Annual Review of Medicine - Volume 51, 2000

The application of sensitive metabolic tests, such as the deoxyuridine suppression test and measurement of homocysteine and methylmalonic acid, to cobalamin status has identified the entity of mild, preclinical cobalamin deficiency. This state, common in the elderly, responds to cobalamin therapy. Preclinical deficiency may exist within the nervous system as well, although this requires further study. Nevertheless, it is well to remember that not all low cobalamin levels and not all abnormal metabolite results reflect cobalamin deficiency. Interpretation of metabolic results still requires caution, as do proposals to raise the cut-off point for low cobalamin levels to capture some normal levels that are associated with metabolic abnormality. The recognition of mild, preclinical deficiency has opened up many important issues. These include identifying its causes, what should be done about it, and what the clinical impact of the hyperhomocysteinemia itself is. Although malabsorptive disorders, especially food-cobalamin malabsorption, underlie about half of all cases of preclinical deficiency, no cause can be found in the remainder of these cases; poor dietary intake appears to be uncommon. In addition, unusual states of neurologically symptomatic cobalamin deficiency are being recognized, such as nitrous oxide exposure in patients with unrecognized deficiency and severe deficiency in children of mildly deficient mothers. All of these have broadened and complicated the picture of cobalamin deficiency while providing greater opportunities for prevention.

Substantial progress has been made in the diagnosis and management of primary breast cancer over the past three decades. As a result, mortality related to this disease has been decreasing gradually for several years, treatment has become more effective, and side effects and complications related to treatment have decreased. In this report, we review the state of adjuvant therapy for breast cancer.

Kidney transplant candidates increasingly are looking to their relatives, spouses, and even friends for a better chance at transplantation. The wait for a cadaver kidney might be 2–5 years. Although kidneys from well-matched family members have been transplanted with excellent results for many years, accepting living donors who are genetically unrelated to the patient has not been encouraged until recently. Results show that, among 1700 patients who received kidney transplants from living unrelated donors in the United States from 1995 through 1998, the one- and projected ten-year graft survival rates were 92% and 67%, respectively. These results are superior to the 87% and 50% rates for more than 26,000 cadaver kidney transplants during the same period. Risks to the donor are low (<0.005% mortality and <0.3% serious complications) but not absent. Thus, motivated spouses, friends, and adopted or stepfamily members can play an important role in the rehabilitation of patients who need a kidney transplant.

Pandemics are the most dramatic presentation of influenza. Three have occurred in the twentieth century: the 1918 H1N1 pandemic, the 1957 H2N2 pandemic, and the 1968 H3N2 pandemic. The tools of molecular epidemiology have been applied in an attempt to determine the origin of pandemic viruses and to understand what made them such successful pathogens. An excellent example of this avenue of research is the recent phylogenetic analysis of genes of the virus that caused the devastating 1918 pandemic. This analysis has been used to identify evolutionarily related influenza virus genes as a clue to the source of the pandemic of 1918. Molecular methods have been used to investigate the avian H5N1 and H9N2 influenza viruses that recently infected humans in Hong Kong. Antigenic, genetic, and epidemiologic analyses have also furthered our understanding of interpandemic influenza. Although many questions remain, advances of the past two decades have demonstrated that several widely held concepts concerning the global epidemiology of influenza were false.

Human herpesvirus 6 is the causative agent of roseola infantum, a generally benign rash illness of infants. Most persons acquire HHV-6 infection by age 2 years, and HHV-6 infection is a common cause of fever and febrile seizures in infants. In adults, primary infection with HHV-6 can produce a mononucleosis-like illness and, more rarely, severe disease, including encephalitis. In addition to primary infections, HHV-6 can cause clinical illness during reactivation, particularly in immunocompromised persons.

Atrial fibrillation is frequently disabling and resistant to antiarrhythmic drugs. Curative treatment by catheter-based ablation has been shown to be feasible either by achieving long linear lesions, mainly in the left atrium, or by targeting the initiating focus, most frequently in the pulmonary veins. This paper reviews the different ablation approaches, their results, potential complications, and relative merits.

Remarkable progress is being made in understanding the molecular basis of disorders of human iron metabolism. Recent work has uncovered unanticipated relationships with the immune and nervous systems, intricate interconnections with copper metabolism, and striking homologies between yeast and human genes involved in the transport of transition metals. This review examines the clinical consequences of new insights into the pathophysiology of genetic abnormalities affecting iron metabolism. The proteins recently found to be involved in the absorption, transport, utilization, and storage of iron are briefly described, and the clinical manifestations of genetic disorders that affect these proteins are discussed. This chapter considers the most common inherited disorder in individuals of European ancestry (hereditary hemochromatosis), a widespread disease in sub-Saharan populations for which the genetic basis is still uncertain (African dietary iron overload), and several less frequent or rare disorders (juvenile hemochromatosis, atransferrinemia, aceruloplasminemia, hyperferritinemia with autosomal dominant congenital cataract, Friedreich’s ataxia, and X-linked sideroblastic anemia with ataxia).

Genetic epidemiologic studies reveal that relatives of bipolar (BIP) probands are at increased risk for recurrent unipolar (RUP), BIP, and schizoaffective (SA) disorders, while relatives of schizophrenia (SZ) probands are at increased risk for SZ, SA, and RUP disorders. The overlap in familial risk may reflect shared genetic susceptibility. Recent genetic linkage studies have defined confirmed susceptibility loci for BIP disorder for multiple regions of the human genome, including 4p16, 12q24, 18p11.2, 18q22, 21q21, 22q11–13, and Xq26. Studies of SZ kindreds have yielded robust evidence for susceptibility at 18p11.2 and 22q11–13, both of which are implicated in susceptibility to BIP disorder. Similarly, confirmed SZ vulnerability loci have been mapped for 6p24, 8p and 13q32. Strong statistical evidence for a 13q32 BIP susceptibility locus has been reported. Thus, both family and molecular studies of these disorders suggest shared genetic susceptibility. These two group of disorders may not be so distinct as current nosology suggests.

The Marfan syndrome (MFS), initially described just over 100 years ago, was among the first conditions classified as a heritable disorder of connective tissue. MFS lies at one end of a phenotypic continuum, with people in the general population who have one or another of the features of MFS at the other end, and those with a variety of other conditions in between. Diagnosis of MFS and these other conditions remains based on clinical features. Mutations in FBN1, the gene that encodes fibrillin-1, are responsible for MFS and (in a few patients) other disorders in the continuum. In addition to skeletal, ocular, and cardiovascular features, patients with MFS have involvement of the skin, integument, lungs, and muscle tissue. Over the past 30 years, evolution of aggressive medical and surgical management of the cardiovascular problems, especially mitral valve prolapse, aortic dilatation, and aortic dissection, has resulted in considerable improvement in life expectancy.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, appear to have clinically significant anticarcinogenic effects in the gastrointestinal tract. Epidemiological data indicate that use of these drugs is inversely associated with the risk of sporadic colorectal cancer, and clinical trials among patients with familial polyposis coli show that NSAIDs can lead to the regression of large bowel adenomas. Animal studies have reported a similar efficacy of NSAIDs against experimental carcinogenesis. A consistent pattern in this research is that continued long-term use of NSAIDs is required for an anticancer effect—up to 15 or 20 years before a reduced risk of colorectal cancer appears. Epidemiological data also suggest possible protective effects in the stomach and esophagus. The mechanisms underlying any chemopreventive effect of NSAIDs are not clear. Inhibition of cyclooxygenase is one possibility, but pathways independent of cyclooxygenase and prostaglandins are also possible.

The standard of care for the evaluation of axillary nodal involvement remains complete lymph node dissection. Lymphatic mapping and sentinel lymph node (SLN) biopsy are changing this long-held paradigm; indeed, several leading institutions already reserve complete axillary dissection for patients with metastasis to the SLN. In addition to reviewing the literature, this chapter describes our lymphatic mapping experience at the H Lee Moffitt Cancer Center and Research Institute with 1147 breast cancer patients. Our results, in addition to a meta-analysis of data from 12 institutions comprising an additional 1842 patients undergoing complete axillary dissection, demonstrate that SLN biopsy is an accurate method of axillary staging. Although the results from small series may exaggerate the probability of false negative results, the risk of nodal disease based on tumor size and other risk factors should be evaluated when considering the results of SLN sampling.

The amyloidoses are diseases in which abnormalities in the secondary structure of precursor proteins result in decreased solubility under physiologic conditions, with subsequent organ compromise. A total of 18 proteins have been definitively identified as amyloid precursors associated with human disease. Mutations in the genes that encode some of these proteins produce autosomal dominant disease in mid to late adult life. Until recently, the late onset has obscured the familial nature of some of the disorders. This is especially true in the apparently sporadic diseaseproducing deposits found even later in life. In many instances, these deposits are derived from precursors encoded by wild-type genes (perhaps influenced by alleles that are polymorphic in the normal population); in other cases, they represent autosomal dominant disease with age-dependent penetrance. The genetic aspects of amyloid diseases produced by the deposition of four different proteins have been investigated in detail and provide insights into the particular diseases and amyloidogenesis in general.