Alpha 1-Antitrypsin deficiency (PiZ) is frequent in Caucasian populations. The predominant clinical correlates of this inborn error, i.e. chronic liver disease, emphysema, and vasculitic syndromes including their pathogenetic background are discussed in the present review.
Estimates of the prevalence of dyspepsia in the community have varied between studies. This is, in large part, because of differences in the definitions used. Roughly speaking, 15-20% of the general population will report recurrent upper abdominal pain over the course of a year. Most of these people do not have endoscopic abnormalities and thus meet the criteria for functional dyspepsia. These symptoms appear to come and go, which makes determination of the incidence of dyspepsia quite difficult. Most studies have not distinguished whether the onset of symptoms represents recurrence or de novo symptoms. Approximately 5-10% of the population will develop symptoms of dyspepsia in a given year, and 50% of people with dyspepsia will lose their symptoms the following year. Regardless of the exact figures, all studies have demonstrated dyspepsia to be exceedingly common in the community.
The main diseases associated with dyspepsia are peptic ulcer disease, gastro-oesophageal reflux disease and non-ulcer dyspepsia. Increased gastric acid secretion is a characteristic of most duodenal ulcer patients and of a small minority of non-ulcer dyspepsia and gastro-oesophageal reflux disease patients. Although acid secretion is normal in most gastro-oesophageal reflux disease patients, the condition is mainly the result of excess exposure of the distal oesophagus to acid refluxing from the stomach. Increased mucosal sensitivity to acid is involved in the aetiology of dyspeptic symptoms in the majority of patients with peptic ulcer disease and gastro-oesophageal reflux disease, and in a minority of non-ulcer dyspepsia subjects. Gastric acid, therefore, plays an important role in both the aetiology of dyspeptic diseases and in the aetiology of dyspeptic symptoms.
The presence of jaundice in the neonate, infant or young child presents a broad differential diagnosis. The 'disease' may be benign, as in breast-milk jaundice, or potentially fatal, as in hereditary fructose intolerance. The cause of the jaundice may be a primary hepatic disorder, such as extrahepatic biliary atresia, or secondary to a non-hepatic cause, such as haemolysis or sepsis. There may be significant hepatic injury and dysfunction, as in fulminant viral hepatitis, or simply elevation of plasma bilirubin, as in Gilbert's syndrome. p] In this chapter we will discuss the familial hyperbilirubinaemia syndromes. This diverse group of disorders is characterized by hepatic dysfunction in the absence of hepatocellular injury. The first section of the chapter will discuss the unconjugated hyperbilirubinaemias: Crigler-Najjar syndrome I, Crigler-Najjar syndrome II and Gilbert's syndrome. The discovery of the gene for bilirubin uridine diphosphate glucuronosyltransferase has increased our understanding of the genetic heterogeneity and clinical presentation of the Crigler-Najjar syndromes. The remainder of the chapter will discuss the conjugated hyperbilirubinaemias: Rotor syndrome and Dubin-Johnson syndrome. These rare diseases share many clinical features; however, they can be readily distinguished by biochemical markers in the urine and bile.
Life expectancy for patients with Cystic Fibrosis (CF) has steadily improved during the last three decades, and death in childhood is now uncommon. Nutrition is a critical component of the management of CF, and nutritional status is directly associated with both pulmonary status and survival. Expert dietetic care is necessary, and attention must be given to ensuring an adequate energy intake in the face of demands which may be increased by inadequately controlled malabsorption, chronic broncho-pulmonary colonisation by bacteria and fungi, exacerbations of acute lung infection, impaired lung function, and the need for rehabilitation, repair and growth.Pancreatic enzyme replacement therapy (PERT) is needed by up to 90% of CF patients in Northern Europe, where the 'severe' mutation Delta F508 predominates, but a smaller proportion in Mediterranean countries and elsewhere, because pancreatic insufficiency is one of few features of CF which correlate with genotype.Complications of CF including liver disease and CF-related diabetes pose further challenges. In addition, deficiency of specific nutrients including fat soluble vitamins (particularly A, E and K) essential fatty acids and occasionally minerals occur for a variety of reasons. Osteopenia is common and poorly understood. Liver disease increases the likelihood of vitamin D deficiency. Glucose intolerance and diabetes affect at least 25% of CIF adults, and the diabetes differs from both types 1 and 2 diabetes mellitus, but it inversely correlates with prognosis.Management consists of anticipating problems and addressing them vigorously as soon as they appear. Supplements of vitamins are routinely given. Energy supplements can be oral, enteral or, rarely, parenteral. All supplements, including PERT, are adjusted to individual needs.
Most cases of inflammatory bowel disease (IBD) can be correctly labelled as Crohn's disease (CD) or ulcerative colitis (UC) with careful initial gross and microscopic examination of biopsy and resection specimens together with close clinical and radiological correlation. Until we understand more of the aetiology and immunology of IBD we should admit that there are limitations imposed by current diagnostic criteria, consider the use of reporting proforma to improve diagnostic accuracy, and accept that in a small number of patients clinicopathological features will overlap, and CD may masquerade as UC.
Wilson disease is a recessively inherited disorder of copper transport. Clinical features are highly variable, with any combination of neurological, hepatic or psychiatric illness. The age of onset varies from 3 to 50 years of age. Diagnosis is challenging because no specific combination of clinical or biochemical features is necessarily definitive. The genetic defect is due to a variety of abnormalities in a copper-transporting membrane ATPase. Most of the more than 80 mutations are present at a low frequency, and mutations differ between ethnic groups. At least two mutations are sufficiently common to aid in rapid diagnosis, in European and Asian populations respectively. Molecular analysis can provide a definitive diagnosis for asymptomatic sibs. Treatment, using chelating agents or zinc, is most effective when started before permanent tissue damage occurs.
Primary, hereditary or genetic haemochromatosis is one of the most common inherited disorders in a Caucasian populations with a disease frequency of 1:300-400 and a carrier frequency of approximately 10%. The basic genetic defect remains unknown, although the haemochromatosis gene has now been cloned and is known to be a member of the MHC non-classical class I family. Many factors--environmental, genetic and non-genetic in nature--influence the degree of iron loading in affected individuals. In particular, pathological and physiological blood loss influence iron stores in haemochromatosis. The iron concentration in the liver is an important determinant of survival because a hepatic iron concentration in excess of 400 mumol/g dry weight is usually associated with cirrhosis. Patients with cirrhosis secondary to haemochromatosis are at risk of hepatocellular carcinoma. The combination of improved awareness of the disease and the appropriate use of genetic testing for the common C282Y mutation should lead to earlier diagnosis and therapy.
Disordered nutrition is common in Crohn's disease and is multifactorial. Regular and systematic monitoring of at least a minimum set of nutrition data is an essential component of care of children and adults with Crohn's disease. However, even in children, monitoring of growth and development may be deficient. Multiple macro- and micronutrient deficiencies are common in Crohn's disease, especially in those with extensive small bowel deficiencies or after multiple surgical resections. Body composition analysis may show differences from simple starvation, and metabolic effects of inflammation are increasingly being recognized. Nutritional support is part of the management of all patients with Crohn's disease, but nutritional intervention with defined formula liquid diet is an effective specific anti-inflammatory therapy. Although meta-analysis of published trials suggest that steroids are more effective than defined formula liquid diets, objective evidence from whole gut lavage fluid analysis and from faecal excretion of radiolabelled leukocytes shows unequivocal benefit of elemental diet based on measuring parameters of tissue damage. Enteral feeding with liquid diets should be considered in patients with incomplete small bowel obstruction, severe painful perianal disease, failure of corticosteroids in active Crohn's disease, borderline intestinal failure and in children with active Crohn's disease or with growth failure.
There is international agreement that dyspepsia refers to pain or discomfort centred in the upper abdomen. However, the term 'discomfort' has been variably defined. While other symptoms may often be simultaneously present, gastro-oesophageal reflux disease can usually be clearly distinguished by the presence of predominant heartburn. Dyspepsia is a frequent reason for consultation in primary care and in gastrointestinal practice. With the widespread availability and utilization of endoscopy, it has become evident that a structural (or organic) explanation is found in only a minority of patients presenting with dyspepsia. Operationally, functional dyspepsia is defined as persistent or recurrent dyspepsia for 3 or more months in the absence of a clinically identifiable structural disease causing the symptoms. It has been proposed, based on symptoms, that functional dyspepsia be subdivided into symptom subgroups to promote patient homogeneity. The initially proposed 'clustering' of symptoms into ulcer-like and dysmotility-like functional dyspepsia has proved a dismal failure because of the considerable overlap observed, the lack of stability over time and the failure to identify robust pathophysiological abnormalities or responses to therapy. A subcategorization based upon the most bothersome symptom is theoretically more attractive but needs to be prospectively and rigorously tested.
An imbalance between a person's energy requirements and his or her dietary protein and caloric supply is the source of protein energy malnutrition (PEM), which compounds the problems of any underlying disease. Malnutrition may occur quite rapidly in critically ill patients, particularly those suffering from sepsis, setting up a vicious cycle with worsening of the PEM. This chapter examines the main consequences of PEM, the means whereby appropriate nutrition may be provided, and risks for severely malnourished paediatric patients in hospital. If the gastrointestinal tract can be used for refeeding, it should be used. When the gastrointestinal tract is unable to meet the protein and energy requirements, parenteral nutrition (PN) is required. PN is efficient but carries a high risk of metabolic complications known as the refeeding syndrome and directly related to the homeostatic changes secondary to severe PEM.Catch-up growth may be achieved by using appropriate nutritional support. Changes in body composition have to be assessed during the course of renutrition.
The quantity and quality of dietary lipids and their metabolism are of major importance for the growth, body composition, development and long-term health of children, both in health and disease. Lipids are the major source of energy in early childhood and supply essential lipid-soluble vitamins and polyunsaturated fatty acids that are required in relatively high amounts during early growth. Lipids affect the composition of membrane structures, and modulate membrane functions as well as the functional development of the central nervous system. Some long-chain polyunsaturated fatty acids serve as precursors for bioactive lipid mediators, including prostaglandins, thromboxanes and leukotrienes, which are powerful regulators of numerous cell functions such as thrombocyte aggregation, inflammatory reactions and immune functions. Here we review some aspects of the biochemistry and physiology of lipids and their implications for lipoprotein metabolism, energy balance and the lipid supply during early childhood through the placenta, human milk, enteral diets and parenteral lipid emulsions.
Functional dyspepsia is a chronic disorder of unknown aetiology. The lack of endoscopic abnormalities in patients with this disorder has led many physicians to believe that gastrooesophageal reflux disease may be responsible for most symptoms. Our group has addressed this issue, by pathophysiological studies in a large cohort of Dundee patients with persistent dyspeptic symptoms. Peptic ulcer and gallstones were excluded in all patients by appropriate tests. Ambulatory pH monitoring showed oesophageal acid reflux that lay above the conventional diagnostic threshold in approximately 20% of patients. This subset was diagnosed as having gastro-oesophageal reflux disease. In the remainder, moderate or severe reflux-like symptoms were reported by approximately 44% patients, who were categorized as reflux-like functional dyspepsia. Reflux symptoms were mild or absent in 36% patients, who were categorized as non-reflux-like dyspepsia. While oesophageal pH profiles lay within the conventional normal range in both of these functional dyspepsia subgroups, patients with reflux-like functional dyspepsia had significantly greater acid exposure values, including total oesophageal acid exposure time, percentage time at a pH of less than 4.0, DeMeester scores and pain reflux event correlation. Hence patients with reflux-like functional dyspepsia have oesophageal acid exposure that lies below the diagnostic threshold for gastro-oesophageal reflux disease but exceeds that of patients with non-reflux dyspepsia. The high pain/reflux event correlation in reflux-like functional dyspepsia suggests that subthreshold oesophageal acid exposure may be associated with troublesome reflux symptoms.
Carbohydrate metabolism in the liver is responsible for plasma glucose homeostasis. Liver glycogen storage diseases are metabolic disorders which result in abnormal storage amounts and/or forms of glycogen, and often (but not always) have hepatomegaly and hypoglycaemia as presenting features. To understand the clinical complexity of the glycogen storage diseases, it is necessary to understand the properties and regulation of the proteins involved in glycogen metabolism. Advances in treatment have greatly improved metabolic control and hence the quality of life and survival. However, the lack of understanding of the molecular basis of some of the clinical features of glycogen storage diseases makes it difficult logically to devise optimal treatment regimens to prevent some of the long-term complications. Recently, molecular biology has greatly advanced our understanding of the proteins and genes involved in liver glycogen metabolism and has led to better and less invasive methods of diagnosis of these disorders.
In the absence of a single initiating aetiological factor, most workers envisage Crohn's disease as the manifestation of poorly regulated immune and inflammatory processes within the gut wall. Initially these responses may arise as a response to common antigens associated with the gut—bacterial products being amongst the most obvious candidates. In genetically predisposed individuals there is overexpression both of local immune response mechanisms in the gut wall (T-cells, B-cells and macrophages) and of systemic inflammatory cells (predominantly polymorphonuclear leukocytes), which are attracted into the inflamed gut through activation of adhesion molecules on the vascular endothelium. As a consequence a large number of pro-inflammatory processes are expressed in the gut wall, inadequately checked by the normal counter-inflammatory processes that should serve to limit inflammation. Defining the relative importance of the individual processes, and identifying critical steps that could be inhibited or enhanced for therapeutic purposes, is a major challenge of Crohn's disease research.
Gastrointestinal motor abnormalities are frequent findings in patients with functional dyspepsia. However, these abnormalities are rather non-specific and seem to be restricted to a proportion of patients. Furthermore, they are not necessarily time-linked to symptom perception. The relationship of digestive motor derangements and symptoms in functional dyspepsia remains, therefore, unsettled. A variety of methodological and conceptual shortcomings characterize many of the studies investigating the relationship between gastrointestinal motility disorders and dyspeptic symptoms, and this obviously contributes to a higher level of uncertainty in the field. Recent reports suggest that gastrointestinal dysmotility is associated with perception of some dyspeptic symptoms, at least in a subset of patients. Well-conducted studies using appropriate methodology are needed to verify whether gastrointestinal motor disorders play a causal role in functional dyspepsia and whether this is of clinical relevance.
To determine whether functional dyspepsia and irritable bowel syndrome are different entities, epidemiological data, factor analysis studies, physiological data and associated psychological symptoms were reviewed. Between 30% and 60% of patients with either diagnosis also meet the criteria for the other diagnosis, a level greater than expected to occur by chance but not sufficient to infer an identity. Most factor analysis studies identify independent clusters of symptoms corresponding to functional dyspepsia and irritable bowel syndrome. Visceral hypersensitivity is seen throughout the gastrointestinal tract in both disorders, but the motility patterns seen in association with functional dyspepsia (principally antral hypomotility and delayed gastric emptying) differ from the motility patterns seen in irritable bowel syndrome. Psychological symptoms are similar in these two disorders but are not believed to be aetiological for either of them. Thus, based on a factor analysis of gastrointestinal symptoms and differences in intestinal motility, functional dyspepsia and irritable bowel syndrome appear to be different entities.
Juvenile haemochromatosis (JH) is an autosomal recessive disorder which leads to early-onset, severe iron overload. The disease affects both sexes equally. Iron parameters and tissue iron distribution are similar to those in middle-life haemochromatosis (which is linked to the HFE gene). Endocrine manifestations, especially hypogonadism, and heart failure are the most prominent clinical features. Liver involvement, although present, is clinically less relevant. Genetic evidence indicates that JH is a disorder distinct from HFE-linked disease. Patients do not have mutations in the HFE gene, and the study of selected families has excluded a linkage to the interval of chromosome 6p where the HFE gene resides. The distinction between the two disorders raises the possibility that the different clinical presentation of JH is not only age-related but probably depends on a different biochemical defect. Early diagnosis of JH is important to avoid cardiac complications which can lead to premature death. As with HFE-linked disease, JH is responsive to phlebotomies.
α1-Antitrypsin deficiency (PiZ) is frequent in Caucasian populations. The predominant clinical correlates of this inborn error, i.e. chronic liver disease, emphysema, and vasculitic syndromes including their pathogenetic background are discussed in the present review.
