bluuebunny/crossref_metadata_2025 huggingface dataset:
Nonalcoholic fatty liver disease
Authors: Anstee Quentin M. , Day Christopher P.
Published: February 2020

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder in the developed world, affecting 20 to 30% of Western adults. Nonalcoholic liver disease occurs with a range of severity from simple steatosis through nonalcoholic steatohepatitis (NASH) to fatty fibrosis and, ultimately, cirrhosis. The condition is a manifestation of the metabolic syndrome, strongly associated with obesity, insulin resistance, and dyslipidaemia. Dietary and genetic factors appear to determine susceptibility to the disease and its progression. In most patients, the condition is discovered incidentally when abnormal values of serum liver-related liver tests are reported. The diagnosis is usually one of exclusion. Liver biopsy is not always required but, in the absence of well-validated noninvasive biomarkers, remains the only way to detect steatohepatitis and accurately stage fibrosis of intermediate severity. However, biopsy is not practical in all cases and so a staged approach to patient assessment and risk stratification is advised. Treatment is directed at components of the metabolic syndrome: weight loss through diet and exercise has been shown to ameliorate disease. A range of novel pharmacological drug treatments are under evaluation.
Vascular disorders of the liver
Authors: Gimson Alexander
Published: February 2020

The liver’s complex blood supply and high metabolic activity may be affected in a number of clinical situations when there is reduced splanchnic inflow and impaired hepatic venous outflow. Budd–Chiari syndrome is caused by obstruction to hepatic venous outflow, usually by thrombosis within the hepatic veins. Causes include myeloproliferative disease, malignancy, and hypercoagulable states. Presentation may be acute, subacute, or chronic, and the diagnosis requires consideration in any patient presenting with acute liver failure, acute hepatitis, or chronic liver disease. Diagnosis is made by Doppler ultrasonography of the hepatic veins and confirmed with CT or MRI scanning. Management depends on the presentation, but involves anticoagulation in all cases, and thrombolysis, measures to decompress the liver, and liver transplantation in some. Survival is about 75% at 5 years. Other conditions discussed include congestive hepatopathy, ischaemic hepatopathy, hepatic artery aneurysm, and portal vein thrombosis.
Primary and secondary liver tumours
Authors: Alexander Graeme J.M. , Lomas David J. , Griffiths William J.H. , Rushbrook Simon M. , Allison Michael E.D.
Published: February 2020

A number of benign and malignant tumours arise in the liver. Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. It is usually asymptomatic unless the cancer is advanced. Cross-sectional imaging with contrast with either CT or MRI is sufficient to make a firm diagnosis. Serum α-fetoprotein is elevated in most cases. Early diagnosis, perhaps through surveillance, increases the proportion of patients that can be considered for curative treatment, including surgical resection, radiofrequency ablation, or liver transplantation. The presence of symptoms denotes a poor prognosis, with less than 10% of patients surviving 3 years. Cholangiocarcinoma accounts for 7 to 10% of primary liver malignancies. The diagnosis of cholangiocarcinoma can be very difficult to make. Resection results in cure for only a few patients. Palliative approaches include photodynamic therapy, conventional radiotherapy, and high-dose local irradiation. Biliary stents relieve jaundice and may reduce the frequency of episodes of cholangitis. Haemangioma, usually an incidental finding, has a prevalence of 2 to 5% in the population. Focal nodular hyperplasia (prevalence 0.4–0.8%) is found predominantly in fertile women and is typically an incidental finding during abdominal imaging. Biopsy is required if there is diagnostic uncertainty and in particular to differentiate from hepatic adenomas. Interventions include surgery, radiofrequency ablation, transarterial embolization, or a combination of each according to location and patient fitness. Secondary tumours may be a presenting feature but more often are found during staging for primary malignancy or during follow-up. Symptoms include abdominal pain and hepatomegaly and later jaundice and ascites. For most patients with multiple metastases to the liver, the prognosis is poor and treatment palliative.
Liver and biliary diseases in infancy and childhood
Authors: Thompson Richard J.
Published: February 2020

Most liver diseases that occur in adults also occur in children, but some present almost exclusively in early childhood. Neonatal jaundice is common and usually short-lived. Onset before 24 h, or continuation beyond 2 weeks, strongly suggests an underlying pathology, when biliary atresia is the most common cause, with liver transplantation allowing some patients to survive to adolescence and adulthood. Some genetic causes of cholestasis (e.g. MDR3 deficiency) can present in adults. A long list of metabolic disorders present with evidence of liver involvement, with later manifesting diseases including those with accumulation of material in the liver. Liver transplantation is an excellent treatment for many of these disorders, and a growing number of metabolic disorders that do not cause liver disease per se are now being successfully managed through liver replacement, with patients surviving into adult life.
Electrocardiography
Authors: Houghton Andrew R. , Gray David
Published: February 2020

The electrocardiograph (ECG) has been recognized as a valuable diagnostic tool since the end of the 19th century. The normal ECG waveform consists of P, QRS, and T waves (and sometimes U waves)—P waves result from atrial depolarization, QRS complexes from ventricular depolarization, and T waves from ventricular repolarization. The standard 12-lead ECG utilizes four limb electrodes and six precordial electrodes to generate 12 leads or ‘views’ of the heart’s electrical activity. There are six limb leads (termed I, II, III, aVR, aVL, and aVF) and six precordial leads (termed V1, V2, V3, V4, V5, and V6). Supplementary ‘views’ can be obtained by using additional leads, such as V7, V8, and V9 to assess the posterior aspect of the heart and right-sided chest leads to look for a right ventricular myocardial infarction.
Cardiac arrhythmias
Authors: Ginks Matthew R. , Lane D.A. , McGavigan A.D. , Lip Gregory Y.H.
Published: February 2020

The term cardiac arrhythmia (or dysrhythmia) is used to describe any abnormality of cardiac rhythm. The spectrum of cardiac arrhythmias ranges from innocent extrasystoles to immediately life-threatening conditions such as asystole or ventricular fibrillation.

The key to the successful diagnosis of cardiac arrhythmias is the systematic analysis of an ECG of optimal quality obtained during the arrhythmia.

Continuous monitoring is necessary for identification when arrhythmias are intermittent. Ambulatory ECG recordings are of most value when they provide correlation between the patient’s symptoms and the cardiac rhythm at that moment. Alternative strategies for the detection of infrequent arrhythmias include the use of a patient-activated recorder, which is applied and activated during symptoms, or an external or implanted loop recorder.
Acute cardiac failure: Definitions, investigation, and management
Authors: Clark Andrew L. , Cleland John G.F.
Published: February 2020

Presentations of acute heart failure fall into three overlapping categories: acute breathlessness and pulmonary oedema; chronic fluid retention and peripheral oedema (anasarca); and cardiogenic shock. Features on examination include tachycardia, hypotension, a raised venous pressure, basal crackles, and peripheral oedema. Auscultation may reveal a third heart sound or features of valvular heart disease. Initial management focuses on confirming the diagnosis and identification of the immediate precipitant (e.g. arrhythmias, myocardial infarction, decompensating valvular heart disease). Initial investigations include a 12-lead electrocardiogram, chest radiograph, full blood count, biochemical screen, troponin, and thyroid function. Natriuretic peptides are useful in confirming the diagnosis where clinical features are present and a normal level of these is helpful in excluding the diagnosis. All patients should undergo echocardiographic assessment early in the course of a hospital admission to assess left ventricular function and to look for underlying valvular heart disease.
Percutaneous interventional cardiac procedures
Authors: Follan Edward D.
Published: February 2020

Percutaneous coronary intervention is the term applied to a variety of percutaneous, catheter-based procedures that accomplish revascularization by angioplasty (enlargement of a vessel lumen by modification of plaque structure), stenting (deployment of an internal armature or stent), atherectomy (removal or ablation of plaque), or thrombectomy (removal of thrombus). The most common single indication for percutaneous coronary intervention is acute coronary syndrome. Randomized trials have shown that direct intervention for ST-elevation myocardial infarction is superior to initial thrombolytic therapy when performed in appropriate centres, and it can be used as a salvage procedure after failed thrombolytic therapy. Balloon angioplasty is the traditional, basic technique of coronary intervention, but this is now uncommonly employed as a stand-alone treatment. A variety of percutaneous techniques can be used to remove atheroma or thrombus from coronary arteries as a prelude to angioplasty/stenting.
Acute aortic syndromes
Authors: Newton James D. , Mitchell Andrew R.J. , Banning Adrian P.
Published: February 2020

The acute aortic syndromes are acute dissection, intramural haematoma, and penetrating ulcer, and all involve disruption of the wall of the aorta with potentially devastating consequences. Although relatively uncommon, left unrecognized and untreated they can carry a mortality rate of up to 2% per hour and 50% within the first few weeks. Physical signs typically reflect the region of the aorta involved and effects of pressure on adjacent structures: evidence of new aortic regurgitation or development of pulse deficits should be actively sought. Abnormalities on the chest radiograph and ECG are common, but neither investigation is diagnostic and further imaging is always necessary by MRI, contrast-enhanced CT, or transoesophageal echocardiography, depending on local availability and the clinical condition of the patient. In the long term, strenuous efforts to control blood pressure are indicated for all patients who have survived aortic dissection, with repeat imaging at least once a year.
Structure and function of the pulmonary circulation
Authors: Morrell Nicholas W.
Published: February 2020

The normal pulmonary circulation distributes deoxygenated blood at low pressure and high flow to the pulmonary capillaries for the purposes of gas exchange. The structure of pulmonary blood vessels varies with their function—from large elastic conductance arteries, to small muscular arteries, to thin-walled vessels involved in gas exchange.

Pulmonary vascular resistance is about one-tenth of systemic vascular resistance, with the small muscular and partially muscular arteries of 50–150 µm diameter being the site of the greatest contribution to resistance. In the normal pulmonary circulation, a large increase in cardiac output causes only a small rise in mean pulmonary arterial pressure because pulmonary vascular resistance falls on exercise. Pulmonary blood flow is heterogeneous: gravity causes increased blood flow in the more dependent parts of the lung; within a horizontal region—or within an acinus—blood-flow heterogeneity is imposed by the branching pattern of the vessels.
Hypertensive urgencies and emergencies
Authors: Lip Gregory Y.H. , Shantsila Alena
Published: February 2020

Hypertensive urgencies and emergencies occur most commonly in patients with previous hypertension, especially if inadequately managed. About 40% of cases have an underlying cause, most commonly renovascular disease, primary renal diseases, phaeochromocytoma, and connective tissue disorders. Hypertensive emergencies occur when severely elevated or sudden marked increase in blood pressure is associated with acute end-organ damage. Malignant phase hypertension is a rare condition characterized by very high blood pressure, with bilateral retinal haemorrhages and/or exudates or cotton wool spots, with or without papilloedema. Presentation is typically with visual disturbance, with or without headaches. Urinalysis may demonstrate proteinuria and haematuria, even in the absence of primary renal disease. Some patients with mild renal impairment at first presentation may improve, or even regain normal renal function, but this is unlikely to occur in those with more severe renal impairment at presentation.
Bronchoscopy, thoracoscopy, and tissue biopsy
Authors: Shah Pallav L.
Published: February 2020

Direct visualization of the airways by bronchoscopy has become an important tool in the diagnosis of respiratory disease since its introduction in Japan in 1966. The ability to visualize specific areas significantly improves diagnostic yield in comparison to blind procedures. Similarly, the diagnosis and treatment of pleural disease has improved significantly with the introduction of thoracoscopy, which allows the direct inspection of the pleural cavity. Tissue biopsy has also evolved, with more procedures now being performed with some form of image guidance. Bronchoscopy, thoracoscopy, and radiologically guided biopsy techniques provide different methods for visualizing and sampling thoracic lesions, the approach chosen in any particular case being based on several factors, including the anatomical location of abnormal areas, presence of coexisting pulmonary disease, presence of comorbidities, and local expertise. CT is useful in both selection and planning of the most appropriate sampling method.
Upper respiratory tract infections
Authors: Little P.
Published: February 2020

Acute upper respiratory tract infections include acute pharyngitis/tonsillitis and acute rhinitis. Acute sinusitis, acute otitis media, and influenza also come under the umbrella of infections of the upper respiratory tract. Otitis media and influenza will be discussed elsewhere: this chapter concentrates on acute pharyngitis/tonsillitis, acute rhinitis, and acute sinusitis. Acute upper respiratory tract infections are one of the commonest reason for patients to seek medical advice in the United Kingdom, and nearly all cases are managed in primary care. Respiratory tract infections are also the commonest reason for antibiotics to be prescribed, leading to serious concern that the inappropriate use of antibiotics for predominantly self-limiting conditions will foster the development of antibiotic resistance, with the danger that serious infections will become untreatable. Thus it is currently an international priority to discourage the use of antibiotics where there is poor evidence of their efficacy.
Pneumonia in the normal host
Authors: Lim Wei Shen
Published: February 2020

Pneumonia is an acute or chronic infection involving the pulmonary parenchyma.

Most cases are caused by microbial pathogens, the commonest being Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydia pneumoniae, legionella, anaerobic bacteria, and viruses (influenza, parainfluenza, and respiratory syncytial virus). Staphylococcus aureus is an important superinfecting pathogen in influenza, and the most common form of embolic pulmonary infection with injected drug use and tricuspid valve endocarditis. The main preventive measures are smoking cessation, and vaccination against influenza and S. pneumoniae. Its classic presentation is with cough and fever, with variable sputum production, dyspnoea, and pleurisy. Most patients have constitutional symptoms and many also have gastrointestinal symptoms. Clinical examination may reveal features indicative of the severity of respiratory compromise and (in some cases) of consolidation.
Mycobacteria
Authors: Jarvis Hannah , Kon Onn Min
Published: February 2020

Mycobacteria are Gram-negative, rod-shaped bacilli comprising the Mycobacterium tuberculosis complex (TB) and non-tuberculous mycobacteria. Infection, usually via inhalation, is often asymptomatic but can lead to primary TB or to latent TB infection which can later develop into ‘reactivation’ or ‘post-primary’ active disease. Pulmonary TB is the commonest manifestation, but extrapulmonary disease can affect almost any organ. Definitive diagnosis is by culture. Standard chemotherapy involves the use of rifampicin, isoniazid, pyrazinamide, and ethambutol. Drug resistance is an increasing problem. Around 1.5 million people die from TB each year. Infection tends to present with a worsening of chronic respiratory symptoms in patients with underlying lung diseases. Diagnosis is difficult because these organisms are common in the environment. A long course of treatment with several drugs is required.
Allergic rhinitis
Authors: Durham Stephen R. , Saleh Hesham A.
Published: February 2020

Allergic rhinitis affects more than 20% of the population of Westernized countries and has a significant impact on quality of life and school/work performance. Important environmental factors include tree and grass pollens (seasonal allergic rhinitis); house dust mite and domestic pets, most often cats (perennial allergic rhinitis); and a variety of occupational exposures (occupational rhinitis). Pathogenesis involves activation of type 2 (Th2) lymphocytes resulting in IgE antibody production and tissue eosinophilia. Immediate symptoms (itching, sneezing, and watery nasal discharge) result from allergen cross-linking adjacent IgE molecules on the surface of mast cells in the nasal mucosa, resulting in the release of histamine and tryptase, and generation of bradykinin. Diagnosis is usually straightforward and based on the history, examination, and (when indicated) the results of skin prick tests and/or serum allergen-specific IgE levels.
Sarcoidosis
Authors: Baughman Robert P. , Lower Elyse E.
Published: February 2020

Sarcoidosis is a disease of unknown cause that is characterized by the presence of non-caseating granulomas in at least two organs. It can present in a wide variety of ways. Differential diagnosis is most commonly from tuberculosis or lymphoma. Most patients with sarcoidosis will experience disease resolution within 2–5 years; about 25% will develop residual fibrosis in the lungs or elsewhere; in a few the disease will become chronic and persist for more than 5 years. Most series from referral centres report 5% disease-related mortality, usually from respiratory failure. There is no single treatment for all patients with sarcoidosis. First-line treatment is usually with corticosteroids, although it is not universally accepted that steroids change the course of the disease. If the dose of steroid cannot be reduced to an acceptable level, or if the patient is not responding, then other agents (e.g. chloroquine/hydroxychloroquine, methotrexate, leflunomide, infliximab) are added.
Pneumoconioses
Authors: Reid P.T.
Published: February 2020

Pneumoconiosis describes the pathological reaction of the lung to inhaled dust, most often, but not exclusively, related to exposures occurring at work. It may be defined as a permanent alteration of lung structure due to the inhalation of mineral dust and the tissue reactions of the lung to its presence, excluding bronchitis and emphysema. The causes of pneumoconiosis are many and varied, but coal worker’s pneumoconiosis, asbestosis, and silicosis are most common. Many epidemiological studies have shown an exposure–response relationship between the total mass of respirable dust to which workers have been exposed and their risk of developing disease. These form the basis of regulations specifying limits to permitted levels of exposure. Workers who develop pneumoconiosis as a consequence of their employment may be entitled to compensation in some countries.
Chronic respiratory failure
Authors: Polkey Michael I. , Calverley P.M.A.
Published: February 2020

Chronic respiratory failure describes a clinical state when the arterial Po2 breathing air is less than 8.0 kPa, which may or may not be associated with hypercapnia (defined as Pco2 more than 6.0 kPa (45 mm Hg)). Four processes cause arterial hypoxaemia due to inefficient pulmonary gas exchange—ventilation–perfusion (V/Q) mismatch, hypoventilation, diffusion limitation, and true shunt, with the most important of these being V/Q mismatching. The arterial CO2 is increased by inadequate alveolar ventilation and/or V/Q abnormality. A wide range of disorders can cause chronic respiratory failure, with the commonest being chronic obstructive pulmonary disease, interstitial lung diseases, chest wall and neuromuscular diseases, and morbid obesity.
Disorders of the thoracic cage and diaphragm
Authors: Shneerson John M. , Polkey Michael I.
Published: February 2020

Disorders of the thoracic skeleton can lead to a severe restrictive ventilatory defect, the risk of respiratory failure being highest with (1) scoliosis—particularly if the following characteristics are present: early onset, severe angulation, high in the thorax, respiratory muscle weakness, low vital capacity; (2) kyphosis—but only if of very sharp angulation (gibbus), most commonly seen following tuberculous osteomyelitis; and (3) after thoracoplasty—historically performed as treatment for pulmonary tuberculosis. While not a disorder of the skeleton, a similar pathophysiological pattern is seen in extreme obesity, and this is the fastest growing cause of referral to home ventilation centres. Arterial blood gases and quality of life can both be readily improved with non-invasive ventilation, usually using a nasal or face mask. Survival in most skeletal disorders after starting ventilation leads to apical bullae, pleural thickening/effusions, and cricoarytenoid arthritis, but rarely causes respiratory failure in the absence of other comorbidities.
Pleural tumours
Authors: Lee Y.C. Gary
Published: February 2020

Benign tumours are rare in the pleural cavity, with solitary fibrous tumour of the pleura the most frequent of these rarities. Malignant pleural tumours are common and can arise from the pleura (most commonly mesothelioma) or as metastases from extrapleural malignancies (especially lung and breast cancer). They typically present with breathlessness, chest pain, and a pleural effusion. Diagnosis requires histocytological confirmation of malignant cells from pleural fluid and/or pleural biopsies. Most cases are due to asbestos exposure, characteristically after a latent period of more than 20 years, with risk related to the duration and intensity of asbestos exposure and the fibre type (worst with needle-like amphiboles). Most tumours that have spread to the pleura are incurable.
Spondyloarthritis and related conditions
Authors: Braun Jürgen , Sieper Joachim
Published: February 2020

The spondyloarthritides are a group of common inflammatory rheumatic diseases with predominant involvement of axial and peripheral joints and entheses, together with other characteristic clinical features, including inflammatory back pain, sacroiliitis, peripheral arthritis (mainly in the legs), enthesitis, dactylitis, preceding infection of the urogenital/gastrointestinal tract, psoriatic skin lesions, Crohn-like gut lesions, anterior uveitis, and a family history of spondyloarthritis (SpA). Five subsets can be distinguished on clinical grounds: (1) axial SpA, including ankylosing spondylitis; (2) reactive (spondylo)arthritis/Reiter’s syndrome; (3) psoriatic (spondylo)arthritis; (4) (spondylo)arthritis associated with inflammatory bowel diseases; and (5) undifferentiated peripheral SpA. Prevalence in any population correlates roughly with that of HLA B27, but the relevance of this to pathogenesis is not known. Another more recent approach is to differentiate the SpA on the basis of the predominant clinical manifestation: predominant axial and/or peripheral SpA.
Systemic lupus erythematosus and related disorders
Authors: Rahman Anisur , Isenberg David A.
Published: February 2020

Systemic lupus erythematosus is an autoimmune rheumatic disorder that can present with symptoms in almost any organ or system of the body. It is 10 times commoner in women than men, and commoner in Afro-Caribbeans than in other ethnic groups. Its aetiology is multifactorial, incorporating genetic, hormonal, and environmental elements. No single abnormality of the immune system can be considered responsible, pathogenesis depending on the interplay of several different factors, including autoantibodies, T lymphocytes, cytokines, the complement system, and apoptosis. Common symptoms are constitutional (fatigue, anorexia), musculoskeletal (arthralgia/arthritis, myalgia), dermatological (alopecia, butterfly rash, vasculitic skin lesions, purpura), cardiopulmonary (breathlessness, pleurisy), and neurological (migraine, seizures, depression, psychosis). Treatment for mild disease is NSAID, analgesics and hydroxychloroquine, more severe disease requires corticosteroid and immunosuppressant drugs.
Sjögren’s syndrome
Authors: Ng Wan-Fai
Published: February 2020

Sjögren’s syndrome is an autoimmune connective tissue disease characterized by dryness of the eyes and mouth and lymphocytic infiltrates in the salivary, lachrymal, and other exocrine glands. Its cause is not known, but it may be primary or associated with other autoimmune diseases (secondary) and it affects women more than men (ratio 9–15:1). The aetiology of SS remains elusive, although genetic susceptibility and environmental triggers both play a role. Genome-wide association studies have identified several disease-susceptibility loci. Infections with various viruses have been associated with an SS-like syndrome. Current evidence suggests that environmental or endogenous antigen triggers immune cell activation and autoantibody production, leading to a self-perpetuating inflammatory response in genetically susceptible individuals, and resulting in destruction of exocrine glands.
Skeletal disorders—general approach and clinical conditions
Authors: Wordsworth B. Paul , Javaid M.K.
Published: February 2020

Bone is made up of (1) cells—osteoblasts, osteoclasts, and ostoecytes; and (2) extracellular mineralized matrix—roughly one-third organic (90% type 1 collagen) and two-thirds inorganic (mainly hydroxyapatite). Common presentations of bone disease include (1) deformity and short stature; (2) bone pain and fracture; (3) myopathy—in osteomalacia and rickets; (4) features of underlying disease (e.g. renal failure, myeloma). Many generalized disorders of the skeleton, such as osteoporosis, have entirely normal routine biochemical values. Radiographic imaging can be diagnostic in some cases, but MRI and CT are increasingly employed in addition to conventional (‘plain’) radiographs and bisphosphonate-labelled isotope scans. Bone biopsy is required for diagnosis in some circumstances. This chapter emphasizes those disorders in which impact on the skeleton is a substantial feature of the underlying condition.
Membranoproliferative glomerulonephritis
Authors: Turner-Stokes Tabitha , Little Mark A.
Published: February 2020

The key histological features of membranoproliferative glomerulonephritis (MPGN) are mesangial hypercellularity, endocapillary proliferation, and capillary wall remodelling. There are two main types: (1) immune complex-mediated disease—caused by chronic infection causing persistent antigenaemia (notably hepatitis C), autoimmune disease, or monoclonal immunoglobulin production by plasma cell dyscrasia, and a few ‘idiopathic’ cases; and (2) complement-mediated disease—caused by dysregulation of the alternative pathway of complement, including by C3 nephritic factor (C3Nef), an autoantibody that stabilizes the alternative pathway C3 convertase. Clinical presentation is varied, including nephrotic syndrome, episodic visible haematuria, hypertension/rapidly progressive glomerulonephritis, asymptomatic nonvisible haematuria, and chronic kidney disease. Treatment depends on the underlying disease. All patients should receive appropriate conservative measures (blood pressure control, angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker). Underlying infection or monoclonal gammopathy should be treated, when possible, in those with immune complex-mediated MPGN. Eculizumab may have a role in treatment of some patients with complement-mediated MPGN. Steroids and cyclophosphamide or mycophenolate mofetil are used in patients with severe idiopathic MPGN.
Chronic tubulointerstitial nephritis
Authors: De Broe Marc E. , Jayasumana Channa , D’Haese Patrick C. , Elseviers Monique M. , Vervaet Benjamin
Published: February 2020

Chronic tubulointerstitial nephritis is usually asymptomatic, presenting with slowly progressive renal impairment. Urinalysis may be normal or show low-grade proteinuria (<1.5 g/day) and/or pyuria. Diagnosis depends on renal biopsy, which reveals variable cellular infiltration of the interstitium, tubular atrophy, and fibrosis. There are many causes including sarcoidosis, drugs (prescribed and nonprescribed), irradiation, toxins, and metabolic disorders. Analgesic nephropathy—characterized by renal papillary necrosis and chronic interstitial nephritis and caused by the prolonged and excessive consumption of combinations of analgesics, mostly including phenacetin. Nonsteroidal anti-inflammatory drugs—the most frequent cause of permanent renal insufficiency after acute interstitial nephritis. Aristolochic acid nephropathy—(1) Chinese herb nephropathy—caused in most cases (but perhaps not all) by aristolochic acid, and is associated with a high incidence of urothelial malignancy. (2) Balkan endemic nephropathy—a chronic, familial, noninflammatory tubulointerstitial disease of the kidneys that is associated with a high frequency of urothelial atypia, occasionally culminating in tumours of the renal pelvis and urethra. 5-Aminosalicylic acid—used in the treatment of chronic inflammatory bowel disease and causes clinical nephrotoxicity in approximately 1 in 4000 patients/year. Chronic interstitial nephritis in agricultural communities (CINAC) —nonproteinuric chronic kidney disease that presents in young, agricultural workers in Central America and Sri Lanka in the absence of any clear aetiology. Lithium—the most common renal side effect is to cause nephrogenic diabetes insipidus. Radiation nephropathy—preventive shielding of the kidneys in patients receiving radiation therapy generally prevents radiation nephropathy, but total body irradiation preceding bone marrow transplantation leads 20% to develop chronic renal failure in the long term. Nephropathies induced by toxins (including lead and cadmium) or by metabolic disorders (chronic hypokalaemia and chronic urate nephropathy).
Renal diseases in the tropics
Authors: Jha Vivekanand
Published: February 2020

Kidney diseases encountered in tropical areas are a mix of conditions that have a worldwide distribution and those that are secondary to factors unique to the tropics (e.g. climatic conditions, infectious agents, nephrotoxic plants, envenomations, and chemical toxins). Cultural factors, illiteracy, superstitions, living conditions, level of access to health care, and nutritional status also affect the nature and course of disease. Knowledge of such conditions and issues is important for medical professionals in all parts of the globe, as ease of travel means that individuals and practices are exported with increasing frequency. Glomerular diseases—there is a high prevalence of infection-related glomerulonephritis (e.g. quartan malarial, schistosomal, and filarial nephropathies) throughout the tropics, with the pattern of injury dependent upon the nature of the prevalent endemic infection in that region. Once established, the course of disease is rarely modified by treatment of underlying infection. Acute kidney injury (AKI)—there is a higher prevalence of community-acquired AKI in the tropics than elsewhere. Medical causes predominate, with diarrhoeal diseases, intravascular haemolysis due to glucose-6-phosphate dehydrogenase deficiency, ingestion of toxic plants, snake bites, insect stings, and locally prevalent infections being responsible for most cases. Falciparum malaria and leptospirosis are the most important infectious aetiologies. Use of indigenous herbs and chemicals by traditional healers (‘witch doctors’) are the most important toxic causes of AKI in sub-Saharan Africa. Chronic kidney disease (CKD)—although the contributions of diabetes and hypertension are growing, many cases are secondary to glomerular diseases, likely infection related, or have CKD of undetermined aetiology. Many of the latter are agriculture or farm workers presenting with chronic tubulointerstitial nephritis of unknown cause.
Drugs and the kidney
Authors: Burns Aine , Ashley Caroline
Published: February 2020

The kidney plays a critical role in the elimination of many drugs from the body, hence consideration should be given to a patient’s renal function whenever any drug is prescribed. Much kidney disease is unrecognized, but the widespread reporting of estimated glomerular filtration rates (eGFR) has brought greater awareness of the prevalence of chronic kidney disease (CKD), thereby encouraging medical practitioners to take account of reduced renal function when prescribing. CKD is very often one of many coexisting comorbid conditions, especially in elderly patients, when particularly careful thought must be given to appropriate drug dosing and the possibility of drug interactions. A reduced GFR is the primary reason for reduced excretion of drugs in renal failure, but drug absorption, distribution, protein binding, metabolism, and pharmacodynamics may all be affected. Key general points—both filtration and secretion of drugs appear to fall in parallel and in proportion to the GFR. The clinical significance of a reduction in GFR and increased drug half-life depends on the relative importance of renal excretion and metabolism as a mode of elimination, and the therapeutic ratio of the drug. If nonrenal clearance accounts for elimination of more than 50% of a drug, then no adjustment needs be made to dose/frequency of administration. Dosages of drugs which are mainly excreted in active form by the kidney may need to be modified to avoid accumulation. Potentially toxic drugs should only be used in patients with renal failure if there is a specific indication for their use and if therapy can be monitored appropriately. If dose adjustment is required, then dose, dose interval, or both can be adjusted to achieve the desired therapeutic profile.
Cellular and molecular basis of haematopoiesis
Authors: Vyas Paresh , Jakobsen N. Asger
Published: February 2020

Haematopoiesis involves a regulated set of developmental stages from haematopoietic stem cells (HSCs) that produce haematopoietic progenitor cells that then differentiate into more mature haematopoietic lineages, which provide all the key functions of the haematopoietic system. Definitive HSCs first develop within the embryo in specialized regions of the dorsal aorta and umbilical arteries and then seed the fetal liver and bone marrow. At the single-cell level, HSCs have the ability to reconstitute and maintain a functional haematopoietic system over extended periods of time in vivo. They (1) have a self-renewing capacity during the life of an organism, or even after transplantation; (2) are multipotent, with the ability to make all types of blood cells; and (3) are relatively quiescent, with the ability to serve as a deep reserve of cells to replenish short-lived, rapidly proliferation progenitors. Haematopoietic progenitor cells are unable to maintain long-term haematopoiesis in vivo due to limited or absent self-renewal. Rapid proliferation and cytokine responsiveness enables increased blood cell production under conditions of stress. Lineage commitment means limited cell type production. The haematopoietic stem cell niche is an anatomically and functionally defined regulatory environment for stem cells modulates self-renewal, differentiation, and proliferative activity of stem cells, thereby regulating stem cell number. Haematopoietic reconstitution during bone marrow transplantation is mediated by a succession of cells at various stages of development. More mature cells contribute to repopulation immediately following transplantation. With time, cells at progressively earlier stages of development are involved, with the final stable repopulation being provided by long-lived, multipotent HSCs. Long-term haematopoiesis is sustained by a relatively small number of HSCs.
Acute myeloid leukaemia
Authors: Russell Nigel , Burnett Alan
Published: February 2020

Acute myeloblastic leukaemia arises in a haematopoietic stem cell as a result of mutations which promote growth or inhibit apoptosis in association with mutations that inhibit differentiation. There is usually no obvious cause, but exposure to chemical and ionizing radiation may be relevant, including previous chemotherapy for solid tumours. This leukaemia arises particularly in older patients, often in the context of antecedent haematological disorders such as myelodysplastic syndromes or myeloproliferative neoplasms. Clinical features are of marrow failure, with anaemia, bleeding (petechiae, purpura, from mucous membranes), and infection. Acute promyelocytic leukaemia should be viewed as a medical emergency characterized by disseminated intravascular coagulation which requires urgent treatment to avoid haemorrhagic death. Aside from providing appropriate supportive care, the first clinical decision to be made is whether to give conventional intensive chemotherapy aiming for disease eradication, or to adopt a more palliative approach. Intensive chemotherapy is the norm up to age 65 to 70 years. Above this age, the biology of the disease tends to be less favourable and patients may have significant comorbidities limiting treatment tolerance. In patients under 60 years, 75 to 80% will achieve initial remission and about 45 to 50% will survive. In older patients given intensive treatment, 50 to 60% will enter remission but only 15 to 20% will survive 2 years. With nonintensive treatments, remissions are seen in 15 to 25% with the median survival being 6 to 9 months. Relapsed disease—more than 50% of patients will ultimately relapse and their overall outcome is generally very poor. The best curative option is allogeneic stem cell transplantation if a second complete remission can be achieved with reinduction chemotherapy.
Eosinophilia
Authors: Weller Peter F.
Published: February 2020

Eosinophilia (eosinophil count >0.45 × 109/litre) is associated with some infections, some allergic diseases, and a variety of other conditions, sometimes neoplastic. Parasitic diseases—eosinophilia is a characteristic feature of infection by multicellular helminth parasites (e.g. Strongyloides stercoralis) with diagnosis typically based on geographical/dietary history, serological tests, and examination of stool or tissues for parasite forms. Other diseases—eosinophilia can be caused by the fungal disease coccidioidomycosis, and modest eosinophilia may accompany retroviral infections such as HIV and HTLV-1. Common allergic diseases—asthma, rhinitis, and atopic dermatitis are associated with modest eosinophilia. Drug reactions—these are a frequent cause of eosinophilia, at times in reactions characterized by rashes and pyrexia. More severe reactions may also manifest with (1) pulmonary eosinophilia and lung infiltrates; (2) interstitial nephritis; (3) hepatitis; (4) myocarditis; (5) drug-induced hypersensitivity vasculitis; (6) gastroenterocolitis; and (7) DRESS syndrome. Other conditions—these include (1) eosinophilic granulomatosis with polyangiitis; (2) hyper-IgE syndromes; (3) chronic myeloid leukaemia, acute myeloid leukaemia, and lymphoma; (4) a variety of pulmonary, skin, gastrointestinal, and endocrine diseases. Hypereosinophilic syndromes are defined by (1) eosinophilia (>1.5 × 109/litre) sustained over a month, (2) lack of an identifiable cause precipitating a secondary eosinophilia, and (3) symptoms and signs of organ involvement. About 30% of patients will have either a myeloproliferative condition (chronic eosinophilic leukaemia) or hypereosinophilia mediated by clonal expansion of specific T cells producing interleukin-5 (IL-5). Treatment—patients without organ damage do not require treatment. Aside from supportive care, chronic eosinophilic leukaemia may respond to tyrosine kinase inhibitors (e.g. imatinib), and nonmyeloproliferative hypereosinophilic syndrome may respond to high-dose corticosteroids, with hydroxyurea, interferon-α or anti-IL-5 monoclonal antibody used in refractory cases.
Introduction to lymphopoiesis
Authors: Jacobson Caron A. , Berliner Nancy
Published: February 2020

Lymphoproliferative disorders occur when the normal mechanisms of control of proliferation of lymphocytes break down, resulting in autonomous, uncontrolled proliferation of lymphoid cells and typically leading to lymphocytosis and/or lymphadenopathy, and sometimes to involvement of extranodal sites (e.g. bone marrow). These include (1) malignant—clonal in nature, resulting from the uncontrolled proliferation of a single transformed cell (e.g. lymphoma); (2) nonmalignant—polyclonal lymphoproliferative disorders may result from conditions including (a) infections—lymphocytosis is commonly caused by viral infections (e.g. Epstein–Barr virus (EBV)), lymphadenopathy is a common feature of a very wide variety of infections; and (b) reactive—conditions such as systemic lupus erythematosus and sarcoidosis frequently cause lymphadenopathy. Distinguishing between the lymphoproliferative disorders clinically and pathologically is not always easy. Clinical assessment—when eliciting the history of a patient with suspected lymphoproliferation, particular note should be taken of their general health, the type and duration of any constitutional symptoms, and any episodes of recent infection/exposure to drugs/travel. Thorough examination of all lymph node sites is required, as is careful examination of the oropharynx, tonsils, skin, spleen, and liver. Investigation—whenever a lymphoproliferative disorder is suspected, the key initial investigation is the full blood count and examination of the blood film, sometimes augmented by immunocytochemistry and flow cytometry. Depending on clinical context, other investigations may include (1) serological studies for viral pathogens; (2) serological studies for rheumatological disease; (3) imaging for mediastinal and intra-abdominal lymphadenopathy; (4) bone marrow examination; and—if no diagnosis is apparent—(5) lymph node biopsy.
Acute lymphoblastic leukaemia
Authors: Vormoor H. Josef , Menne Tobias F. , Moorman Anthony V.
Published: February 2020

Acute lymphoblastic leukaemia (ALL) is a malignant proliferation of lymphoid blasts, most commonly of B-lineage origin. The clinical symptoms and signs are either a consequence of bone marrow failure (infections, bruising, petechiae, pallor, and tiredness) or a consequence of the uncontrolled proliferation of the blasts (lymphadenopathy, hepatosplenomegaly, and cranial nerve palsies). Its peak incidence is in young children but ALL occurs at all ages. More than 80% of all affected children are cured with modern chemotherapy, but unfortunately the outcome of adults is much worse despite some improvements led by the introduction of paediatric-inspired protocols and tyrosine kinase inhibitors in BCR-ABL1-positive ALL. Standard chemotherapy for ALL consists of several months of intensive multidrug induction, consolidation and intensification chemotherapy (including steroids, vincristine, asparaginase and anthracyclines), intrathecal methotrexate to target blasts in the central nervous system, and low-intensity maintenance therapy (with oral 6-mercaptopurine and methotrexate) for up to 3 years. Treatment is stratified according to the response and other prognostic biomarkers (including genetics). Allogeneic haematopoietic stem cell transplantation is used predominantly in the relapse setting for children but in frontline therapy for adult patients to consolidate chemotherapy. Novel targeted small molecules and, in particular, immunotherapy are promising to offer new treatment options for patients with high-risk or relapsed disease.
Anaemia: pathophysiology, classification, and clinical features
Authors: Weatherall David J. , Hatton Chris
Published: February 2020

Anaemia is defined by the World Health Organization as a reduction of the haemoglobin concentration to less than 130 g/litre (males) or less than 120 g/litre (females). It is a common problem, with a prevalence around 3% for middle-aged men and 14% for middle-aged women in the United Kingdom, and is seen more frequently with age. There is a much greater prevalence in the developing world. Anaemia can be caused by the defective production of red cells or an increased rate of loss of cells, either by bleeding or premature destruction (haemolysis). The causes of defective production of red cells include (1) deficiency of key haematinics, including iron, vitamin B12, or folate; (2) anaemia of chronic disease; (3) reduced erythropoietin production typically seen in chronic kidney disease; and (4) primary diseases of the bone marrow. Haemolytic anaemias may be classified as either genetic or acquired. The key issues are to determine the degree of disability caused by the anaemia and hence how quickly treatment must be started, and the cause of the anaemia. The main causes of anaemia can usefully be classified according to the associated red cell morphological changes: (1) hypochromic, microcytic—including iron deficiency (the commonest cause of anaemia) and thalassaemia (common in some populations); (2) normochromic, macrocytic—vitamin B12 or folate deficiency, alcohol, and myelodysplasia; (3) polychromatophilic, macrocytic—haemolysis; (4) normochromic, normocytic—chronic disorders, renal failure, and diseases of the bone marrow; and (5) leucoerythroblastic—myelofibrosis, leukaemia, and metastatic carcinoma. The reticulocyte count also provides a good way of thinking about the underlying cause of anaemia—whether due to defective production or excess consumption of red cells.
Erythrocyte enzymopathies
Authors: Zanella Alberto , Bianchi Paola
Published: February 2020

Numerous enzymes, including those of the hexose monophosphate and glycolytic pathways, are active in the red cell. They are required for the generation of ATP and the reductants NADH and NADPH. 2,3-Diphosphoglycerate, an intermediate of glucose metabolism, is a key regulator of the affinity of haemoglobin for oxygen, and accessory enzymes are also active for the synthesis of glutathione, disposal of oxygen free radicals, and for nucleotide metabolism. With the exception of heavy metal poisoning and rare cases of myelodysplasia, most red cell enzyme deficiency disorders are inherited. They may cause haematological abnormalities, (most commonly nonspherocytic haemolytic anaemias, but also rarely polycythaemia or methaemoglobinaemia, manifest with autosomal recessive or sex-linked inheritance), and may also be associated with nonhaematological disease when the defective enzyme is expressed throughout the body. Some may mirror important metabolic disorders, without producing haematological problems, making them of diagnostic value. Others are of no known clinical consequence. With rare exceptions, it is impossible to differentiate the enzymatic defects from one another by clinical or routine laboratory methods. Diagnosis depends on the combination of (1) accurate ascertainment of the family history; (2) morphological observations—these can determine whether haemolysis is present, rule out some causes of haemolysis (e.g. hereditary spherocytosis and other red blood cell membrane disorders), and diagnose pyrimidine 5′-nucleotidase deficiency (prominent red cell stippling); (3) estimation of red cell enzyme activity; and (4) molecular analysis. The most common red cell enzyme defects are glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, glucose-6-phosphate isomerase deficiency, pyrimidine 5′-nucleotidase deficiency—which may also induced by exposure to environmental lead—and triosephosphate isomerase deficiency.