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.

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.

There is international agreement that dyspepsia refers to pain or discomfort centered 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.

In this chapter, an abbreviated account is presented on the subject of hereditary diseases and the liver. However, it is incomplete because Alagille syndrome, storage disorders, alpha-1-antitrypsin deficiency and Wilson disease are not included as they appear in other chapters of this volume. Biliary atresia is omitted because all available evidence does not support any significant genetic association. Molecular biological techniques have enabled linkage of several liver cholestatic disorders to chromosomal loci, and further characterization of the canalicular bile salt transporter (cBST) will advance our understanding of pathogenetic mechanisms involved in benign and progressive cholestatic syndromes. Disorders that have been treated as separate entities may have common 'roots', exemplified by the concept of the ductal plate malformation in fibropolycystic disease. Whereas the majority of disorders referred to in this chapter present early in life, there are several that are associated with liver failure in the neonatal period, which makes early recognition particularly important. Liver transplantation offers a cure for many hereditary disorders affecting the liver but it is not applicable to all.

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. 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 hyper-bilirubinemias: 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.

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.

Available evidence supports the concept that alcoholic liver disease (ALD) is a multifactorial disease with a heritable component. A number of polymorphic genes with small and additive effects will thus encode susceptibilty to this 'polygenic' disease. Molecular genetic studies of ALD are in their infancy, and methods available for the genetic dissection of complex traits are discussed. Some candidate genes have been identified, and studies have been undertaken to test for association between specific alleles and ALD susceptibility. There is evidence to support a role for alleles of two genes encoding enzymes involved in the oxidative metabolism of alcohol (acetaldehyde dehydrogenase2*2 and cytochrome P4502E1 c2 allele) in susceptibility to ALD. More recently, attention has focused on cytokines, and there are now data showing association of specific alleles of both tumour necrosis factor alpha and interleukin-10 with predisposition to ALD. These candidate genes need to be subjected to rigorous evaluation in different populations. Such research should help to define more precisely the molecular mechanisms underlying the development of ALD in a sub-population (< 20%) of alcoholics, thereby improving the hepatologist's ability to develop rational treatments.

Autoimmune polyglandular syndrome type 1 (APS1) is characterized by a variable combination of disease components: (1) mucocutaneous candidiasis; (2) autoimmune tissue destruction; (3) ectodermal dystrophy. The disease is caused by mutations in a single gene called APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy) or AIRE (autoimmune regulator) coding for a putative transcription factor featuring two zinc-finger (PHD-finger) motifs. APS1 shows a penetrance of 100%, lack of female preponderance and lack of association with HLA-DR. Typically, onset of APS1 occurs in childhood and multiple autoimmune manifestations evolve throughout lifetime. Organ-specific autoantibodies associated with hypoparathyroidism, adrenal and gonadal failures, IDDM, hepatitis and vitiligo are discussed, and autoantibody patterns in APS1 patients are compared with autoantibodies in APS type 2 (APS2). APS2 is characterized by adult onset adrenal failure associated with IDDM and/or hyperthyroidism. APS2 is believed to be polygenic, characterized by dominant inheritance and association with HLA DR3.

Alagille syndrome (AS) (arteriohepatic dysplasia, Alagille-Watson syndrome) is a multi-system disorder with hepatic, skeletal, eye, cardiac and renal manifestations. It results from mutation of the JAG1 gene, located on chromosome 20, which encodes a ligand for Notch receptor(s). The interactions of Notch receptors and their ligands are crucial in controlling cell fate decisions in a variety of developmental processes. AS varies in its severity, even in the same family, from asymptomatic gene carriers through to lethality due to inoperable cardiac or end-stage liver disease. However, advances in medical and surgical therapy have improved the prognosis at the severe end of the spectrum. It is hoped that the enhanced understanding of the biology of AS resulting from the cloning of the JAG1 gene will enable us to develop additional strategies for more effective treatments.

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.

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.

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.

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.

Helicobacter pylori is a conventional gram-negative bacteria that causes an infection of the gastric mucosa. The organism is sensitive to most common antibiotics and theoretically should be easy to eradicate, provided that the patient takes antibiotics to which the organism is sensitive using a sufficient dose and duration of therapy. Unfortunately, the infection has proved difficult to cure. There are many other examples of bacterial infections that resist treatment with antibiotics even when the individual organisms demonstrate antibiotic sensitivity in vitro (e.g., Salmonella in the biliary tract). Failure can be due to the presence of antibiotic-resistant organisms, features of the infection may make it inaccessible to the antibiotics despite having antibiotic-sensitive organisms (a resistant infection), or both. Acquired resistance of H. pylori to clarithromycin, metronidazole, tetracycline, and amoxicillin have all been described.

Rectal pain sensitivity has been called a biological marker for irritable bowel syndrome, but this conclusion may be premature. This article is a critical review of the evidence for psychological influences on perception.