bluuebunny/crossref_metadata_2025 huggingface dataset:
Disorders of purine and pyrimidine metabolism
Authors: Marinaki Anthony M. , Fairbanks Lynette D. , Watts Richard W.E.
Published: February 2020

Disorders of purine and pyrimidine metabolism are due to abnormalities in the biosynthesis, interconversion, and degradation of the purines—adenine and guanine—and of the pyrimidines—cytosine, thymine, and uracil. The purine nucleotides, their cyclic derivatives (cAMP and cGMP), and their more highly phosphorylated derivatives have functions in many aspects of intermediary metabolism. Purine compounds also function as signal transducers, neurotransmitters, vasodilators, and mediators of platelet aggregation. Disorders of purine metabolism—the end point of purine metabolism in humans is uric acid. When uric acid levels become supersaturated in body fluids, uric acid and sodium urate monohydrate crystallize, causing gout. This results from either overproduction or underexcretion of urate, or from a combination of these defects. Decreased net tubular urate secretion is most often due to genetic polymorphism in uric acid transporters and is the commonest cause of primary (‘idiopathic’) gout. Gout may be secondary to a wide variety of renal disorders. Gout is also a consequence of enzymatic defects that accelerate de novo purine synthesis. Acute attacks of gout are treated with nonsteroidal anti-inflammatory drugs, colchicine, or steroids. Hypouricaemia may be caused by inherited disorders of uric acid biosynthesis or may be due to inherited or acquired renal tubule transport defects. Disorders of pyrimidine metabolism—the de novo synthesis of pyrimidine nucleotides involves a series of six reactions beginning with the formation of carbamyl phosphate and concluding with orotidine monophosphate, which then undergoes a series of interconversion and salvage reactions. The inherited disorders of pyrimidine metabolism, which can present in a wide variety of ways, are much less common and/or much less easily recognized than disorders of purine metabolism.
Hereditary disorders of oxalate metabolism: The primary hyperoxalurias
Authors: Fargue Sonia , Milliner Dawn S. , Danpure Christopher J.
Published: February 2020

Primary hyperoxalurias (PHs) are rare inherited disorders characterized by an increased endogenous synthesis of oxalate caused by a deficiency in one of several liver and kidney enzymes involved in glyoxylate metabolism. The excess oxalate is eliminated from the body by the kidneys. High concentrations of oxalate in the urine increase the risk of calcium oxalate deposition in the kidney (resulting in nephrocalcinosis) and in the urinary tract (leading to urinary stones). Primary hyperoxaluria is characterized by recurring calcium oxalate stones, presenting from early childhood to late adult life. Over time, deposition of calcium oxalate crystals in kidney tissue leads to kidney damage with progressive loss of kidney function. Primary hyperoxaluria type 1 is the most severe form with a median age at end-stage renal failure reached during young adulthood. Patients with PH type 2 and PH type 3 may show preservation of kidney function well into adulthood. Systemic deposition of calcium oxalate (oxalosis) can follow kidney failure and increased plasma oxalate levels. Diagnosis is made by DNA analysis of peripheral blood samples, or more rarely by enzyme assay of liver biopsy tissue. Treatment relies on high fluid intake, inhibitors of calcium oxalate crystallization, and, when required, urological procedures for stone removal. Some patients with PH1 respond to vitamin B6 treatment. Management of end-stage renal failure is difficult as dialysis, whether haemo- or peritoneal, cannot match oxalate production. Isolated kidney transplantation places patients at risk of recurring oxalate deposition in the graft in PH1 patients not responsive to vitamin B6. Liver transplantation, usually combined with kidney transplantation, is a curative treatment for PH1 but carries significant risks.
Principles of hormone action
Authors: Fowkes Rob , Chatterjee V. Krishna , Gurnell Mark
Published: February 2020

Hormones, produced by glands or cells, are messengers which act locally or at a distance to coordinate the function of cells and organs. Types of hormone include: peptides (e.g. hypothalamic releasing factors) and proteins (e.g. insulin, growth hormone)—these generally interact with membrane receptors located on the cell surface, causing activation of downstream signalling pathways leading to alteration in gene transcription or modulation of biochemical pathways to effect a physiological response; steroids (e.g. cortisol, progesterone, testosterone, oestradiol) and other lipophilic substances (e.g. vitamin D, retinoic acid, thyroid hormone)—these act by crossing the plasma membrane to interact with intracellular receptors, with hormone action via nuclear receptors altering cellular gene expression directly.
Disorders of the posterior pituitary gland
Authors: Karavitaki Niki , Ahmed Shahzada K. , Wass John A.H.
Published: February 2020

The posterior pituitary produces arginine vasopressin, which has a key role in fluid homeostasis, and oxytocin, which stimulates uterine contraction during birth and ejection of milk during lactation. Cranial diabetes insipidus is the passage of large volumes of dilute urine due to vasopressin deficient synthesis and/or release. The most common cause is lesions of the neurohypophysis or the hypothalamic median eminence damaging the magnocellular neurons. MRI of the neurohypophysis is required to delineate the cause. Mild polyuria can be managed simply by ensuring adequate fluid intake; treatment with the long-acting vasopressin analogue, desmopressin is used for more severe cases. The syndrome of inappropriate antidiuresis is diagnosed when there is hyponatraemia with hypotonic plasma, inappropriate urine osmolality, and urinary sodium more than 20 mmol/litre, together with no evidence of volume overload or hypovolaemia, and normal renal, adrenal, and thyroid function.
Disorders of male reproduction and male hypogonadism
Authors: Bouloux P.-M.G.
Published: February 2020

The adult testis performs two principle functions: the synthesis and secretion of androgens, and the production of male germ cells, the spermatozoa. Testosterone is essential for male sexual differentiation, growth, and function of the male genital tract, secondary sexual characteristics, sexual potency, and production of spermatozoa. Hypogonadism may be due to disorders of the pituitary/hypothalamus (secondary or hypogonadotropic hypogonadism) or testes (primary or hypergonadotropic hypogonadism). Its symptoms and signs depend on the age of onset of androgen deficiency. Prepubertal presentation is with sexual infantilism, delayed puberty, and eunuchoidal body proportions. Male infertility may affect 5% of men of reproductive age and is caused by a heterogeneous group of disorders. The commonest cause (60% of cases) is ‘idiopathic’ azoo/oligozoospermia, although many cases are now recognized as due to discrete gene defects associated with impaired spermatogenesis. Other causes include cryptorchidism, testicular tumours, genital tract infection, obstructive azoospermia, and sperm autoimmunity.
Sexual dysfunction
Authors: Eardley Ian
Published: February 2020

Male sexual dysfunction is common, with the most common types being erectile dysfunction, premature ejaculation, penile deformity, and priapism. Erectile dysfunction is common, becomes commoner with increasing age, and is often associated with cardiovascular disease and its risk factors. Patient assessment should seek to identify causative risk factors and treatment in the first instance is usually the management of risk factors and oral pharmacotherapy with a phosphodiesterase type 5 inhibitor. In women, sexual desire disorders are commoner in older postmenopausal women and a new treatment, flibanserin, has recently been licensed for this indication. Sexual arousal disorders in women also become more common postmenopausally and have a multifactorial aetiology. Treatment should be directed at the aetiological factor in the first instance while trials of oral pharmacotherapy for this condition have been disappointing.
Diabetes
Authors: Dayan Colin , Platts Julia
Published: February 2020

Diabetes mellitus can be defined as a state of chronic hyperglycaemia sufficient to cause long-term damage to specific tissues, notably the retina, kidney, nerves, and arteries. It is due to inadequate production of insulin and/or ‘resistance’ to the glucose lowering and other actions of insulin, and is a significant and growing threat to global health, affecting more than 400 million people worldwide. Diabetes is a significant and growing threat to global health. Worldwide, diabetes affects more than 400 million people. This number was more than 10-fold less in 1985 (30 million) and the world prevalence is predicted to reach 640 million by 2040, with 10% of all adults affected.
The pineal gland and melatonin
Authors: Arendt J. , Cox Timothy M.
Published: February 2020

The pineal gland transduces light–dark cycles for the timing of body rhythms by secretion of melatonin, an endogenous indoleamine derived from tryptophan, the concentrations of which in plasma and cerebrospinal fluid are up to 100 times higher at night than in the daytime. This exerts its effects through transmembrane, G-protein coupled receptors (MT1 and MT2), and nuclear receptors primarily in the suprachiasmatic nucleus, pars tuberalis of the pituitary gland and hypothalamus. The natural period of the human circadian system is on average 24.1 to 24.3 h, and the principal resetting agent is light. Exogenous melatonin can shift the timing of the internal clock to earlier and later times, and synchronize a free-running clock that is not properly entrained to the 24-h day, hence it may have a therapeutic role for disorders of sleep rhythm including jet lag, in shift workers, and in blind people.
Nutrition in pregnancy
Authors: Williams David J.
Published: February 2020

Nutritional requirements for healthy pregnancy vary according to a woman’s pre-pregnancy nutritional state and her access to food during pregnancy: there is no unifying nutritional advice that is appropriate for all pregnant women throughout the world, or even within nations. Around the world, obesity and excessive gestational weight gain are now more common risk factors for pregnancy complications than undernutrition. Compared with mothers who have a normal body mass index or BMI (18.5–24.9 kg/m2), obese mothers have an increased risk of gestational diabetes, pre-eclampsia, caesarean delivery, stillbirth, congenital malformations, and large for gestational age babies. Underweight mothers have an increased risk of small for gestational age babies, and preterm birth. Paternal obesity has a negative effect on fetal growth, probably mediated by inheritance of insulin resistance. Both low birth weight and high birth weight babies have an increased risk of obesity in later life.
Diabetes in pregnancy
Authors: Jones Bryony , Dornhorst Anne
Published: February 2020

Diabetes in pregnancy is predominantly either pre-existing type 1 or type 2 diabetes mellitus, or gestational diabetes, the latter defined as diabetes or glucose intolerance first diagnosed during the pregnancy. Gestational diabetes usually arises in the late second trimester and is common, affecting from 2–6% to 15–20% of pregnant women depending on diagnostic criteria and country of origin. Gestational diabetes is most commonly diagnosed on the basis of an oral glucose tolerance test performed at 24–28 weeks’ gestation by a plasma glucose at 0 minutes of more than 5.1 (or >5.6, depending on the authority) mmol/L, or at 120 minutes of more than 8.5 (or >7.8) mmol/L. The effect of pregnancy on maternal glycaemic control ceases very quickly post-partum, hence women with pre-existing diabetes taking insulin should immediately revert to their pre-pregnancy regimen after birth, but with a lower insulin dose.
Neurological conditions in pregnancy
Authors: Dassan Pooja
Published: February 2020

Pregnancy can influence the clinical course of an underlying neurological problem or precipitate the first presentation of a neurological disease. This chapter looks at the various ways pregnancy can affect those suffering from epilepsy, multiple sclerosis, or cerebrovascular disease. In epilepsy, sodium valproate is associated with higher risk of major congenital malformations and impaired neuropsychological development than other antiepileptic drugs: lamotrigine or levetiracetam are preferred. Women taking antiepileptic drugs can breastfeed. In multiple sclerosis, the relapse rate is reduced in pregnancy, but substantially increased for three months post-partum. For cerebrovascular disease, stroke syndromes specific to pregnancy include pre-eclampsia, which can lead to posterior reversible vasoconstriction syndrome. Reversible cerebral vasoconstriction syndrome presents after delivery and has many similarities to posterior reversible vasoconstriction syndrome. There are conflicting opinions as to whether pregnancy or delivery increases the risk of cerebral aneurysm or arteriovenous malformation rupture.
Maternal infection in pregnancy
Authors: Burton Rosie
Published: February 2020

This chapter will consider infection with human immunodeficiency virus (HIV), tuberculosis, and malaria in pregnancy. The global roll-out of antiretroviral therapy has significantly improved survival for people living with HIV and reduced mother-to-child transmission, but HIV infection remains a leading cause of maternal mortality, infant death, and early childhood death. Most women with HIV infection are in sub-Saharan Africa, where the highest prevalence is among young women of reproductive age. Meanwhile, tuberculosis is a major cause of maternal mortality. Active tuberculosis also adversely affects pregnancy outcomes, with an increased risk of preterm delivery, growth restriction, and perinatal death. Malaria is a major cause of maternal and neonatal morbidity and mortality. Pregnant women are more susceptible to malaria, have more severe disease, and may deteriorate rapidly. In severe malaria, mortality is 15–20% in non-pregnant women, compared to 50% in pregnancy. Primigravidae are at highest risk of severe malaria and death.
Blood disorders in pregnancy
Authors: Perry David J. , Lowndes Katharine
Published: February 2020

Plasma volume increases by more during pregnancy than does red cell mass, leading to haemodilution and a fall in the haematocrit from about 40% to 33%, with a nadir usually reached at 24–32 weeks’ gestation. Anaemia during pregnancy is defined as a haemoglobin concentration of below 105 g/L during the second and third trimesters and below 110 g/L in the first trimester. The commonest haematological problem encountered in pregnancy is iron-deficiency anaemia. Routine iron supplementation in all pregnant women is probably not justified in developed countries, but if iron deficiency is detected it is advisable to treat as early as possible. Normal pregnancy is associated with marked changes in all aspects of haemostasis, the overall effect of which is to generate a state of hypercoagulability. These changes in haemostasis, while reducing the risks of excessive blood loss at delivery, significantly increase the risk of venous thromboembolic disease in pregnancy.
Upper gastrointestinal endoscopy
Authors: East James E. , Webster George J.
Published: February 2020

Endoscopy is the procedure of choice in patients with retrosternal or upper abdominal symptoms who require investigation, and is essential in significant gastrointestinal bleeding to identify and—in most cases—treat the cause, with various therapeutic methods possible for erosions, ulcers, and oesophageal varices. More recent developments in the practice of upper gastrointestinal endoscopy include the use of enteroscopy for direct vision of the small bowel, video capsule endoscopy for diagnosis of obscure bleeding lesions, and an expanding range of minimally invasive therapeutic techniques. Endoscopic retrograde cholangiopancreatography is the standard of care for the removal of gallstones from the common bile duct, and palliating obstructing pancreatobiliary tumours.
Immune disorders of the gastrointestinal tract
Authors: Bhattacharyya Joya , Kaser Arthur
Published: February 2020

Immune homeostasis in the gut is the result of a delicate balance between peaceful coexistence with commensal microbiota, immunomodulatory effects of dietary antigens, and appropriate responses to pathogens. Immune disorders of the gut arise when defects in the integrity of these components lead to a dysregulated immune response to the commensal environment. Primary immunodeficiency syndromes can present with intestinal inflammation but are commonly characterized by an increased susceptibility to infections in childhood. Secondary immunodeficiency can occur in a protein-losing enteropathy where loss of immunoglobulins and lymphocytes increase susceptibility to infections, or as a result of metabolic diseases (e.g. diabetes or liver cirrhosis), infections (e.g. HIV), or drugs (e.g. chemotherapy). Immunosuppressive medication can not only lead to secondary immunodeficiency but in the context of neutropenia, cytotoxic gastrointestinal mucosal injury can lead to neutropenic typhlitis. Graft-versus-host disease arises from host antigen-presenting cells engaging with donor T cells and triggering an inflammatory cascade. Immunotherapy with checkpoint inhibitors can have significant gastrointestinal immune-related adverse effects, most notably enterocolitis. Autoimmune diseases can impact gastrointestinal function. Autoimmune dysautonomia can result in gastrointestinal-specific dysmotility and systemic IgG4-related disease can lead to autoimmune pancreatitis. Systemic autoimmune diseases can have gastrointestinal manifestations related to the primary autoimmune process or as an adverse effect of treatment. Hypersensitivity reactions to dietary antigens (e.g. peanuts) result in food allergies and can be either IgE or non-IgE mediated. Food intolerance which is not immunologically mediated is the result of pharmacological (e.g. monosodium glutamate), enzyme-related (e.g. lactose intolerance), or noncoeliac gluten sensitivity. Eosinophilic gastrointestinal tract disorders are often associated with a food allergen: treatment is with steroids and avoidance of the allergen.
Hormones and the gastrointestinal tract
Authors: Scott Rebecca , Tan T.M. , Bloom S.R.
Published: February 2020

The gastrointestinal tract is the largest endocrine organ in the body, with its component cells dispersed along its length rather than being clustered in glands. More than 20 gut peptides integrate gastrointestinal function by regulating the actions of the epithelium, muscles, and nerves; they also affect the growth and development of the gut and have a major role in appetite control. They mostly work in an autocrine or paracrine manner.

Gastrointestinal hormones include the gastrin–cholecystokinin family, the secretin superfamily, preproglucagon derivatives, the motilin–ghrelin family, the pancreatic polypeptide-fold family, and various other gut peptides. Gastrointestinal and other diseases may cause abnormalities of these gut peptides, for example: (1) achlorhydria (from atrophic gastritis or drug-induced) causes elevation of circulating gastrin; (2) malabsorptive conditions are associated with a decrease in the amount of peptides produced in the affected region, and a compensatory elevation of other peptides; and (3) obesity is associated with orexigenic (appetite-stimulating) and less satiating hormonal changes, and the beneficial effects of bariatric surgery are partly explained through alterations in gut hormones.
Bacterial overgrowth of the small intestine
Authors: Middleton Stephen J. , Playford Raymond J.
Published: February 2020

Small intestinal bacterial overgrowth can be defined as the presence of excessive bacteria in the small intestine which can interfere with digestion and absorption. Predisposing causes include sustained hypochlorhydria induced by proton pump inhibitors, small intestinal dysmotility and stasis due to anatomical or motor abnormalities, and reduced antibacterial activity as seen in immunological deficiency and chronic pancreatitis. Presentation is predominantly from consequences of malabsorption, including gastrointestinal symptoms (e.g. diarrhoea or steatorrhoea) and features of specific nutrient malabsorption (e.g. osteoporosis, anaemia, neuropathy, and night blindness). Definitive diagnosis is difficult, requiring a properly collected and appropriately cultured aspirate from the proximal small intestine revealing a total concentration of a mixed growth of bacteria generally greater than 105 organisms/ml. Alternative investigations frequently used include glucose/lactulose breath tests or either the 13C- or 14C-xylose breath test, with elevated levels of 13CO2 or 14CO2 found in the breath. There may be low levels of cobalamin (metabolized by Gram-negative anaerobes), increased serum folate (synthesized by overgrowth flora), and increased urinary indicans (intraluminal product of bacterial tryptophan metabolism). Aside from treatment of any nutritional deficiencies, specific treatment is with an antimicrobial that is effective against both aerobic and anaerobic enteric bacteria (e.g. doxycycline, amoxicillin–clavulanic acid, rifaximin, or ciprofloxacin), which can be administered in rotation to reduce antibiotic resistance. Where possible and appropriate, correction of any underlying cause should also be performed.
Whipple’s disease
Authors: Fenollar Florence , Raoult Didier
Published: February 2020

Whipple’s disease is an uncommon infection caused by the actinomycete Tropheryma whipplei, most commonly diagnosed when overt small intestinal disease leads to malabsorption, but with protean other clinical manifestations (e.g. systemic, neurological, or cardiological). Diagnosis usually depends upon demonstration of classical histological features in the small intestine, and positive identification of T. whipplei DNA by polymerase chain reaction. Treatment is with antibiotics, initially doxycycline and hydroxychloroquine followed by long-term therapy with doxycycline. Clinical improvement occurs within a few weeks, but prolonged treatment for at least a year is recommended. Relapse can occur, even after many years, especially when progressive central nervous system disease occurs in the absence of other systemic manifestations.
Miscellaneous disorders of the bowel
Authors: Gimson Alexander
Published: February 2020

A wide range of miscellaneous disorders can affect the bowel. Those discussed in this chapter include cystic disorders (colitis cystica profunda and pneumatosis cystoides intestinalis), protein-losing enteropathy, vascular disorders of the intestine (spontaneous intramural haemorrhage and ortoenteric fistulas), intestinal pseudo-obstruction (acute colonic pseudo-obstruction, chronic intestinal pseudo-obstruction), various disorders of the colon and rectum (including microscopic, collagenous, and lymphocytic colitis, malakoplakia, solitary rectal ulcer syndrome, and stercoral ulcers), complications of parenteral nutrition and intestinal failure, peritoneal disorders, and endometriosis.
Cirrhosis and ascites
Authors: Fernández Javier , Arroyo Vicente
Published: February 2020

Ascites is the accumulation of fluid in the peritoneal cavity and the most common complication of cirrhosis, when it is associated with a poor prognosis. It occurs only when portal hypertension has developed and is mainly due to renal sodium retention secondary to splanchnic arterial vasodilation that leads to homeostatic activation of vasoconstrictor and sodium-retaining systems. Clinical presentation is with abdominal distension. The initial evaluation of a patient with ascites must include (1) history and physical examination; (2) liver and renal function tests including serum and urine electrolytes; (3) analysis of ascitic fluid (diagnostic paracentesis) for cell count and culture, and protein/albumin concentration; other tests such as cytology (suspicion of malignancy), amylase (pancreatic disease), and polymerase chain reaction and culture for mycobacteria (tuberculosis) should be done only when the diagnosis is unclear; (4) abdominal ultrasonography for evidence of cirrhosis, portal hypertension, or malignancy. First-line manoeuvres include dietary salt restriction, and therapeutic or total paracentesis. Water restriction is only recommended if there is severe dilutional hyponatraemia. Refractory ascites is managed by repeated paracentesis or insertion of a transjugular intrahepatic portosystemic shunt. Cirrhotic patients with ascites should be considered for liver transplantation. All patients with cirrhosis and ascites are at risk of spontaneous bacterial peritonitis (SBP). Typical symptoms are abdominal pain and fever, but the condition may be asymptomatic. Treatment with appropriate antibiotics should be started as soon as a presumptive diagnosis is made following diagnostic paracentesis. Mortality is around 10% for the acute episode and 75% at 1 year; hence (unless contraindicated), all patients with SBP should be considered for liver transplantation. Patients with cirrhosis and ascites are also at high risk of other complications.
Liver transplantation
Authors: O’Grady John G.
Published: February 2020

Liver transplantation is an established treatment for liver conditions that broadly fall into the categories of acute liver failure, end-stage chronic liver disease, primary hepatic malignancy, and metabolic disease. The expected 1-year survival rate is over 90% and some patients are alive more than 40 years after transplantation. Disease severity scores for cirrhosis heavily influence selection of patients with cirrhosis for transplantation. The prototype is the MELD (Model for End-Stage Liver Disease) score, based on serum bilirubin, serum creatinine, and INR: a score of 16 is considered the threshold that confers benefit from liver transplantation. Hepatocellular carcinoma accounts for most of the malignancy group and selection is largely determined by tumour bulk assessed by the number and size of lesions. Immunosuppression strategies based on tacrolimus, with or without other drugs including mTOR (mechanistic target of rapamycin) inhibitors, antiproliferative agents, or prednisolone, are highly effective in preventing loss of the graft through classical rejection processes. Recurrence of original disease is the main cause of loss of graft function, with recurrence of hepatitis C a particularly challenging problem, although new direct-acting antiviral agents are likely to radically improve outcomes. Technical problems can also result in graft loss due to hepatic artery thrombosis or diffuse ischaemic cholangiopathy, especially in livers harvested from donors after cardiac death. Anastomotic biliary strictures are the commonest technical complication, with 15 to 20% of patients requiring some form of endoscopic or surgical intervention. There is a considerably increased risk of myeloproliferative disease and skin cancers in transplant recipients, as well as aetiology-specific risk. Many patients die having achieved a normal life expectancy, and death with a functioning graft is the commonest terminal scenario.
Primary biliary cholangitis
Authors: Dyson Jessica K. , Jones David E.J.
Published: February 2020

Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis, is a chronic, cholestatic liver disease in which the biliary epithelial cells lining the small intrahepatic bile ducts are the target for immune-mediated damage, leading to progressive ductopenia and cholestasis. The cause is unknown but presumed to be autoimmune. The disorder affects women (>90% of cases) and usually has an insidious onset in middle age. Younger patients are less common but have a more aggressive disease course. Fatigue and pruritus are the most common presenting symptoms. Findings on examination vary widely, ranging from no abnormality to jaundice with hyperpigmentation, scratch marks, and rarely the features of advanced liver disease. Diagnosis of PBC is based on three criteria: (1) cholestatic liver function tests, with increases in serum alkaline phosphatase and γ-glutamyl transferase, (2) presence of serum antimitochondrial antibodies (found in more than 95% of cases), and (3) compatible liver histology. Many asymptomatic patients are recognized following the incidental discovery of antimitochondrial antibodies or elevated levels of serum alkaline phosphatase. First-line treatment is with ursodeoxycholic acid which can lead to significant improvement in liver biochemical values. Second-line treatment is with obeticholic acid. No immunosuppressive drug regimen has been proven effective. Progression may be slow, but eventually patients can develop cirrhosis. Cholestyramine is used as first line to treat pruritus. There is no recognized treatment for fatigue. Liver transplantation is indicated in some cases.
Diseases of the gallbladder and biliary tree
Authors: Johnson Colin , Wright Mark
Published: February 2020

Diseases of the gallbladder and bile ducts are common, with gallstones and their complications being most frequent. Less common are biliary strictures, usually malignant, which are caused by adenocarcinomas of the pancreas, bile ducts, ampulla of Vater, and gallbladder. Rarely encountered are sclerosing cholangitis and a variety of congenital disorders. Disorders of the biliary system include gallstones, which cause biliary colic and cholecystitis by obstruction of the cystic duct, and bile duct obstruction (cholestasis), with jaundice, dark urine, and pale stools, itching, and sometimes constant right hypochondrial pain. Fevers and rigors may indicate bacterial infection of the biliary tract (cholangitis), which frequently accompanies partial obstruction. Weight loss may be due to fat malabsorption but can also be caused by malignancy. Prolonged biliary obstruction leads to skin changes of increased pigmentation (due to melanin) and cholesterol deposition (xanthelasma and xanthoma). Biliary cirrhosis can cause portal venous hypertension and liver cell failure. Disorders of the biliary system generally give rise to the biochemical picture of cholestasis: the serum (conjugated) bilirubin concentration may be normal or raised; serum alkaline phosphatase, γ-glutamyl transferase, and bile acids are elevated; serum transaminases show only modest elevation. Bilirubinuria is present, with the disappearance of urobilinogen from the urine indicating complete biliary obstruction. Imaging is critical in the diagnosis of biliary disease, initially by ultrasonography, with CT and MRI in more complicated cases. However, these investigations sometimes provide insufficient anatomical detail for diagnosis or planning of treatment, and further imaging with the cholangiographic techniques of magnetic resonance cholangiopancreatography, endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) are required. ERCP and PTC can be used to place biliary stents.
Acute pancreatitis
Authors: Carter R. , Dickson Euan J. , McKay C.J.
Published: February 2020

Acute pancreatitis affects 300 to 600 new patients per million population per year and is most commonly caused by gallstones or alcohol. Careful imaging reveals that most so-called idiopathic acute pancreatitis is due to small (1–3-mm diameter) gallstones. Diagnosis is made by a combination of a typical presentation (upper abdominal pain and vomiting) in conjunction with raised serum amylase (more than three times the upper limit of normal) and/or lipase (more than twice the upper limit of normal). Several other acute abdominal emergencies can mimic acute pancreatitis and may be associated with a raised serum amylase. In equivocal cases, a CT scan is indicated to exclude other causes and confirm the diagnosis. Initial management is with (1) analgesia, (2) ensuring adequate oxygenation, and (3) intravenous fluid administration. The revision of the Atlanta classification separates patients clinically into (1) mild—with early resolution without complications, (2) moderate—local complications without organ failure, and (3) severe—complications associated with organ failure. Mild acute pancreatitis responds to analgesia and intravenous fluids. If gallstones have been identified, then cholecystectomy (or endoscopic retrograde cholangiopancreatography (ERCP) sphincterotomy where clinically appropriate) should be performed during the same admission, or at least within 2 to 4 weeks to prevent recurrent attacks. Severe acute pancreatitis carries a high mortality (up to 20%). Management in the early stages is centred on organ support (respiratory, circulatory, and renal failure). Later management involves surgical or radiological intervention for sepsis, usually within a specialist pancreatic unit.
Chronic pancreatitis
Authors: Bruno Marco J. , Cahen Djuna L.
Published: February 2020

Chronic pancreatitis is a major source of morbidity, loss in quality of life, and healthcare expenditure. It is most commonly caused by chronic alcoholism in adults and cystic fibrosis in children, but there are many other causes. Patients typically present with severe abdominal pain, but this may vary and even be absent. Exo- and endocrine insufficiency usually occur late in the disease course and reflect permanent loss of pancreatic parenchyma due to ongoing inflammation and fibrosis, exocrine insufficiency manifesting as steatorrhea and weight loss due to fat maldigestion and endocrine insufficiency as diabetes mellitus. Diagnosis is confirmed by imaging investigations such as CT, MRI, and endoscopic ultrasonography. Endoscopic retrograde cholangiopancreatography to diagnose chronic pancreatitis is obsolete. Hormone stimulation tests (e.g. secretin–cholecystokinin stimulation test) to diagnose exocrine insufficiency are largely abandoned because of their complexity and burden to patients. They are replaced by faecal elastase testing, even though this test is less sensitive. Management focuses on the treatment of pain using a stepwise approach. Initially, nonopioid analgesics are prescribed. Next, when feasible, endoscopic therapy is initiated, including pancreatic stone fragmentation by extracorporeal shock-wave lithotripsy, endotherapy to remove stone fragments, and placement of plastic stents to dilate any concomitant pancreatic duct stricture. If that fails or when, for example, the pancreatic head is enlarged, surgical intervention is indicated. Medical management includes enteric-coated pancreatic enzyme preparations and treatment of diabetes mellitus, usually by means of insulin. Abstinence from alcohol and smoking cessation are important predictors of disease and treatment outcome.
Syncope and palpitation
Authors: Rajappan K. , Rankin A.C. , McGavigan A.D. , Cobbe S.M.
Published: February 2020

Syncope is a transient episode of loss of consciousness due to cerebral hypoperfusion. Its causes can be subdivided on the basis of pathophysiology, including neurally mediated—or reflex—syncope; orthostatic hypotension; cardiac causes; and cerebrovascular or psychogenic causes. Neurocardiogenic syncope, or simple faint, is the commonest cause and is benign, but it is always important to exclude or establish the diagnosis of cardiac syncope, because this has an adverse prognosis that may be improved with appropriate treatment. Meanwhile, palpitation is the awareness of one’s heart beating—it may be due to an awareness of an abnormal cardiac rhythm, or an abnormal awareness of normal rhythm. It is most commonly due to premature beats (ectopics) and is benign. Correlation between symptoms and cardiac rhythm is the initial aim of investigations in patients presenting with palpitations.
Myocarditis
Authors: Mason Jay W. , Schultheiss Heinz-Peter
Published: February 2020

Myocarditis can be acute, subacute, or chronic and may affect either focal or diffuse areas of the myocardium. It has many infectious and non-infectious aetiologies, but viral infections are the main cause in most regions, with notable exceptions such as Chagas myocarditis in South America. The condition often results in congestive heart failure and is a common cause of chronic dilated cardiomyopathy, also called inflammatory cardiomyopathy. It can present with (a)typical chest pain, palpitations, ventricular arrhythmias, syncope, or even fulminant heart failure. Patients with lymphocytic myocarditis are usually young (average age in the forties) and often report an antecedent viral illness. The disease can be diagnosed by demonstration of lymphocyte infiltration and adjacent myocyte damage on endomyocardial biopsy, and molecularly by the detection of viral genomic material and tissue markers of immune activation in biopsy specimens.
The cardiomyopathies: Hypertrophic, dilated, restrictive, and right ventricular
Authors: Guttmann Oliver P. , Elliott Perry
Published: February 2020

The term cardiomyopathy is used to describe heart muscle disease unexplained by abnormal loading conditions (hypertension, valve disease, and others), congenital cardiac abnormalities, and ischaemic heart disease. The current classification is based on the predominant phenotype, that is, hypertrophic, dilated, arrhythmogenic right ventricular, restrictive, and unclassifiable (including left ventricular non-compaction), and— where possible— incorporating inheritance and genotype. The diagnosis of hypertrophic cardiomyopathy is based on the demonstration of unexplained myocardial hypertrophy, defined as a wall thickness measurement exceeding two standard deviations above normal for gender and age. In practice, in an adult of normal size, the presence of a left ventricular myocardial segment of 1.5 cm or greater in thickness is diagnostic. Less stringent criteria should be applied to first-degree relatives of an unequivocally affected individual.
Specific heart muscle disorders
Authors: Guttmann Oliver P. , Elliott Perry
Published: February 2020

Systemic immune-mediated diseases are autoimmune and autoinflammatory diseases affecting at least two-organ systems. Autoinflammatory diseases are a family of conditions characterized by episodes of unprovoked inflammation in the absence of high autoantibody titres or autoreactive T lymphocytes, reflecting a primary dysfunction of the innate immune system. Autoimmune diseases are characterized by aberrant B, T, and dendritic cell responses with predominantly cell-mediated or autoantibody-mediated responses to self-antigens in genetically susceptible individuals. Cardiovascular involvement is systemic immune-mediated diseases may be occult and often goes undetected, but is associated with a poor prognosis. As any anatomical structure in the heart may be involved, patients can present with one or more features consistent with pericarditis, myocarditis, endocarditis, and vasculitis. There is often no correlation between the extent of systemic disease and cardiac involvement.
Congenital heart disease in the adult
Authors: Thorne S.A.
Published: February 2020

Adults with congenital heart disease are a growing population, and now outnumber children with congenital heart disease in the United Kingdom. Many patients with repaired hearts can now, with specialist care, expect to live a normal or near normal lifespan. Other survivors have complex, surgically altered hearts and circulations that reflect the surgical and interventional practices of the preceding two decades. Their long-term outlook is unknown and they remain at lifelong risk of complications that may require further intervention. The organization of services to provide specialist care is key to their long-term survival. As the population of adults with congenital heart disease ages, so the number developing heart failure increases. Services caring for patients need to develop a robust end-of-life pathway that focuses on symptoms and quality of life, and runs in parallel with other therapies.
Pulmonary hypertension
Authors: Morrell Nicholas W.
Published: February 2020

Symptoms of unexplained exertional breathlessness or symptoms out of proportion to coexistent heart or lung disease should alert the clinician to the possibility of pulmonary hypertension, and the condition should be actively sought in patients with known associated conditions, such as scleroderma, hypoxic lung disease, liver disease, or congenital heart disease. Heterozygous germ-line mutations in the gene encoding the bone morphogenetic protein type II receptor (BMPR2) are found in over 70% of families with pulmonary arterial hypertension. Pulmonary hypertension is defined as a mean pulmonary arterial pressure greater than 25 mm Hg at rest, and may be due to increased pulmonary vascular resistance (e.g. pulmonary arterial hypertension), increased transpulmonary blood flow (e.g. congenital heart disease), or increased pulmonary venous pressures (e.g. mitral stenosis). Exercise tolerance and survival in pulmonary hypertension is ultimately related to indices of right heart function, such as cardiac output.
Deep venous thrombosis and pulmonary embolism
Authors: Stein Paul D. , Matta Fadi , Firth John D.
Published: February 2020

Deep venous thrombosis (DVT) and pulmonary embolism (PE) are sometimes described together using the term ‘thromboembolism’. PE is a complication of DVT, with thrombi in 80% or more of cases originating in the legs. Deep venous thrombosis (DVT) is diagnosed in 1–2% of hospitalized patients, but is often silent and is found much more frequently at autopsy. Patients typically complain of pain and/or swelling of the leg, but often the diagnosis will be considered only when the physician detects unilateral leg swelling. Management strategies of PE have been developed that are based on the diagnosis of either PE or DVT, provided the patient has good respiratory reserve. Treatment with anticoagulants is the same for both. Some physicians believe that patients can be managed better if it is known whether acute PE is present, even if a diagnosis of DVT is already established.
Anaphylaxis
Authors: Brown Anthony F.T.
Published: February 2020

The term anaphylaxis describes both immunoglobulin E (IgE) immune-mediated reactions, plus non-IgE immune-mediated, and non-allergic, non-immunologically triggered events. Comorbidities such as asthma or infection, exercise, alcohol, or stress and concurrent medications such as β-blockers and aspirin increase the risk, a concept known as ‘summation anaphylaxis’. Activated mast cells and basophils release preformed, granule-associated mediators and newly formed lipid mediators, and generate cytokines and chemokines. These cause vasodilatation, increased capillary permeability, and smooth muscle contraction, as well as attracting new cells to the area. Positive feedback enhancing mechanisms amplify the reaction in a ‘mast cell—leucocyte cytokine cascade’, although conversely reactions can be self-limiting. Parenteral penicillins, hymenopteran stings, and food are the most common causes of IgE immune-mediated fatalities, with radiocontrast media, aspirin, and other non-steroidal anti-inflammatory drugs most commonly responsible for non-IgE and non-allergic fatalities.
Acute respiratory failure
Authors: Leaver Susannah , Cordingley Jeremy , Finney Simon , Griffiths Mark
Published: February 2020

Acute respiratory failure is defined clinically by hypoxaemia with (type 2) or without (type 1) hypercapnia. It is one of the most common problems afflicting critically ill patients and is a common indication for transfer to an intensive care unit. Critical illness may be manifest solely as respiratory insufficiency, especially in patients with covert infection. Acute respiratory failure frequently coexists with other organ system failures in the critically ill, and delayed recognition of the condition adversely affects outcome. The signs of critical illness tend to be similar whatever the precipitating cause and are manifest in failure of the respiratory, cardiovascular, and neurological systems. Full and repeated physical examination may be required to assess the cause and severity of acute respiratory failure and its associated complications, but in severe cases should not delay the instigation of life-saving support and treatment.
Bronchiectasis
Authors: Wilson R. , Bilton D.
Published: February 2020

A bronchiectatic lung contains permanently dilated subsegmental airways that are inflamed, tortuous, and often partially or totally obstructed with secretions. Pathogenesis involves airway inflammation which can cause further bacteria-driven host-mediated lung damage. Causes include developmental defects, damage caused by previous infection, immune deficiency, mucociliary clearance defects, and mechanical obstruction, but in many cases (40–60%) the cause is unknown. Bronchiectasis should be suspected when there is a history of persistent cough productive of sputum throughout the year, with chest infections leading to increased symptoms. About 80% of patients have upper respiratory tract symptoms. Clinical examination is often normal, although ‘classical’ severe cases show finger clubbing and widespread coarse crackles. Management involves the treatment of the specific underlying cause (when possible) and treatment of the bronchiectasis itself, with the most important elements being sputum clearance by physiotherapy and antimicrobials, which need to be given in high dose.
Pulmonary Langerhans’ cell histiocytosis
Authors: Bourke S. J.
Published: February 2020

Pulmonary Langerhans’ cell histiocytosis is characterized by a reactive monoclonal proliferation of activated histiocytes in the distal bronchioles, resulting in inflammatory nodules, cyst formation, and fibrosis. Langerhans’ cells are a particular type of histiocyte derived from dendritic cells in the bone marrow. They normally migrate in the blood to the squamous epithelium of the skin, lungs, gastrointestinal, and female genital tract, where they are involved in antigen presentation to T cells. It presents with cough, breathlessness, and (sometimes) systemic symptoms. Chest radiography and CT typically show nodules which then cavitate and may rupture, causing pneumothorax. Corticosteroids and/or cytotoxic drugs are of some benefit, and lung transplantation is an option for progressive disease.
Pulmonary alveolar proteinosis
Authors: Bourke S. J.
Published: February 2020

In 90% of cases pulmonary alveolar proteinosis is caused by autoimmune antibodies to GM-CSF which impair the function of alveolar macrophages in clearing surfactant from the alveoli, giving rise to impaired gas exchange, breathlessness, and respiratory failure. Chest radiography shows extensive alveolar shadowing simulating pulmonary oedema, and CT scanning shows a characteristic ‘crazy paving’ pattern. The presence of GM-CSF antibodies in the serum is useful in diagnosis. Bronchoalveolar lavage or lung biopsy demonstrates alveolar secretions that are strongly PAS-positive. Treatment is by physical removal of the lipoproteinaceous material from the alveoli by whole-lung lavage. Massive inhalation of dust and fumes may overwhelm macrophage function, giving rise to secondary pulmonary alveolar proteinosis.
Toxic gases and aerosols
Authors: Stenton Chris
Published: February 2020

Acute exposure to noxious agents causes pulmonary effects that are determined by the size of aerosol particles and by the solubility of gases. Large particles (>10 um) and soluble agents such as CS gas, ammonia, or sulphur dioxide affect primarily the upper respiratory tract, causing lacrimation, blepharospasm, rhinitis, cough, and breathlessness. Nitrogen oxides, ozone, and other agents of low solubility affect mainly the lungs, with pneumonitis and pulmonary oedema that can develop 24 hours or more after exposure. Smoke inhalation, intermediate solubility gases such as chlorine, and overwhelming exposures have effects throughout the respiratory tract. Some inhaled gases such as carbon monoxide and methane act as simple asphyxiants. Other reactions occur, such as metal fume fever with zinc and cadmium, and pulmonary haemorrhage with crack cocaine. Management is essentially supportive. Carboxyhaemoglobin and lactate levels should be measured with smoke inhalation.