bluuebunny/crossref_metadata_2025 huggingface dataset:
The seriously ill or deteriorating patient
Authors: Foot Carole , Hickson Liz
Published: February 2020

The first step in the clinical approach to a patient who is very ill is the recognition of this fact. While experienced clinicians will intuitively recognize a seriously ill or deteriorating patient, a large body of data has demonstrated that warning signs are often missed or not acted upon, resulting in preventable harm to patients. This has led to the development and adoption of ‘track and trigger’ systems. Track and trigger systems aim to ensure that hospitalized patients undergo regular review and objective observation, with abnormal observation or staff concerns being triggers to escalate care. Escalated care may be urgent review by the treating team, or the calling of a ‘rapid response team’ to attend to a more critically ill patient. While calling criteria and team composition varies from country to country, the principle of rapidly taking skilled care to critically ill patients remains the unifying underlying principle.
Metabolic and endocrine changes in acute and chronic critical illness
Authors: Boonen Eva , Berghe Greet Van den
Published: February 2020

Critical illness, an extreme form of severe physical stress, is characterized by important endocrine and metabolic changes. The development of critical care medicine has made possible survival from conditions that were previously rapidly fatel, and as a result many patients now enter a prolonged phase of chronic or persistent critical illness. Acute endocrine adaptations are directed towards providing energy and substrates for the vital fight or flight response in the context of exogenous substrate deprivation. Distinct endocrine and metabolic alterations characterize the chronic phase of critical illness, which seems to no longer be solely beneficial and may hamper recovery and rehabilitation. Onset of the stressful event causes an acute activation of pulsatile hormonal release from the anterior pituitary, followed by suppression in the chronic phase of illness, ultimately resolving to normality if recovery occurs.
Respiratory function tests
Authors: Gibson G. J.
Published: February 2020

Respiratory function tests are used in diagnosis, assessment, and prognosis and in monitoring the effects of treatment of various respiratory conditions. In the diagnosis of specific diseases, respiratory function tests—like functional tests of other organs—inevitably have limitations. Their use as a diagnostic tool is in recognizing patterns of abnormality which characterize particular types of disease; more often they are used to quantify the severity of functional disturbance or to locate the likely anatomical site(s) of disease (airways, alveoli, or chest wall). The commonly applied tests are most conveniently classified as (1) tests of respiratory mechanics, (2) carbon monoxide uptake, (3) arterial blood gases and acid–base balance, and (4) exercise.
Bronchiolitis obliterans and cryptogenic organizing pneumonia
Authors: Kouranos Vasilis , Wells A.U.
Published: February 2020

The nomenclature of the bronchiolitides is complicated by the interchangeable use of pathological and clinical descriptions and a diversity of classification systems. The four primary histological patterns are: organizing pneumonia (also termed proliferative bronchiolitis and bronchiolitis obliterans organizing pneumonia); bronchiolitis obliterans (also termed obliterative bronchiolitis and constrictive bronchiolitis); follicular bronchiolitis; and diffuse panbronchiolitis. The most characteristic abnormality is a filling of alveoli with granulation tissue and buds of loose collagen and connective tissue matrix cells with a uniform appearance. Presentation is typically subacute with non-productive or minimally productive cough, insidious dyspnoea, and systemic symptoms including malaise, fever, or chills, weight loss, and myalgia. Clinical signs are non-specific. Corticosteroid therapy is usually effective, with other immunosuppressive agents given to fulminant cases or those that do not respond. Prognosis is usually good, with overall mortality less than 5%.
Lymphocytic infiltrations of the lung
Authors: Bourke S. J.
Published: February 2020

Lymphocytic infiltrations of the lung arise from the proliferation of bronchus-associated lymphoid tissue, resulting in a spectrum of rare conditions ranging from benign polyclonal lymphoid interstitial pneumonia to monoclonal primary malignant lymphomas of the lung. Lymphoid interstitial pneumonia is most commonly seen in Sjögren’s syndrome or other connective tissue diseases, and in association with HIV infection, and is characterized by reticulonodular shadowing on CT imaging and (usually) a good response to corticosteroids. Primary pulmonary lymphomas fall into three categories: lymphomatoid granulomatosis, low-grade B-cell lymphoma, and high-grade B-cell lymphoma. The latter require treatment with cytotoxic drugs and have a poor prognosis.
Clinical presentation and diagnosis of rheumatological disorders
Authors: Deighton Christopher , Pearce Fiona
Published: February 2020

Most rheumatological diagnoses are made through effective history taking and physical examination rather than investigation. Systemic symptoms, such as weight loss, anorexia, and fever, point to systemic diseases such as rheumatoid arthritis, other polyarthritides, systemic lupus erythematosus, polymyalgia, and vasculitides. Swelling of joints is a symptom commonly reported by patients with no objective evidence of this on examination. Inflammatory arthropathies should not be diagnosed unless the physician is able to identify objective swelling, if necessary by arranging a prompt review during an active episode. Diagnostic criteria for the systemic rheumatic diseases are useful in directing the history taking to verify a suspected diagnosis. Investigations are best used to confirm a strongly suspected diagnosis, already made on the basis of history and examination, not as a screening tool for rheumatic disease.
Osteoarthritis
Authors: Barr Andrew J. , Conaghan Philip G.
Published: February 2020

Clinical osteoarthritis (OA) is a syndrome of joint pain associated with structural deterioration of synovial joints that over time involves the whole joint organ. It is the most common form of arthritis and a leading cause of chronic pain, disability, and socioeconomic burden. Affected individuals report pain (especially on weight bearing) and joint stiffness leading to loss of muscle strength and poor joint function. This results in reduced participation in valued activities, low mood, sleep disturbance, and poor quality of life. The aetiology of joint deterioration, pain, and the interaction of the two remains unclear. OA is associated with a variety of both modifiable and non-modifiable risk factors including obesity, age, gender, occupational injury, trauma, and genetic predisposition. Obesity is the strongest potentially modifiable risk factor.
Introduction
Authors: Isenberg David A. , Giles Ian
Published: February 2020

About 1 in 20 people develop an autoimmune disease, many of which involve the musculoskeletal system. Young women are particularly at risk, but the development at any age of symptoms such as unexplained fever, rash, polyarthritis, Raynaud’s phenomenon, or mouth ulcers should encourage serological screening for autoimmune rheumatic or vasculitic disorder. The autoimmune rheumatic diseases are a heterogeneous group of disorders characterized by clinical involvement of the joints, connective tissues, muscles, internal organs, Raynaud’s phenomenon, and cutaneous manifestations. They include a broad clinical spectrum of disease, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome, scleroderma, dermatomyositis, polymyositis, antiphospholipid syndrome (APS), and the vasculitides.
Polyarteritis nodosa
Authors: Guillevin Loïc
Published: February 2020

Polyarteritis nodosa (PAN) is a necrotizing angiitis, often associated with hepatitis B infection, that predominantly affects medium-sized arteries. Patients usually have systemic features; specific manifestations include peripheral neuropathy, mononeuritis multiplex, skin lesions (subcutaneous nodules, purpura), hypertension, renal insufficiency, gastrointestinal haemorrhage/perforation, and orchitis. Elevated markers of inflammation are found in most patients, but serum antineutrophil cytoplasmic antibodies are not present. Standard treatment of hepatitis B negative cases is with corticosteroids (typically initiated with intravenous methylprednisolone) and cyclophosphamide; hepatitis B positive cases are treated with an antiviral agent, corticosteroid and plasma exchange, with corticosteroid discontinued as soon as disease comes under control. Severe gastrointestinal involvement is the primary cause of early death; later deaths may result from treatment side effects.
Small vessel vasculitis
Authors: Watts Richard A.
Published: February 2020

Small vessel vasculitis is vasculitis affecting predominately small intraparenchymal arteries, arterioles, capillaries, and venules. There are two main types: antineutrophil cytoplasmic antibody associated and immune complex mediated. The ANCA associated vasculitides are discussed in chapter 19.3 IgA vasculitis (IgAV) was formerly known as Henoch Schönlein purpura. The revised nomenclature reflects the importance of IgA vasculitis in pathogenesis. The Chapel Hill Consensus Conference defined IgA vasculitis as ‘vasculitis with IgA1-dominant immune deposits, affecting small vessels (predominantly capillaries, venules, or arterioles)’. IgA vasculitis often involves skin and gut, and frequently causes arthritis. Glomerulonephritis indistinguishable from IgA nephropathy may occur. Its aetiology is unknown, but it frequently occurs after an infection several days to weeks before. The most frequently isolated organism is beta-haemolytic streptococcus. Drugs such as a penicillin, ampicillin, erythromycin, and non-steroidal anti-inflammatory drugs have been reported as precipitating agents. There is an association with HLA-DRB1*01 in Caucasians and there appears to be a familial association.
Osteomyelitis
Authors: McNally Martin A. , Berendt Anthony R.
Published: February 2020

Bacteria can penetrate bone from a contiguous focus of infection (e.g. a diabetic foot ulcer or local injury) or by haematogenous spread. Osteomyelitis is most commonly caused by Staphylococcus aureus, β-haemolytic streptococci, and—in some situations—aerobic Gram-negative rods. An acute inflammatory response causes oedema within bone and soft tissue, and thrombosis in vessels that can result in bone infarction. Pus may form within cancellous bone and beneath the periosteum, stripping it from the bone and leading to extensive necrosis that sometimes involves an entire bone. The process may become chronic and relapsing. Definitive diagnosis can only be confirmed with culture of bacteria from representative bone samples, supported by histological evidence of inflammation. This cannot be achieved in all cases and diagnosis is commonly made on the basis of clinical features and imaging. MRI is the standard and best method.
Bone cancer
Authors: Hatcher Helen
Published: February 2020

Benign bone tumours are common, usually asymptomatic, and discovered incidentally. Malignant primary bone tumours are uncommon but cause significant morbidity and mortality, particularly in adolescents and young adults. Bony metastases are the tumours most frequently seen in bone. Malignant bone tumours typically present with localized pain or swelling. With patients in whom the diagnosis is not clearly metastatic disease, determination of tumour size and extent is best achieved by magnetic resonance imaging, and bone biopsy is mandatory to establish a precise histological diagnosis. Osteosarcoma, chondrosarcoma, and Ewing sarcoma are the three commonest primary bone tumours. In determining management, the main clinical distinction is between localized and metastatic disease. Non-metastatic primary tumours are treated with surgery (when possible) and chemotherapy (osteosarcoma and Ewing sarcoma, sometimes chondrosarcoma). Symptomatic bony metastases are usually treated with external beam radiotherapy.
Structure and function of the kidney
Authors: Harper Steve , Unwin Robert
Published: February 2020

The kidneys are the archetypal organs of homeostasis. Their primary function is filtration and segregation. Through these processes they rebalance the continual electrolyte and chemical disturbances that derive from physiological and pathological metabolic processes. Electrolytes, hydrogen (H+) ions from metabolic acids, amino acids, fatty acids, plasma proteins, immunoglobulins, and metabolic products are either retained, reabsorbed, and recycled; or they are filtered, secreted, concentrated, and excreted. These processes convert approximately 120 ml/min of primary glomerular filtrate into 1 ml/min of urine. In addition, the kidneys play crucial roles in bone mineralization, the maintenance of cardiovascular tone, systemic blood pressure, and bone marrow synthetic function via their contribution to vitamin D production, the renin–angiotensin system, and erythropoiesis.
Disorders of potassium homeostasis
Authors: Firth John D.
Published: February 2020

Hypokalaemia is defined as a serum potassium concentration lower than 3.5 mmol/litre and is the most common electrolyte abnormality seen in clinical practice, found in about 20% of hospital inpatients. Clinical features and investigation—mild hypokalaemia is asymptomatic, but nonspecific symptoms develop with more severe disturbance, and serious neuromuscular problems sometimes arise at serum potassium concentrations lower than 2.5 mmol/litre. Emergency management is rarely required, but intravenous infusion of potassium should be given in the rare circumstances of life-threatening cardiac arrhythmia or muscular paralysis. There are a very large number of possible causes of hypokalaemia, the most common causes being diuretics (particularly thiazides), vomiting, and diarrhoea. The most common genetic cause is Gitelman’s syndrome. Management is with potassium and magnesium supplements. Other causes of tubular wasting of potassium include Bartter’s syndrome and mineralocorticoid excess. There are several rare conditions in which hypokalaemia is associated with episodes of extreme weakness/paralysis, including thyrotoxic periodic paralysis and familial hypokalaemic periodic paralysis. Hyperkalaemia, defined as a serum potassium concentration of greater than 5.0 mmol/litre, is asymptomatic, and severe hyperkalaemia (>7 mmol/litre) is the most serious of all electrolyte disorders because it can cause cardiac arrest. The electrocardiogram (ECG) is the best guide to the significance of hyperkalaemia in any particular individual. Patients with ECG manifestations more severe than tenting of the T waves should be given intravenous calcium gluconate (10 ml of 10%) followed by intravenous insulin and glucose, or nebulized salbutamol. There are many causes of hyperkalaemia, but by far the most common are renal failure and/or drugs. Other causes include exhaustive exercise, acidosis, drugs, and hyperkalaemic periodic paralysis (very rare).
Peritoneal dialysis
Authors: Davies Simon
Published: February 2020

Peritoneal dialysis is achieved by repeated cycles of instillation and drainage of dialysis fluid within the peritoneal cavity, with the two main functions of dialysis—solute and fluid removal—occurring due to the contact between dialysis fluid and the capillary circulation of the parietal and visceral peritoneum across the peritoneal membrane. It can be used to provide renal replacement therapy in acute kidney injury or chronic kidney disease. Practical aspects—choice of peritoneal dialysis as an effective modality for renal replacement in the short to medium term (i.e. several years) is, for most patients, a lifestyle issue. Typically, a patient on continuous ambulatory peritoneal dialysis will require three to four exchanges of 1.5 to 2.5 litres of dialysate per day. Automated peritoneal dialysis and use of the glucose polymer dialysis solution icodextrin enables flexibility of prescription that can mitigate the effects of membrane function (high solute transport). Peritonitis—this remains the most common complication of peritoneal dialysis, presenting with cloudy dialysis effluent, with or without abdominal pain and/or fever, and confirmed by a leucocyte count greater than 100 cells/µl in the peritoneal fluid. Empirical antibiotic treatment, either intraperitoneal or systemic, with cover for both Gram-positive and Gram-negative organisms, should be commenced immediately while awaiting specific cultures and sensitivities. Long-term changes in peritoneal membrane function influence survival on peritoneal dialysis if fluid removal is less efficient (ultrafiltration failure), especially in the absence of residual kidney function. This is the main limitation of treatment, along with avoiding the risk of encapsulating peritoneal sclerosis—a life-threatening complication of peritoneal dialysis, particularly if of long duration (15–20% incidence after 10 years), that is characterized by severe inflammatory thickening, especially of the mesenteric peritoneum, resulting in an encapsulation and progressive obstruction of the bowel.
Proliferative glomerulonephritis
Authors: Salama Alan D. , Little Mark A.
Published: February 2020

Proliferative glomerulonephritis describes the finding of increased cellularity of the glomerulus, which may be due to proliferation of intrinsic glomerular cells, infiltration of leucocytes, or both. This principally occurs in the context of glomerular deposition of immunoglobulins, immune complexes, or complement components. Different subtypes are described based on histological features: proliferation of mesangial cells, endocapillary proliferation, diffuse proliferation, or extracapillary proliferation (also termed crescentic glomerulonephritis). Patients will typically have haematuria, and this may be associated with proteinuria and/or impairment of excretory renal function and/or hypertension. The best characterized proliferative glomerulonephritis is poststreptococcal glomerulonephritis. This most commonly affects children, who present with nephritis about 2 weeks after pharyngitis or skin infection caused by streptococci of Lancefield group A. Treatment is directed at eradicating the infection with an appropriate antimicrobial and providing symptomatic relief. Recovery is the rule, although haematuria and proteinuria may persist.
The kidney in rheumatological disorders
Authors: Lightstone Liz , Beckwith Hannah
Published: February 2020

Many rheumatological conditions have systemic effects. Antibody production, complement activation, and protein deposition can all result in damage to the kidney, sometimes with devastating sequelae. Systemic lupus erythematosus—lupus nephritis is clinically evident in up to 75% of patients with systemic lupus erythematosus (SLE), and endstage renal disease is seen in 5 to 10% of patients at 10 years. Proteinuria is the most common clinical presentation, closely followed by nonvisible haematuria and tubular abnormalities. Patients with active lupus nephritis often have features of active SLE. The gold standard for lupus nephritis diagnosis is a renal biopsy, with treatment related to histopathological features observed. Adjunctive immunosuppressive agents such as rituximab and tacrolimus are emerging as increasingly important lupus nephritis therapies. Systemic sclerosis is a multiorgan connective tissue disease. Most renal manifestations are clinically silent. By contrast, the scleroderma renal crisis is characterized by accelerated-phase hypertension and impaired renal function. It carries a high mortality risk. Rheumatoid arthritis can affect the kidneys in many ways, most commonly by causing amyloid A amyloidosis. This presents with proteinuria, often severe enough to cause nephrotic syndrome, with 50% progressing to endstage renal failure after 5 years (90% at 10 years). Renal vasculitis, mesangiocapillary glomerulonephritis, and mesangial IgA proliferative glomerulonephritis are also described. Gold and penicillamine (now rarely used) can cause proteinuria, sometimes with nephrotic syndrome. Renal involvement in Sjögren’s syndrome is generally mild, but up to a quarter of patients develop acute or chronic kidney disease, typically with evidence of tubular dysfunction. Glomerular abnormalities are rare and the most common histological abnormality is tubulointerstitial nephritis. Drug nephrotoxicity—conventional antirheumatics and over-the-counter nonsteroidal anti-inflammatory drugs are used exceptionally widely in the community and are nephrotoxic. Their almost ubiquitous use, especially during intercurrent illnesses, means they are frequent contributors to acute and chronic kidney damage.
The kidney in sarcoidosis
Authors: Hilderson Ingeborg , Donck Jan
Published: February 2020

Sarcoidosis is associated with a broad spectrum of renal manifestations, but clinically important disease occurs in few patients. The most common cause of renal dysfunction is abnormal calcium metabolism: untreated chronic hypercalcaemia and hypercalciuria causes progressive tubulointerstitial inflammation with associated calcium deposits, leading to nephrocalcinosis, which is the leading cause of chronic kidney disease. Interstitial granulomatous nephritis is the most typical histological finding, but development of renal insufficiency is unusual. A range of glomerulopathies can be associated with sarcoidosis. When treatment is required, steroids are the first line, with various steroid-sparing agents used in cases that are refractory.
Disorders of renal calcium handling, urinary stones, and nephrocalcinosis
Authors: Pugh Christopher , Worcester Elaine M. , Evan Andrew P. , Coe Fredric L.
Published: February 2020

Renal stones are common, with a prevalence of 5 to 10% worldwide. Acute stone passage almost always produces the severe pain of renal colic, but stones are often asymptomatic and discovered incidentally on imaging. Prevalence of both symptomatic and asymptomatic disease appears to be rising, although the relative contributions of increasing use of more sensitive imaging modalities and real changes relating to diet and lifestyle are debated. The initial evaluation of patients with renal colic optimally includes noncontrast CT to accurately visualize the size and location of stones in the urinary tract. Initial management of stones less than 5 mm in diameter in patients without anatomical abnormalities of the urinary tract is to provide adequate analgesia coupled with α-blockade, followed by watchful waiting to allow time for stone passage. The presence of urinary tract infection, inability to take oral fluids, or obstruction of a single functioning kidney requires hospitalization and active management. Once the acute episode of stone passage or removal is over, thought should be given to diagnosis of the underlying causes and steps taken towards prevention. Since stone analysis is the cornerstone of diagnosis, the patient should be encouraged to collect any stones passed and retain them for analysis. Most stones (66–76%) are formed of calcium oxalate: other types include calcium phosphate (12–17%), uric acid (7–11%), struvite (magnesium ammonium phosphate, 2–3%), and cystine (1–2%). They form because urine becomes supersaturated with respect to the solute, and treatment to lower its concentration can prevent recurrence. This chapter describes the aetiology, pathogenesis, diagnosis and treatment of calcium oxalate stones, calcium phosphate stones, uric acid stones, struvite stones, cystine stones, and nephrocalcinosis.
Disorders of tubular electrolyte handling
Authors: Knoers Nine V.A.M. , Levtchenko Elena N.
Published: February 2020

Glycosuria—glucose reabsorption in the proximal tubule is carried out by two different pairs of apical Na+-dependent (SGLT1 and -2) and basolateral Na+-independent (GLUT1 and -2) glucose transporters. Abnormalities in renal glucose transport can be seen in association with other defects of proximal tubular transport. Familial renal glycosuria is a rare autosomal recessive condition caused by mutations in the SGLT2-encoding gene, SLC5A2. Phosphate-handling disorders—the plasma concentration of inorganic phosphate depends on the balance between intestinal absorption, renal excretion, and the internal contribution from bone. Changes of serum phosphate levels can be caused by numerous inherited and acquired conditions. Disorders associated with increased urinary phosphate excretion and low serum phosphate levels produce symptoms that mainly affect the bones: rickets in children and osteomalacia in adults. Magnesium-handling disorders—normal plasma magnesium concentration is achieved by variation of urinary magnesium excretion in response to altered uptake by the intestine. The main site of magnesium absorption is the small bowel, via paracellular simple diffusion at high intraluminal concentrations, and via active transcellular uptake through the magnesium channel TRPM6 at low concentrations. Regulation and fine-tuning of serum magnesium concentration occurs primarily in the kidney. Genetic disorders of magnesium handling include Gitelman’s syndrome. Aminoaciduria and renal Fanconi’s syndrome—most amino acids (except for tryptophan, which is protein bound) are freely filtered by the glomerulus, after which 95 to 99.9% are reabsorbed in the proximal tubules by apical Na+-dependent cotransporters and Na+-independent cotransporters. Aminoaciduria is defined as urinary excretion of more than 5% of the filtered load of an amino acid. Renal Fanconi’s syndrome is characterized by a generalized defect of both Na+-coupled and receptor-mediated proximal tubular transport.
Diagnostic techniques in the assessment of haematological malignancies
Authors: Erber Wendy N.
Published: February 2020

The diagnosis of haematological malignancies requires an understanding of the diseases and the uses and limitations of the range of available investigations. The relative importance of different investigations varies by disease entity. The blood count is one of the most widely used tests in all of medicine and often the first indication of an underlying haematological malignancy. Some blood count features are ‘diagnostic’ and others may give an indication of a bone marrow defect. Morphological assessment of a stained blood film adds value to an abnormal blood count. It may identify abnormal morphology of red cells, leucocytes, or platelets which may be specific and diagnostic, or give clues suggesting a diagnosis. Bone marrow aspirate (liquid sample) gives cytological detail, and trephine biopsy provides information about marrow cellularity, architecture, cellular distribution, and extent of fibrosis. Immunophenotyping detects cellular antigens in clinical samples and is essential in the diagnosis and classification of haematological malignancies. It is also used for disease staging and monitoring, to detect surrogate markers of genetic aberrations, identify potential immunotherapeutic targets, and to aid prognostic prediction. Cytogenetics assesses the number and structure of whole chromosomes and chromosomal regions in neoplastic cells and is performed to diagnose and classify some haematological malignancies. Molecular genetic methods facilitate the detection of mutations, rearrangements, or translocations in genes. Applications in malignant haematology include confirming clonality, detecting disease-associated genotypes, determining prognosis, disease monitoring following therapy, predicting imminent clinical relapse, and identifying patients who are likely (or not) to respond to new targeted inhibitor therapies.
Primary myelofibrosis
Authors: Braunstein Evan M. , Spivak Jerry L.
Published: February 2020

Myelofibrosis is a reactive process common to many malignant and benign disorders. Primary myelofibrosis is a chronic myeloproliferative neoplasm arising in a pluripotent haematopoietic stem cell. It results in abnormalities in red cell, granulocyte, and platelet production in association with marrow fibrosis and extramedullary haematopoiesis. While the precise aetiology is unclear, primary myelofibrosis is known to be a clonal disorder caused by acquired genetic mutations in haematopoietic stem cells. Many patients are asymptomatic at the time of diagnosis, but common presenting manifestations include fatigue, weight loss, night sweats, fever, dyspnoea, and abdominal discomfort due to splenomegaly. The major complications are the consequences of bone marrow failure and extramedullary haematopoiesis. About 20% of patients develop acute myeloid leukaemia as a terminal event. Anaemia is the most consistent abnormality, with the blood film showing evidence of a leucoerythroblastic reaction due to extramedullary haematopoiesis. The presence of marrow fibrosis is essential for diagnosis and usually results in the inability to aspirate marrow from a properly placed needle (‘dry tap’). Treatment is aimed at improving symptoms. Splenomegaly is generally the most distressing complication, and the nonselective JAK2 inhibitor, ruxolitinib, is effective in reducing spleen size and alleviating constitutional symptoms in a majority of patients. Patients with good performance status as well as those with advanced stage disease who have a matched, related donor should be considered for allogeneic bone marrow transplantation. Other therapies found to be effective include low-dose interferon, low-dose thalidomide and prednisone, low-dose busulfan, hydroxycarbamide, splenectomy, and splenic irradiation. Folic acid supplementation is often given to prevent deficiency in the context of increased folate requirements, and hyperuricaemia should be treated with allopurinol.
Chronic lymphocytic leukaemia
Authors: Zent Clive S. , Polliack Aaron
Published: February 2020

Chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma is the most prevalent lymphoid neoplasm in Europe and North America. The ‘cell of origin’ is a mature B lymphocyte with a rearranged immunoglobulin gene. CLL cells express modest amounts of surface immunoglobulin, and are characterized by defective apoptosis. The cause of CLL is unknown. Most patients show no specific clinical features of disease and are diagnosed during evaluation of an incidental finding of peripheral blood lymphocytosis, lymphadenopathy, or splenomegaly. A small percentage of patients (<10%) present with symptomatic disease resulting from (1) tissue accumulation of lymphocytes such as disfiguring lymphadenopathy, splenomegaly with abdominal discomfort, profound fatigue, drenching night sweats, weight loss, and fever; or (2) manifestations of marrow failure with cytopenias including anaemia and thrombocytopenia. All CLL patients have an increased risk of infection, autoimmune cytopenias, and second haematological (e.g. diffuse large B-cell lymphoma) and nonhaematological malignancies. Diagnosis is usually made by analysis of the immunophenotype of the monoclonal circulating cells in the peripheral blood. In patients with the small lymphocytic variant of CLL without a detectable circulating monoclonal B-cell population, the diagnosis is made using tissue from the bone marrow, lymph nodes, or spleen. Treatment—there is no standard curative therapy and patients should not be treated until they have progressive and symptomatic disease or develop anaemia or thrombocytopenia due to bone marrow failure. If a decision is made to treat, then the best initial treatment should be given, based on evaluation of the patient’s disease characteristics with specific attention to the integrity of TP53 (coding for p53) and patient fitness.
Plasma cell myeloma and related monoclonal gammopathies
Authors: Rajkumar S. Vincent , Kyle Robert A.
Published: February 2020

The monoclonal gammopathies, also referred to as paraproteinaemias, are a group of neoplastic (or potentially neoplastic) diseases associated with the proliferation of a single clone of immunoglobulin-secreting plasma cells. Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic clonal plasma cell disorder characterized by a serum monoclonal (M)-protein level less than 30 g/litre, less than 10% of monoclonal bone marrow plasma cells, and no evidence of hypercalcaemia, renal insufficiency, anaemia, or bone lesions related to the plasma cell proliferative process, and no evidence of any other myeloma-defining events. Observation is the standard of care. Plasma cell myeloma is a clonal plasma cell malignancy that accounts for about 10% of haematological cancers. The cause is unknown. Fluorescence in situ hybridization of bone marrow plasma cells reveals specific primary translocations or trisomies in more than 90% of patients. The presence of del 17p, t(4;14), t(14;16), and t(14;20) occur in 20 to 25% of patients, and indicate higher-risk disease. Waldenström’s macroglobulinaemia (WM) is characterized by the presence of an IgM M-protein, 10% or more lymphoplasmacytic infiltration of the bone marrow, and symptoms such as anaemia, lymphadenopathy, and hyperviscosity. Rituximab, a monoclonal antibody directed against CD20, is used as initial therapy in conjunction with other active drugs. Ibrutinib is a new agent that is highly active against WM. The median survival is longer than 5 years. Immunoglobulin light-chain amyloidosis is a clonal plasma cell disorder characterized by tissue deposition of fibrils consisting of monoclonal κ or λ light chains. Standard treatment is with bortezomib, cyclophosphamide, dexamethasone, and autologous stem cell transplantation in selected patients.
Erythropoiesis
Authors: Sankaran Vijay G.
Published: February 2020

Erythropoiesis is a highly regulated, multistep process in which stem cells, after a series of amplification divisions, generate multipotential progenitor cells, then oligo- and finally unilineage erythroid progenitors, and then morphologically recognizable erythroid precursors and mature red cells. The ontogeny of erythropoiesis involves a series of well-coordinated events during embryonic and early fetal life. In the fetus, the main site of erythropoiesis is the liver, which initially produces mainly fetal haemoglobin (HbF, α2γ2) and a small component (10–15%) of adult haemoglobin (HbA, α2β2), with the fraction of HbA rising to about 50% at birth. After birth, the site of erythroid cell production maintained throughout life is the bone marrow, with the final adult erythroid pattern (adult Hb with <1% fetal Hb) being reached a few months after birth. Regulation of erythropoiesis—the main regulator is erythropoietin, a sialoglycoprotein that is produced by interstitial cells in the kidney in response to tissue hypoxia and exerts its effect by binding to a specific receptor on erythroid burst-forming units, erythroid colony-forming units, and proerythroblasts. Abnormal erythropoietin production—anaemia can be caused by acquired or congenital deficiency in erythropoietin production, most commonly in chronic kidney disease. Impaired tissue oxygen delivery is a common cause of erythropoietin-driven secondary erythrocytosis. Some kidney cancers increase erythropoietin production and hence cause secondary erythrocytosis. Other causes of abnormal erythroid production include (1) acquired and congenital defects in erythropoietin signalling; (2) acquired and congenital defects in the transcription factors GATA1 or EKLF; (3) acquired or congenital abnormalities in ribosome synthesis or splicing factors; and (4) factors that lead to premature red cell destruction.
Megaloblastic anaemia and miscellaneous deficiency anaemias
Authors: Hoffbrand A.V.
Published: February 2020

Megaloblastic anaemias are characterized by red blood cell macrocytosis. They arise because of inhibition of DNA synthesis in the bone marrow, usually due to deficiency of one or other of vitamin B12 (cobalamin) or folate, but sometimes as a consequence of a drug or a congenital or acquired biochemical defect that disturbs vitamin B12 or folate metabolism, or affects DNA synthesis independent of vitamin B12 or folate. Acquired pernicious anaemia—antibodies in serum and gastric juice directed against parietal cells (85–90% of cases) and intrinsic factor (50%), and raised serum gastrin are associated with autoimmune gastritis and failure of absorption of vitamin B12. Treatment and prevention of megaloblastic anaemia—vitamin B12 deficiency—may be treated with intramuscular hydroxocobalamin (1-mg doses, six given in the first 2–3 weeks, then every 3 months). Oral therapy is practised by a minority and is unlikely to be useful in pernicious anaemia. Neurological complications are irreversible unless treated early. Folate deficiency—high-dose oral folic acid (5 mg daily) overcomes folate malabsorption, but this should not be given alone where vitamin B12 deficiency coexists because neurological disease may be precipitated or exacerbated (although the haematological abnormalities improve). Where folate metabolism is disturbed by methotrexate, oral or parenteral folinic acid is given to restore DNA synthesis. Prevention—dietary folate fortification is an accepted and highly effective public health measure in many countries (none in Europe) for reducing the incidence of neural tube birth defects.
Anaemias resulting from defective maturation of red cells
Authors: Fuller Stephen J. , Wiley James S.
Published: February 2020

Defective maturation of red cells leads to premature destruction of nucleated red cell precursors before they leave the haematopoietic bone marrow, which results in expansion of the marrow, haemolytic jaundice, peripheral signs of increased erythroid turnover on blood films, and (in long-standing disorders) iron overload due to enhanced absorption. Causes of ineffective erythropoiesis include (1) inhibition of erythroid DNA synthesis (e.g. megaloblastic anaemias (vitamin B12 or folate deficiency), drugs blocking DNA synthesis); (2) clonal disorders of erythropoiesis (e.g. refractory anaemia, acquired idiopathic sideroblastic anaemia, acute erythroleukaemia); (3) genetic disorders of erythropoiesis (e.g. thalassaemia syndromes, hereditary sideroblastic anaemia, congenital dyserythropoietic anaemia); and (4) other causes (e.g. alcohol). Sideroblastic anaemias—these result from defects in haem biosynthesis, with most cases being acquired as a clonal disorder of erythropoiesis, with varying degrees of myelodysplasia. Other causes are (1) hereditary (e.g. inherited deficiency of the erythroid-specific 5-aminolaevulinic acid synthase 2 gene on the X-chromosome causes congenital sideroblastic anaemia); (2) acquired (e.g. due to drugs or toxins such as ethanol, isoniazid, or lead; following chemotherapy or irradiation; or of unknown cause (idiopathic)). Diagnosis, treatment, and prognosis—diagnosis is achieved by finding ring sideroblasts (erythroblasts containing five or more iron-positive granules arranged in a perinuclear location around one-third or more of the nucleus) on bone marrow aspirate stained with Prussian blue iron reagent. Aside from supportive care with blood transfusion and iron chelation, a trial of pyridoxine is generally indicated (25% of hereditary cases—but few acquired cases—show some response). Acquired idiopathic sideroblastic anaemia has a median survival of 42 to 76 months, with 3 to 12% progressing to acute leukaemia.
Disorders of the red cell membrane
Authors: Gallagher Patrick G.
Published: February 2020

The integrity of the red cell membrane depends on molecular interactions between proteins and the phospholipid membrane: vertical interactions stabilize the membrane lipid bilayer; horizontal interactions provide resistance against shear stress. Hereditary spherocytosis—affects 1 in 25 000 individuals of northern European descent. There is typically a dominant family history, but the condition is genetically heterogeneous: combined spectrin and ankyrin deficiency is the most common defect observed, followed by band 3 deficiency, isolated spectrin deficiency, and protein 4.2 deficiency. These affect vertical membrane interactions with loss of surface area relative to red cell volume. Clinical features—the key clinical manifestations are anaemia and signs of persistent haemolysis, with jaundice and a marked propensity to gallstones. Complications and treatment—parvovirus B19 infection of erythropoietic precursors may cause acute aplastic crises. Megaloblastic anaemia due to folate deficiency occurs in response to increased requirements during growth and pregnancy, but is preventable with supplementation. Splenectomy can alleviate the anaemia in many patients and reduces the risk of gallstones. Hereditary elliptocytosis—occurs with a frequency of 1 in 2000 to 1 in 4000 worldwide, and is more frequent in parts of Africa. The inheritance is usually dominant, with defects in red cell proteins such as α- and β-spectrin causing disturbances in horizontal interactions in the erythrocyte membrane. Clinical features, diagnosis, and treatment—most patients are asymptomatic and are typically diagnosed incidentally during testing for unrelated conditions, but about 10% experience haemolysis, anaemia, splenomegaly, and intermittent jaundice. Diagnosis is based on the presence of elliptocytes on a peripheral blood smear. Treatment is rarely required. Other conditions include hereditary pyropoikilocytosis, South-East Asian (or Melanesian) ovalocytosis, stomatocytosis, and acanthocytosis.
Glucose-6-phosphate dehydrogenase deficiency
Authors: Luzzatto Lucio
Published: February 2020

Deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD) in red blood cells is an inherited abnormality due to mutations of the G6PD gene on the X chromosome that renders the cells vulnerable to oxidative damage. The condition is widespread in many populations living in or originating from tropical and subtropical areas of the world because it confers a selective advantage against Plasmodium falciparum malaria. Clinical features—G6PD deficiency is mostly an asymptomatic trait, but it predisposes to acute haemolytic anaemia in response to exogenous triggers, including (1) ingestion of fava beans—favism; (2) certain bacterial and viral infections; and (3) some drugs—notably some antimalarials (e.g. primaquine), some antibiotics (e.g. sulphanilamide, dapsone, nitrofurantoin), and even aspirin in high doses. Other manifestations include (1) severe neonatal jaundice; and (2) chronic nonspherocytic haemolytic anaemia—the latter is only seen with rare specific genetic variants. The acute haemolytic attack typically starts with malaise, weakness, and abdominal or lumbar pain, followed by the development of jaundice and passage of dark urine (haemoglobinuria). Most episodes resolve spontaneously. Diagnosis relies on the direct demonstration of decreased activity of G6PD in red cells: a variety of screening tests are available, with (ideally) subsequent confirmation by quantitative assay. Prevention is by avoiding exposure to triggering factors of previously screened subjects. Prompt blood transfusion is indicated in severe acute haemolytic anaemia and may be life-saving.
Genetic disorders of coagulation
Authors: Pollak Eleanor S. , High Katherine A.
Published: February 2020

Haemophilia is a familial X-linked disorder due to deficiency of either factor VIII (haemophilia A) or factor IX (haemophilia B), components of the intrinsic enzymatic complex that activates factor X. Clinical features and diagnosis—the main manifestations are bleeding into joints and soft tissues, with haemophilic arthropathy and joint deformity being inevitable complications in untreated patients. Other features include pseudotumours, bleeding into the urinary system, and bleeding following clinical procedures. Laboratory diagnosis is based on a modification of the classic activated partial thromboplastin time (APTT) assay, with inhibitor screening used to exclude other causes of prolonged APTT. Treatment—involves the administration of the deficient factor VIII or factor IX, most commonly ‘on demand’ in response to bleeding, with prophylactic treatment given before surgery. Von Willebrand’s disease is a common autosomal dominant disorder of platelet function caused by a functional deficiency of von Willebrand factor (VWF). VWF, normally synthesized by megakaryocytes, prevents degradation of factor VIII; VWF, also made by endothelial cells, enhances platelet activation and recruitment at sites of tissue damage. Treatment—mild von Willebrand’s disease is treated with desmopressin 1-deamino-8-d-arginine vasopressin (DDAVP), which releases factor VIII and VWF from endothelial cells. Other treatments include ε-aminocaproic acid, oestrogens, and factor VIII concentrates. Other hereditary disorders of coagulation, including (1) hereditary deficiency of the plasma metalloproteinase ADAMTS13; (2) combined deficiency of coagulation factors V and VIII; (3) factor XI deficiency; (4) inherited deficiencies of factors II, V, VII, and X; and (5) deficiency of the contact activating factors, factor XIII, and fibrinogen, and hypercoagulable diseases due to deficiencies of anticoagulants or propensity to thrombosis are discussed in this chapter.
Autoimmune bullous diseases
Authors: Taghipour Kathy , Wojnarowska Fenella
Published: February 2020

Autoimmune bullous diseases of the skin are a heterogenous group of blistering diseases that affect the skin and/or mucosal membranes. They are associated with significant morbidity and mortality and may present to several different specialists. They are broadly divided into two groups depending on the location of the blisters formed in the skin, which may be subepidermal (pemphigoids, linear IgA disease, dermatitis herpetiformis, epidermolysis bullosa acquisita) or intraepidermal (pemphigus group). Pathogenic autoantibodies (IgG, IgA) target either the proteins that provide keratinocyte adhesion (intraepidermal disease) or the proteins of hemidesmosomes that attach the basal cell layer to the basement membrane zone (subepidermal disease).
Photosensitivity
Authors: Fassihi Hiva , McGregor Jane
Published: February 2020

Normal human skin is photosensitive in that it reddens following acute sunlight exposure and tans and thickens following chronic sunlight exposure. Skin cancer, particularly non-melanoma skin cancer, is also a consequence of high cumulative sun exposure in genetically predisposed normal individuals (predominantly those with fair skin).

Outside the range of normal photosensitivity, there are several conditions in which patients exhibit diverse abnormal cutaneous reactions to sunlight. These are broadly described together as the photosensitivity disorders, but in fact they comprise a very heterogeneous group of skin conditions. Abnormal cutaneous photosensitive responses range from easy sunburn (as in drug phototoxicity and the DNA repair photodermatoses) and pain (erythropoietic protoporphyria), through to complex inflammatory responses such as urticaria, eczema, or epidermal necrosis induced by specific wavelengths of sunlight, the so-called idiopathic photodermatoses.
Management of skin disease
Authors: Sinclair Rod
Published: February 2020

Topical therapy of skin disease employs a vehicle (ointments, creams, lotions, gels) to deliver an active ingredient to the skin, to provide a protective barrier, or to hydrate and moisturize the skin. There are many types of topical treatments, including antipruritics, are used to relieve itching; keratolytics are used to remove hyperkeratotic skin; tars act by reducing the thickness of the epidermis; corticosteroids have anti-inflammatory and immunosuppressive effects that are useful in treating many skin disorders; calcipotriol reduces epidermal proliferation and is used in local treatment of plaque psoriasis; calcineurin inhibitors for eczema and other diseases; retinoids influence immune function and have some anti-inflammatory activity and are used in acne; immunomodulatory drugs such as imiquimod for some human papillomavirus infections, superficial basal cell carcinomas, and other diseases.