Annual Review of Medicine - Volume 46, 1995

The role for HLA typing in autoimmune disease is changing with the recognition that HLA markers can identify patients with poor prognosis in some autoimmune disease. Aggressive therapeutic intervention in patients with such HLA prognostic markers has the potential to improve or prevent progressive disease outcomes in a select group of patients.

Elderly people have a very high prevalence of hypertension, which markedly increases their risk for cardiovascular morbidity and mortality. Convincing evidence demonstrates the effectiveness of antihypertensive therapy in reducing these risks significantly. With appropriate caution, most elderly hypertensives can be treated and thereby protected from many of the debilities of old age.

This review defines subclinical hypothyroidism and examines its influence on the occurrence and course of major depression. Recommendations are presented for the identification and treatment of patients with coexisting mood disorders and borderline thyroid failure.

Tuberculosis (TB) remains an important public health problem worldwide, resulting in an estimated 8 to 10 million new cases and 2 to 3 million deaths each year. Between 1953 and 1985, the number of TB cases in the US declined by an average of 6% per year. However, since 1985, TB has been increasing in the US. Approximately 64,000 additional cases of the disease have been reported beyond the number expected had the rate of decline observed from 1980 to 1984 continued from 1985 through 1993. Increases in the number of TB cases have been significant in racial and ethnic minorities, in persons born outside the US, and in children less than 15 years of age. Infection with the human immunodeficiency virus (HIV) has also been recognized as a major risk factor for the development of active TB in persons with latent Mycobacterium tuberculosis infection. The unusual radiographic findings and the increased likelihood of extrapulmonary TB in HIV-infected persons make diagnosis of the disease problematic. Lastly, concomitant with the resurgence of TB has been the emergence of drug resistance. All of these factors make successful control of TB in the US difficult.

The human transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of rapidly progressive disorders characterized by a spectrum of clinical abnormalities that include cognitive impairment, ataxia, myoclonus, and visual, pyramidal, and extrapyramidal signs. They share a spongiform (vacuolar) degeneration and variable amyloid plaque formation. Examples of TSEs are kuru, an infectious disease; Creutzfeldt-Jakob disease (CJD), which may take an infectious, genetic, or sporadic form; and Gerstmann-Sträussler-Scheinker disease (GSS) and fatal familial insomnia (FFI), rare familial disorders. With the exception of FFI, all of these disorders have been experimentally transmitted to nonhuman primates and laboratory rodents. The pathogenic PrP protein accumulating in the brain of TSE patients is a protease-resistant and insoluble product of a precursor protein molecule of unknown function that is encoded by the PRNP gene on chromosome 20. Different mutations in this gene are responsible for various phenotypes of TSE in its familial form, and a polymorphism at codon 129 controls susceptibility to the infectious and perhaps sporadic forms of disease. TSEs are transmissible amyloidoses in which the host-encoded protein has the propensity to acquire a beta-sheet conformation and produce amyloid; the accumulation of amyloid eventually destroys the neurons and induces the deadly disease.

Fetal surgery, as defined for the purpose of this chapter, is the act of opening the gravid uterus, surgically correcting a fetal abnormality, and returning the fetus to the uterus for postoperative recovery and continued gestational development. By this definition, human fetal surgery has now been performed for more than a decade, primarily at a single center (1). Tremendous progress has been made in our understanding of the natural history and pathophysiology of fetal disease, in solving the technical challenges of fetal surgery, and in intra- and postoperative care and monitoring of the maternal-fetal unit. However, success and general application of fetal surgery continue to be limited by a number of unsolved and formidable problems. The most important of these is the control of preterm labor, which is the Achilles heel of fetal surgery. Preterm labor is to the infantile field of fetal surgery what rejection was to the field of transplantation. The discovery of effective tocolysis would be analogous to the development of effective immunosuppression and would allow fetal surgery to achieve its full potential. In addition, less invasive methods of operating on the fetus are emerging that will further reduce the maternal and fetal risk of this currently highly invasive treatment.

Diabetic patients go through several stages of renal disease, moving from normo- to micro- to macroalbuminuria. Good metabolic control can prevent or postpone the development of microalbuminuria, the earliest sign of diabetic renal disease. Thus, efforts should focus on obtaining the best possible control before the onset of microalbuninuria. In patients with microalbuminuria, blood pressure starts to increase, and early antihypertensive treatment becomes important. Good glycemic control may be difficult to achieve. With overt nephropathy, defined as clinical proteinuria, a relentless decline in glomerular filtration rate (GFR) occurs unless patients are carefully treated with antihypertensive agents. Protein restriction may also be necessary, but a clear beneficial effect of optimized diabetes care is difficult to document. Early screening is recommended, with an emphasis on testing for albuminuria, including microalbuminuria, along with careful control of blood pressure.

Management of bleeding esophageal varices due to portal hypertension has traditionally relied on endoscopic sclerotherapy and operative intervention with placement of a portosystemic shunt. Although percutaneous decompression of portal hypertension was investigated 25 years ago, it was not clinically feasible until recently. With the advent of intravascular stents, the technique of creating a transjugular intrahepatic portosystemic shunt (TIPS) can now be effectively applied to treat the complications of portal hypertension, including variceal hemorrhage and refractory ascites. Since its introduction in 1989, TIPS has enjoyed widespread clinical application. The initial results with this procedure are encouraging and suggest that it is an effective means of reducing the frequency of variceal hemorrhage in patients with portal hypertension. The long-term patency rate and frequency of complications, however, have not been clearly defined. Similarly, the role of TIPS in the treatment of refractory ascites, Budd-Chiari syndrome, and hepatorenal syndrome remains unclear because sufficient data do not yet exist to support its general use in these settings.

Tissue factor pathway inhibitor (TFPI) is a multivalent, Kunitz-type plasma proteinase inhibitor that regulates tissue factor-induced coagulation. TFPI directly inhibits activated factor X and, in a factor Xa-dependent fashion, produces feedback inhibition of the factor VIIa/tissue factor catalytic complex. The properties of this rediscovered inhibitor appear, at least in part, to explain the clinical requirement for both the extrinsic and intrinsic pathways of the cascade and waterfall theories of blood clotting and have led to a reformulation of the coagulation mechanism. In the revised hypothesis, factor VIIa/tissue factor is responsible for the initiation of coagulation, but owing to TFPI-mediated inhibition, sustained hemostasis requires the persistent and amplified procoagulant action of intrinsic factors VIII, IX, and XI.

Neuroimaging provides an unprecedented means by which to study psychiatric disorders. Structural imaging methods, i.e. computerized tomography (CT) and magnetic resonance imaging (MRI), have revealed subtle differences in the brains of schizophrenic patients that appear to be present before symptom onset. Radionuclide functional methods such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) have led to hypotheses about dysfunction in specific neuronal networks in schizophrenia. New advances in MRI allow functional data to be obtained noninvasively in a single individual using conventional MRI scanners. This chapter discusses the parallels between the historical technical developments in neuroimaging and the deepening understanding of the etiology and manifestations of schizophrenia.

Although older individuals drink less and report fewer alcohol-related problems than do younger individuals, alcohol use and abuse are significant health issues for older patients. The signs and symptoms of alcohol problems and dependence in the elderly may not only differ from those of young problem drinkers, but may also be present at lower levels of alcohol consumption. Older alcoholics do well in alcohol treatment. Therefore, discussion of alcohol consumption is a critical part of every history and physical examination for all patients, including older individuals.

New discoveries are expanding our knowledge of mechanisms involved in amyotrophic lateral sclerosis (ALS) pathogenesis. Some recent advances in our understanding of motoneuron death in familial ALS (fALS) and sporadic ALS (sALS) are reviewed, with emphasis on molecular similarities that may further unite these phenotypically linked diseases.

With the widespread introduction of laparoscopic cholecystectomy in late 1989, the practice and expectations of general surgery were changed forever. The techniques of laparoscopy were not new—they had been adopted by gynecologists and orthopedic surgeons at least a decade before—but it was laparoscopic cholecystectomy that captured the attention of the surgical profession and the public and spawned the tremendous growth in what has come to be called minimally invasive surgery. Although this surgery has tremendous appeal, offering quicker recovery, less pain, and possibly greater safety, it presents new challenges in the areas of training, credentialing, and quality assessment and raises serious questions about the real benefits of new technology at a time when the political and economic sensitivity of these issues is greater than ever.

In this chapter I limit myself to a discussion of laparoscopy in general surgery, with a focus on what we have learned from laparoscopic cholecystectomy and on what this knowledge suggests for the future of other laparoscopic general surgical procedures.

Over the past decade, transcatheter interventions have become increasingly important in the treatment of patients with congenital heart defects. These procedures may be broadly grouped as dilations (valvuloplasty, angioplasty, and endovascular stenting) or as closures (vascular embolizations and device closure of defects). Balloon valvuloplasty has become the treatment of choice for simple valvar pulmonic stenosis in all age groups and, although not curative, appears at least comparable to surgery for noncalcific aortic stenosis in newborns through young adults. Balloon angioplasty is successfully applied to a wide range of aortic, pulmonry artery, and venous stenoses. Catheter-delivered coils are used to embolize a wide range of arterial, venous, and prosthetic vascular connections. Although still investigational, devices have been successfully used for closure of large numbers of atrial and ventricular septal defects.

In this review, the current role of each major catheter intervention is discussed and results are compared with alternative forms of therapy. Catheter-based therapeutics are then placed in context in a discussion of combined catheter-surgical treatment of patients with complex congenital heart defects.

Marrow transplants from human leukocyte antigen (HLA)-compatible unrelated volunteer donors have become feasible for more than 30% of patients without a family match and have allowed long-term, disease-free survival in 15–65% of patients with a variety of hematological disorders. However, unrelated donor transplants have a higher incidence of graft failure and graft versus host disease (GVHD) than do HLA-matched sibling transplants. This increase may be due to disparities between donor and recipient for undetected HLA determinants or for non-HLA histocompatibility genes. Because of the large number of HLA loci and their high degree of polymorphism, fully compatible donors will not be found for most patients. Fortunately, a limited degree of HLA mismatch does not necessarily impair long-term survival in patients with hematologic malignancy. Current studies are defining the risk associated with mismatching for each histocompatibility locus and are developing methods for marrow transplantation that can decrease morbidity and improve survival despite genetic disparity between donor and recipient.

Fulminant hepatic failure is characterized by severe metabolic derangements, neurologic complications and, ultimately, multiorgan failure. In the past three decades, improved intensive care has increased mean survival from 15% to 50% in certain patient groups by providing metabolic support and management of specific, frequent, and potentially fatal complications. However, outcome remains highly dependent on etiology. While intensive care is sufficient therapy in some patients (Group I), those with irreparable hepatic damage (Group III) can only survive if transplanted. In intermediate cases (Group II), the liver retains the potential to regenerate if the patient receives hepatic functional support. Major areas of current research in this field include development of hepatic support devices, strategies to accelerate and maximize hepatic regeneration, and criteria for accurate prognostic classification of patients.

Adult respiratory distress syndrome (ARDS) remains a highly lethal complication of autodestructive inflammation. This syndrome originally referred to a single organ failure but is now considered a component, usually the first, of the multisystem organ failure syndrome (MOFS). Cytokines, neutrophils, and endothelial adherence molecules initiate the disease process, with cell injury caused by oxidants and proteases released from inflammatory cells. ARDS, if progressive, will result in pulmonary fibrosis. Improved ventilatory support techniques have not been shown to decrease mortality. Pharmacologic manipulation of the inflammatory response is a more promising method of controlling the disease process.

Health care workers exposed to blood and body fluids have a low but measurable risk of occupational infection with human immunodeficiency virus (HIV). This risk is related to the prevalence of HIV among patients, the frequency of exposure to infected blood, and the method of exposure. The magnitude of risk is thus difficult to assess for any given situation, although the overall risk following percutaneous exposure is approximately 0.3%. Risk can be reduced by paying close attention to infection control procedures and by minimizing risky procedures. Exposure management should include preexposure education and immediate postexposure care and counseling. Chemoprophylaxis is widely used despite doubts as to its effectiveness, and much research is clearly needed to develop more effective prophylaxis. For patients, the risk of nosocomial acquisition of HIV remains extremely low and can be minimized by strict adherence to proper infection control procedures.

Hypertrophic cardiomyopathy (HCM) is genetically and phenotypically a heterogeneous disease. Genes identified include the β myosin heavy chain gene (βMHC) on chromosome 14q1, the troponin T gene on chromosome 1q, and the α tropomyosin gene on chromosome 15q. In addition, a fourth locus is present on chromosome 11q11, but the gene remains to be identified. More than 35 missense mutations in the βMHC, 3 mutations in troponin T, and 2 mutations in α tropomyosin gene in HCM patients have been identified. Functional studies have shown that the mutant βMHC protein has impaired acto-myosin interaction and that expression of the mutant myosin disrupts the assembly of sarcomere in feline cardiocytes. Genotype-phenotype correlations of βMHC mutations have shown that mutations such as Arg403Gln, Arg453Cys, and Arg719Trp are associated with a high incidence of sudden cardiac death and a significantly decreased life expectancy, whereas mutations Gly256Glu and Leu908Val have a near-normal life span. Preclinical genetic diagnosis should help in genetic counseling and therapeutic stratification.