the mucus membranes in the mouth, then the gastric mucosa and small intestine. Ethanol is a small molecule and easily traverses cell membranes or enters the synaptic junctions in the central nervous system (CNS). The CNS is, of course, where most of the acute effects of alcohol ingestion occur. Alcohol is a nervous system depressant. It binds strongly to GABA (gamma-aminobutyric acid) receptors, thereby activating inhibitory cascades, which in turn lead to sedation, cognitive dysfunction, decreased coordination, muscle relaxation, and many other neurological and psychosocial effects. The short-term pleasurable effects of alcohol consumption are due to increases in neurotransmitters like dopamine and serotonin, as well as endorphins. These effects are, of course, temporary, but explain the anxiolytic effects, sense of well-being, and interactions that appeal to social drinkers. The pleasure effects are not experienced uniformly. Side-effects like nausea and headache may be more prominent and others with relative or functional enzyme deficiencies (like the alcohol dehydrogenase and acetaldehyde dehydrogenase relative deficiencies common in Asians) experience both pleasurable and unpleasant toxic effects more acutely.

The conventional teaching is that the body metabolizes ethanol at 0.016g% per hour. So, for example, it will take 10 hours for a person with a blood alcohol reading of 0.16 to reach zero. This is, however, hugely variable based on genetic polymorphisms, medications, co-ingestion of other drugs, alcohol consumption history, weight, fat composition, smoking, liver function, co-consumption of food, hydration status, etc. This means that estimating blood alcohol levels based on consumption is, at best, guesswork. From a legal perspective, exhibiting signs and symptoms of alcohol consumption typically override the BAC (blood alcohol concentration) measurement even if it is below the 'legal' limit. Alcohol is a volatile organic compound so once it reaches the lungs via the circulatory system, it readily diffuses into the alveoli and is expired during respiration. Breathalyzers work by detecting the ethanol concentration in expired air. As the individual expires, the device continuously monitors the sample breath using an infrared cell (other more complex methods are available in portable breathalyzers, but the infrared cell method is most common). The concentration of ethanol increases as expiration continues. Once the ethanol level stabilizes, a reading is obtained from an infrared cell. Ethanol absorbs infrared wavelengths—the greater the concentration of ethanol in expired air the more the infrared beam is absorbed.

Ethanol metabolism

The first step in ethanol metabolism results in acetaldehyde production and three possible enzymes perform this biochemical step (Figure 1). Most of the ethanol is oxidized via alcohol dehydrogenase. Cytochrome P450 2E1 (CYP2E1) is also capable of ethanol oxidation, but it is usually only induced when ethanol concentrations are very high. Catalase metabolizes only a small fraction of alcohol. Acetaldehyde is a highly toxic compound and is further oxidized to acetate by aldehyde dehydrogenase.

Acetate can be catalyzed to acetyl-CoA by acetyl-CoA synthetase, and the acetyl-CoA formed feeds into the citric acid cycle or may be used in lipid biosynthesis. Ethanol consumption is, therefore, a rich energy source and in addition to the chronic complications discussed below, is a common cause of weight gain.

Small amounts of alcohol may also interact with fatty acids to form compounds called fatty acid ethyl esters (FAEEs). These are toxic, especially to hepatic and pancreatic cells.

Figure 1 The oxidation of ethanol.

Complications of alcohol abuse

The chronic complications of alcohol are due to ethanol itself, acetaldehyde, and other biochemical by-products. In addition to the effects on neurotransmission and the increase in endorphin release, which may have long-term sequelae like the depletion of serotonin and dopamine stores, alcohol is itself toxic. Ethanol is an organic solvent and anyone who has carried out practical laboratory work will attest to the ease with which ethanol damages cell membranes.

Acetaldehyde is highly toxic. It forms adducts with proteins and nucleic acids. Some of these acetaldehyde-protein and acetaldehyde-DNA adducts are irreversible, which means that cellular functions are globally compromised, and DNA damage is common. Acetaldehyde toxicity spares no cell type, and it is unsurprising therefore that chronic alcohol abuse affects all physiological systems.

One of the toxic by-products of alcohol metabolism is the reactive oxygen species. These also cause oxidation of biomolecules and may induce apoptosis.

Finally, alcohol withdrawal is an extremely dangerous long-term complication. In chronic alcohol abuse, the abrupt cessation of alcohol use can trigger delirium tremens, which is the most severe form of withdrawal. Left untreated, the mortality rate is approximately 35%. A symptom triggered regimen of benzodiazepines is still the mainstay treatment. Barbiturates, anticonvulsants, adrenergic drugs, and GABA agonists are also used.

Closing remark

Alcohol is an extremely hazardous toxin. It is clear that were any other medication, toxin, or recreational drug associated with the hazardous effects such as those related to alcohol, they would be made illegal without hesitation. Of course, attempts were made to outlaw alcohol production (the prohibition years in the USA) and its usage has previously been regulated (e.g., during the COVID pandemic). These were, however, spectacular failures, which underlines the profound psychosocial effects of alcohol consumption.

Dr PM Durand · April 2023

Malaria: complex history and pharmacological

management of a supreme killer

The aim of this educational newsletter is twofold. Part 1 is non-clinical and (hopefully) edifying. I provide a brief history of the remarkable story of malaria. Part 2 provides a summary of the pharmacological treatment guidelines.

PART 1: The complex history of malaria story

Organisms and origins

The causative agents of malaria in humans are Plasmodium spp. Conventional teaching usually cites six species: P. falciparum, P. vivax, P. malariae, P. ovale (comprising two distinct species P. ovale curtisi and P. ovale wallikeri), and P. knowlesii. In truth, however, we don’t know how many species infect humans. For example, in southeast Asia the macaque parasites P. knowlesi and P. cynomolgi both infect and cause malaria in humans but do not appear to be commonly transmitted between different human hosts. P. cynomolgi naturally causes human infection but between human transmission may not yet occur, and P. inui can establish an infection when experimentally introduced into humans. In South America, P. simium and P. brasilianum naturally infect platyrrhine monkeys but the two species, may be indistinguishable from P. vivax and P. malariae, respectively. Further phylogenetic and genomic data are required to determine whether they are different species, subspecies or potentially the same species.

The malaria story goes well beyond humans and non-human primates (Figure 1). An analysis of the genus phylogeny reveals a convoluted relationship with animals. One of the striking features is the evidence for multiple movements across host taxa. Plasmodium species infect vertebrates across at least three classes (mammals, birds, and reptiles). [Interesting aside: many penguin colonies comprising different species are frequently decimated by malaria.] Perhaps the clearest distinction in the complex history of human Plasmodium evolution is that P. falciparum seemingly arose from the cross-species transmission of a parasite that had previously diversified in gorillas. This gorilla parasite lineage has been named P. praefalciparum to emphasize the evolutionary origin of P. falciparum. There is strong evidence to suggest this zoonotic event happened once only.

The emergence of the non-falciparum species is a lot less clear. Although there remain disagreements it seems likely that P. vivax emerged in African humans from an ancestral stock of parasites that infected chimpanzees, gorillas, and potentially other primates. The parasite passed through an evolutionary bottleneck (the “out of Africa” hypothesis) and diversified in Asia with the protective Duffy-negative mutation subsequently eliminating P. vivax from human populations in Africa.

The evolution of P. malariae and P. ovale species is a lot more vexed. There are several reasons for this. Genomic data are sparser and aligning their theoretical origins with current distribution patterns requires complicated cross-species transmission events. There are, however, some well supported conclusions. In both cases, there were likely multiple transmission events to humans and this may be ongoing. It is not clear, for example, whether P. brasilianum and P. malariae are, in fact, different species. If they are, then transmission between humans and many primates that harbour P. brasilianum was, and may still be, common. In the case of P. ovale, there are two distinct, non-recombining species: P. o. curtisi and P. o. wallikeri. They emerged independently though extreme bottle necks and subsequently infected overlapping populations. They two species are known to co-circulate but remain genetically distinct.

Figure 1 Plasmodium phylogeny (from Loy et al., 2017)

The history of malaria in humans

Malaria is usually associated with warmer climes, but this is a recent phenomenon. Cases of malaria were documented north of the Arctic circle in the very early 1900s, during the American civil war, and in southern Europe towards the end of WW II. Disease transmission was via other vectors, but malaria has a global history.

The disease burden of malaria is of tremendous historical significance and written in our genomes. Take for example the many red cell disorders associated with malaria. It is difficult to know precisely which of the red cell diseases can be causally attributed to malaria resistance because it is not always clear whether the in vitro evidence translates into clinical significance and fitness costs. Some of the coevolutionary relationships are clear. For example, the heterozygous fitness advantage of sickle cell disease in malaria endemic areas is well established while the association with, say, interferon and complement receptor polymorphisms is perhaps more dubious. There are, however, many red cell-malaria correlations, some of which are certainly translatable into causal relationships. Table 1 lists the most well described huma-malaria coevolutionary genetic relationships.

Table 1 Hereditary human erythrocyte disorders and polymorphisms that protect against P. falciparum malaria.

Evidence that these disorders and polymorphisms protect against malaria has come from in vitro and/or clinical and/or epidemiological data. For items with an asterisk (*), there is only in vitro evidence available (from Durand and Coetzer, 2008).

Etymology

The etymology of the disease name reveals its ancient origins. Roman accounts of humans dying from fevers that were assumed to emerge from foul-smelling bogs in Europe and the British Isles. The Italian term “mal'aria” (bad air) was introduced into England 300 years later by Horace Walpole in 1740: “There is a horrid thing called the malaria, that comes to Rome every summer, and kills one.”, while others considered the term unscientific and preferred the name “paludisme” (‘palus’ in Latin means ‘swamp’), which is still used in French. Nevertheless, the word remained and is restricted to the disease and its symptoms (and not its causative agent or the observation of a parasitaemia).

PART 2: pharmacological management

Living in South Africa, a high index of suspicion should always be maintained. This is so even in non-endemic areas because of the highly mobile populations in sub Saharan Africa and the notorious cases of ‘taxi malaria’. As with all guidelines for infectious diseases in South Africa, the protocols and guidelines recommended are those published by the NICD. For dosages, please see https://www.nicd.ac.za/national-malaria-treatment-guidelines.

Malaria is a notifiable disease. It should also be remembered that uncomplicated malaria may rapidly progress to severe malaria, especially in clinically vulnerable individuals like children (especially under 5yrs), pregnancy, and those with co-morbidities.

Treatment for uncomplicated malaria

1. Parasite species: P. falciparum, P. malariae or P. knowlesi

Pharmacotherapy: artemether-lumefantrine (Coartem) or, if Coartem is unavailable, then oral quinine plus either doxycycline or clindamycin

If unsure of the species then treat as for P. falciparum

2. Parasite species: P. ovale or P. vivax or mixed infections of P. falciparum plus P. vivax or P. ovale

Pharmacotherapy: artemether-lumefantrine followed by primaquine [NOTE: Primaquine is contraindicated in severe G-6-PD deficiency, pregnant women, and infants under six months].

Severe malaria

Severe malaria is almost always caused by P. falciparum. Clinical features include impaired consciousness, prostration, convulsions, respiratory distress, pulmonary oedema, shock, anuria, jaundice, etc. The following laboratory finding indicate severe malaria: hypoglycaemia (<2.2mmol/l), acidosis (plasma bicarbonate <15mmol/l), anaemia (<7g/dl), hyperparasitaemia (>5%), haemoglobinuria, lactate>5mmol/l, creatinine >265μmol/l.

Pharmacotherapy: IV artesunate or, if unavailable, then IV quinine. Once stable and able to tolerate oral treatment then follow with artemether-lumefantrine or, if Coartem is unavailable then quinine (plus doxycycline or clindamycin).

Primaquine should always be used in patients with P. ovale and P. vivax infections to clear the latent hepatic hypnozoite stage of the parasite.

References

Loy, DE, et al. 2017. Out of Africa: origins and evolution of the human malaria parasites Plasmodium falciparum and Plasmodium vivax. International Journal for Parasitology 47, 87-97.

Durand, PM and Coetzer, TL. 2008. Hereditary red cell disorders and malaria resistance. Haematologica 93.

https://www.nicd.ac.za/national-malaria-treatment-guidelines.