Chapter 3 SYSTEMIC DISEASES
The foundations of modern medicine may be traced to the nineteenth century when the principles of exact sciences were first applied to the study of the human body and its diseases. The teachings of cellular pathology, founded by Rudolf Virchow in the 1860s, have dominated our view of health and disease ever since. The original concepts have been modified since then by new discoveries and expanded by the contributions of other basic sciences, especially biochemistry, biophysics, and molecular biology.
Contemporary clinical medicine is based on scientific principles and the application of basic sciences to the study of health and diseases. Clinical medicine is also an empirical discipline and as such must be pragmatic and practical. Thus, the clinician must study diseases not only to better understand them but also to cure, prevent, or eradicate them. For each disease the clinician must determine its:
For practical purposes diseases can be classified as organ-centered or systemic. For example, Alzheimer’s disease involves the brain and is thus classified as an organ-centered disease. Gout is a metabolic disorder that affects many organs and is therefore classified as a systemic metabolic disease. Acute appendicitis is an example of an organ-based infection, but if untreated, appendicitis may give rise to bacteremia and become a systemic disease. The line separating organ-based and systemic diseases is fuzzy and often arbitrary. Furthermore, even a strictly organ-based disease such as cirrhosis due to hepatitis C usually produces systemic disturbances, and many systemic diseases, such as systemic lupus erythematosus, first manifest with symptoms of skin or kidney disease. Thus, in this book we use the terms organ-centered and systemic with the understanding that many organ-centered diseases have systemic effects, and, conversely, many systemic diseases may be organ-centered.
In this chapter we discuss several diseases that could be used as prototypes for all other diseases in each of these eight categories. We use hereditary hemochromatosis as an example of a genetic disease because it illustrates how a mutation of a gene encoding a single protein (HFE—involved in regulating the intestinal absorption of iron) can affect multiple organ systems. We discuss gout as an example of a metabolic disease and show how the same metabolic abnormality (hyperuricemia) has several causes and still produces the same set of clinical signs and symptoms. As an example of toxic diseases we discuss alcohol abuse. Alcoholism demonstrates how substance abuse can cause major health problems. The complexities of circulatory disturbances are discussed in the example of shock and closely related multiple organ failure. Acquired immunodeficiency syndrome (AIDS) is our example of a systemic infectious disease, illustrating the consequences of the primary viral infection and bacterial, viral, fungal, and parasitic superinfections that complicate this disease complex. As an example of autoimmune disorders we examine systemic lupus erythematosus (SLE), an immune complex-mediated hypersensitivity reaction that can affect numerous organs. Finally, the systemic effects of a malignant tumor are illustrated by discussing carcinoma of the lung, not only because it is the number one cause of cancer-related death, but also because of its multiple systemic effects.
Acquired immunodeficiency syndrome (AIDS) Immunodeficiency induced by human immunodeficiency virus (HIV) infection, characterized by a low count of helper T cells (CD4+ cells) and opportunistic infections involving the skin, FI system, lungs, or the central nervous system.
Autoimmune diseases Group of chronic diseases characterized by abnormal immune reactions to self antigens. Such diseases may be accompanied by overproduction of autoantibodies or abnormal T-cell reactions, and pathological or functional changes in various organs.
Hereditary hemochromatosis Common genetic disease associated with abnormal intestinal absorption of iron and iron overload that damages several vital organs, most notably the liver, islets of the pancreas and other endocrine organs, the heart, and the skin.
Hypersensitivity Increased reactivity to exogenous or endogenous antigens, characterized by an overproduction of antibodies or abnormal cell-mediated reactions. Hypersensitivity to foreign antigens is also called allergy.
Hyperuricemia Increased concentration of uric acid in blood in excess of the empirically determined upper limit of normal (>7 mg/dL for females, >8 mg/dL for males); it may be asymptomatic or it may be lead to a deposition of urate crystals in tissues, resulting in gout, urate nephropathy, or urolithiasis.
Sepsis Presence of infectious pathogens or their derivatives in blood. Clinical consequences of sepsis are called septicemia and include fever, loss of vascular tone, and at least some signs of shock and multiple organ failure.
Hereditary hemochromatosis is a common autosomal recessive disorder marked by iron storage caused by abnormal absorption of iron in the intestines. In approximately 85% of cases hereditary hemochromatosis is caused by a mutation of the HFE gene, encoding a protein (HFE) that regulates the absorption of iron in the duodenum. The remaining 15% of cases are classified as non-HFE-related hereditary hemochromatosis.
The HFE gene is linked to the HLA-A locus on the short arm of chromosome 6 (6p). A mutation accounting for the cysteine-to-tyrosine substitution at amino acid 282 (called the C282Y mutation) inactivates the protein. Homozygotes are found at a rate of 1:220, and heterozygotes at a rate of approximately 1 in 10 persons. The signs of the disease occur only in 20% of homozygotes because the mutated gene has low penetrance. C282Y mutation is found in more than 85% of patients of northern European origin, but in only 60% of those of Mediterranean origin. Another mutation involving the substitution of histidine to aspartic acid at position 63 (H63D) is found in some persons, but it is not associated with iron overload unless combined by C282Y mutation on the other allele.
Under normal circumstances iron is absorbed in the duodenum mostly in form of ferrous (Fe2+) iron (Fig. 3-1). The absorption of iron depends on the iron stored in the body, but normally enterocytes in the duodenum absorb only 10% of the total amount of iron entering the duodenum (i.e., 1–2 mg, from the 10–20 mg of iron ingested) daily in the typical American diet.
Figure 3-1 Iron absorption. The absorption of iron in the duodenum depends on the total iron stores of the body. Total iron body stores are reflected in the saturation of transferrin, the principal iron transport protein in the plasma. Transferrin binds to the immature precursors of normal enterocytes, which serve as iron sensors in the intestine. HFE gene product on these immature cells acts together with the transferrin receptor to differentiate into absorptively active enterocytes. Absorptively active enterocytes take up ferrous iron through the action of divalent metal transporter 1 (DMT-1). Absorbed iron is either stored in the cytoplasm as ferritin or transferred to the interstitial space by the basolateral protein called ferroportin. The action of DMT-1 and ferroportin in enterocytes and ferroportin in macrophages is regulated hepcidin, a liver-derived plasma protein. In hemochromatosis liver secretes less hepcidin than normal, and the HFE mutation affects its normal function.
Low iron stores increase iron absorption in mature enterocytes on the surface of the intestinal villi. These cells absorb iron through the action of divalent metal transporter 1 (DMT-1). Absorbed iron is in part stored in the enterocytes and in part transported into the interstitial fluid by a laterobasal protein called ferroportin. The activity of DMT-1 and ferroportin is normally suppressed by hepcidin, a regulatory protein circulating in the plasma. Hepcidin prevents abnormally high absorption of iron in the duodenum. It is synthesized by the liver in response to iron. Hepcidin also inhibits the release of iron from macrophages. Plasma hepcidin levels are low in persons with hereditary hemochromatosis.
The absorption of iron depends also on the transferrin iron sensors, which are expressed on the immature crypt cells. Note that these sensor cells do not participate in the absorption of iron in the intestine; instead they express receptors for transferrin and HFE gene product, which prime them to become absorptive enterocytes by activating the DMT-1/ferroportin system.
In hereditary hemochromatosis the mutation of HFE leads to an uncontrolled absorption of iron in the duodenum. The total iron stores, which are normally around 2.5 g for women and 3.5 g for men can be increased 10 to 20 times and even more. The saturation of the iron transport protein transferrin is also increased, and the excess iron is also excreted into the urine.
Iron is deposited in the form of ferritin, which aggregates into hemosiderin granules. Hemosiderin may be detected in many organs, where it causes tissue injury and functional disturbances. Excess iron also results in the formation of free radicals, which have the following adverse effects:
Hemochromatosis may damage many organs, but most often the pathologic changes are seen in the liver (95%), skin (90%), pancreas (65%), joints (35%), and the heart (15%) (Fig. 3-2). Clinical symptoms usually manifest after age 40. Symptoms are 5 to 10 times less common in women, because normally women lose blood during menstruation and are thus less prone to accumulate iron. The symptoms occur later and are typically encountered several years after the onset of menopause.
Liver. Iron accumulates in Kupffer cells, hepatocytes, and even in bile duct cells (Fig. 3-3). Deposits of iron pigment lead to fibrosis, gradually progressing to frank cirrhosis. Clinically these changes are associated with hepatomegaly, portal hypertension with splenomegaly, and esophageal varices. Other signs and symptoms of liver failure are also present in advanced cases. Liver cell carcinoma develops in 20% to 30% of patients with cirrhosis.
Figure 3-3 Hemochromatosis. Hemosiderin, demonstrated in this slide of a liver biopsy specimen as bluish pigment resulting from the Prussian blue reaction, is seen in the form of granules in liver cells and Kupffer cells.
Skin. Brown hyperpigmentation occurs in almost all patients who have cirrhosis. The hyperpigmentation, often described as “bronzing,” is due to accumulation of hemosiderin in dermal macrophages and the increased amount of melanin in the epidermis.
Endocrine glands. Accumulation of hemosiderin in the pancreas is associated with diabetes and related to injury of the islets of Langerhans. Diabetes mellitus develops more readily in persons who have a genetic predisposition and a family history of diabetes. Other endocrine organs may be affected as well, most notably the thyroid and the gonads. Testicular atrophy and consequences of reduced testosterone production (e.g., loss of libido, erectile dysfunction, gynecomastia) are common.
Joints. Deposits of hemosiderin cause joint injury typically associated with calcification of synovium and secondary changes in the adjacent bone. Many joints can be affected, but for unknown reasons the disease tends to begin with symptoms related to the second and third metacarpophalangeal joints.
Serum ferritin. Normal serum contains less than 200 μg/dL of ferritin. In hereditary hemochromatosis serum ferritin is over 1000 μg/L. An elevation of serum ferritin by 1 μg/L corresponds to approximately 65 mg of iron in the body stores.
Urinary iron excretion. Normally the urine collected over 24 hours contains less than 2 mg of iron. In hereditary hemochromatosis urinary excretion is increased at least five times over the normal limit.
These tests are usually performed as a battery to avoid false positive or negative results. For example, the serum ferritin level is markedly increased after extensive liver cell necrosis. Serum iron levels may be elevated in chronic alcoholics. Transferrin is a negative acute-phase protein, and its production is reduced in response to acute and many chronic diseases, as well as to malnutrition. Hence, its relatively high rate of saturation may be misleading sometimes.
Deposits of iron in the liver can be estimated subjectively in liver biopsy specimens stained with Prussian blue reacting with hemosiderin (see Fig. 3-3). Furthermore, the iron content of the liver biopsy specimen can be quantitated biochemically and expressed as iron in milligrams per gram of liver tissue. Liver containing increased amounts of iron appears denser than normal on CT or MRI examination. Genetic testing provides the final diagnosis. Genetic testing should also be offered to first-degree relatives. Treatment includes weekly phlebotomy to reduce the total iron content of the tissues.
Gout is a syndrome that includes hyperuricemia and periodic deposition of uric acid crystals in tissues, leading to formation of tophaceous nodules and recurrent crystal-mediated arthritis or renal injury. The reasons for the deposition of uric acid crystals are not fully understood, and the role of hyperuricemia in the pathogenesis of gouty arthritis has not been fully defined. To appreciate the complexity of gout and its relationship to hyperuricemia consider the following facts:
Only 2% to 3% of adults develop gout, even though 10% of the total adult population has hyperuricemia, defined empirically as an elevation of uric acid concentration in blood over 7 mg/dL (0.41 mmol/L). There is a sex-related difference in uric acid metabolism, and thus the actual upper limit of normal is 7 mg/dL for females and 8 mg/dL for males.
Gout is much more common in men than in women. The male to female ratio for this disease is 9:1.The serum concentration of uric acid is lower in women than in men, but this explains only in part the considerably lower incidence of gout in women.
Although hyperuricemia does not always cause gout, it is associated with an increased risk of gouty arthritis: in persons with normal uric acid the risk of gout is 1% and in those with concentrations 2 to 3 mg/dL above the upper limit of normal, the risk rises 20% to 30%. In general terms, the higher the concentration of uric acid the higher is the risk of gout.
Uric acid concentration in blood depends on the balance between production and excretion of uric acid.
Uric acid is the end product of the degradation of adenine and guanine. The immediate metabolic precursor of uric acid is xanthine (Fig. 3-4). Xanthine may be produced directly from guanine or from hypoxanthine through the action of xanthine oxidoreductase. This enzyme has a dual function, acting as oxidase and dehydrogenase. It also transforms xanthine into uric acid. Although the breakdown of nucleic acids occurs in all tissues, uric acid is produced only in organs, such as the liver and the intestines, that contain xanthine oxidoreductase.
Figure 3-4 Formation of uric acid. Uric acid is formed from xanthine, and is the end product of the degradation of adenine and guanine. Note that inosinic acid forms from phospho-α-D-ribosylpyrophosphate (PRPP) under negative feedback control (dotted line), and that the overproduction of xanthine from hypoxanthine and guanine is regulated by hypoxanthine-guanine phosophoribosyltransferase (HGPRT) in the so-called salvage pathway.
Overproduction of xanthine is prevented by hypoxanthine-guanine phosphoribosyl transferase (HGPRT), the primary enzyme involved in the so-called salvage pathway, which replenishes the inosinic and guanylic acid pools. Inosinic acid may be converted into adenylic acid and guanylic acid, both of which have a negative feedback effect on the formation of inosinic acid from phospho-α-D-ribosylpyrophosphate (PRPP).
The body contains approximately 1800 mg of uric acid, one third of which is turned over daily. Approximately two thirds of all uric acid is derived from the degradation of the purines, adenine and guanine (Fig. 3-5). The remaining third is derived from the diet. Two thirds of uric acid is eliminated from the blood in urine, and the remaining third through the intestines.
Figure 3-5 Metabolism of purines. Purines are derived from food, are newly synthesized, or formed from DNA. Purines are metabolized into uric acid, which is excreted in the kidneys or the intestines. Deposition of uric acid crystals in tissue leads to gout.
Ionized uric acid binds to sodium, and in blood it is predominantly found in the form of monosodium urate. Under physiologic conditions monosodium urate is saturated at a concentration of 6.8 mg/dL (415 μmol/L), and at higher concentrations one would expect it to precipitate and form crystals. This, however, does not occur, because the blood contains some stabilizing substances that prevent such crystallization. The solubility of monosodium urate decreases at low temperature, which accounts for the deposition of urate crystals in the joint tissue of the big toe during attacks of gouty arthritis.
Uric acid is filtered in the glomeruli, but almost all of it entering the proximal tubule is reabsorbed. Uric acid is then secreted back into the tubules and again reabsorbed to a large extent, so that only 10% of the uric acid is finally excreted into the urine. One third of the blood uric acid is excreted into the lumen of the intestine, where it undergoes uricolysis by the normal intestinal flora.
Hyperuricemia can result from overproduction or underexcretion of uric acid. Excessive dietary intake of purines can play a role under both conditions. Furthermore, in some patients both overproduction and underexcretion of uric acid occur. Alcohol, one of the most common triggers of gouty arthritis, can stimulate overproduction and prevent excretion.
Overproduction of uric acid is found in an isolated form in only 10% of all patients with gout. The defect can be primary, as in some inborn errors of metabolism, or secondary, when the excessive production of purines is related to increased cell lysis or turnover.
Primary uric acid overproduction. The prototype of this condition is Lesch-Nyhan syndrome. This inborn error of purine metabolism related to the deficiency of HGPRT is a rare X-linked cause of primary hyperuricemia. The deficiency of HGPRT results in a dysfunction of the salvage pathway and an overproduction of uric acid and gout of early onset. Several other genetic diseases also produce hyperuricemia, but fortunately these conditions are rare.
Secondary hyperproduction of uric acid. Uric acid overproduction typically occurs in tumor lysis syndrome after chemotherapy. Chemotherapy-induced killing of tumor cells results in a release of purine and pyrimidines from damaged nuclei; purines are then metabolized into uric acid. Leukemia, lymphoma, and chronic hemolytic anemia also cause hyperuricemia. Chronic diseases characterized by epithelial proliferation—such as psoriasis or excessive bone formation, such as occurs in Paget’s disease of bones—are also associated with overproduction of uric acid.
Overproducers of uric acid excrete uric acid in the urine in excess of 750 to 1000 mg/day, which may lead to the formation of uric acid stones in the urinary system. Overproduction of uric acid should be suspected if the attack of gout occurs at an early age, if there is a family history of early onset of gout, or if the uric acid renal stones are the first clinical sign of hyperuricemia.
Chronic renal disease. Hyperuricemia occurs relatively late in the course of chronic renal failure, only after the disease has destroyed a significant number of nephrons. Patients who have polycystic kidney disease also cannot properly excrete uric acid in the urine.
Drugs. Hyperuricemia may be a side effect of treatment with diuretics, especially thiazides. Chronic ingestion of salicylates also may affect the tubular function and cause hyperuricemia. Levodopa and cyclosporine also cause hyperuricemia.
Patients who have hyperuricemia tend to form deposits of monosodium phosphate in the connective tissue capsule of joints. These aggregates, called microtophi, may then spontaneously release monosodium urate into the synovial fluid, or a larger bolus of it is released due to mechanical trauma. Crystals in the synovial fluid have an irritating effect on the synovium and also have a chemotactic effect on neutrophils, which enter the joint cavity, thus contributing to the inflammation. The crystals also become coated with complement and immunoglobulin from exudated plasma. Complement and immunoglobulin act as opsonins, thus enabling the neutrophils to phagocytize the crystals. Activated neutrophils also produce oxygen radicals, arachidonic acid derivatives, and cytokines, which stimulate inflammation, cause vasodilation, and increase vascular permeability. These events account for the redness of the joint and its swelling. Crystals ingested into the phagocytic vacuoles of neutrophils tend to pierce the lysosomes, thus allowing a discharge of lytic enzyme into the extracellular space. Once initiated, the inflammation is autocatalytic and self-sustained, lasting for several days until it slowly abates (Fig. 3-6).
Figure 3-6 Acute arthritis in gout. Crystals of monosodium urate initiate the inflammation and act as chemoattractants for neutrophils. Crystals are covered with immunoglobulin and complement C3, which serve as opsonins, facilitating the phagocytosis of crystals. Lytic enzymes released from phagocytic vacuoles contribute to inflammation.
Microscopic aggregates of monosodium urate crystals tend to enlarge with time until they transform into nodular masses visible by the naked eye or in radiographs in the periarticular bone. These nodules are called tophi (from the Latin word tophus, meaning porous stone). Most often they are found around the joints and the subchondral bone or subcutaneous tissue (Fig. 3-7). Typical locations are the metatarsophalangeal joint of the big toe, Achilles and infrapatellar tendons, the elbow and fingers, or the pinna of the ear. Tophi may form also in internal organs, such as the kidneys, but less commonly than in subcutaneous sites and around joints.
Tophi act as space-occupying lesions and may cause pain, deformities of joints, and chronic inflammation. Bulging tophi may ulcerate the skin, and those inside the bone may erode the bone and cause large defects.
Prolonged hyperuricemia may affect the function of renal tubules (urate nephropathy). Deposits of monosodium phosphates are found in the medulla, where they may cause tissue injury and predispose a person to secondary infection (pyelonephritis). Uric acid stones are formed in acid urine. The incidence of calcium phosphate stones is also increased.
Ethyl alcohol (ethanol) is present in all alcoholic beverages such as beer, wine, or hard liquor. At least 70% of adults in the United States drink alcoholic beverages occasionally, but only about 10% of those drink excessive amounts that could adversely affect health. Still, alcohol abuse is widespread, and probably 10 to 12 million Americans are chronic alcoholics. Alcohol-related health problems account for a significant number of hospital admissions, traffic accidents, family violence, and chronic professional disability.
Acute intoxication (drunkenness). Psychological and somatic consequences of alcohol overdose. Like intoxication with other psychotropic substances alcohol intoxication is characterized by a depression of the central nervous system (CNS). Depending on the amount of alcohol consumed CNS depression may manifest as sedation and drowsiness, loss of motor coordination, delirium, or loss of consciousness that may progress to lethal coma.
Alcohol abuse. A repetitive pattern of drinking that continues even though it has adverse effects in one or more of the following five spheres of life: marital, social, legal, occupational, or physical. The consensus opinion of a scientific panel of the American Psychiatric Association is that a diagnosis of alcohol abuse should be used only if the patient has been drinking excessively for more than a month and he or she does not meet the criteria for alcohol dependence.
Alcohol dependence. This term is used to describe uncontrollable alcohol intake associated with tolerance to the effects of alcohol and symptomatic withdrawal when alcohol is not available. The diagnosis is made if at least three of the criteria listed in Table 3-1 are met.
Modified from Greene HL, Fincher RM, Johnson WP (eds): Clinical Medicine, 2nd ed. St. Louis, Mosby, p. 748, 1996.
Alcohol acts on brain cells as a toxin. It changes the fluidity of cell membranes, affecting the transmission of neural impulses, thus causing depression of neural activity. Alcohol has a sedative effect on most neural centers, but the suppression of some centers may lead to a loss of inhibition of others. This may induce a feeling of relaxation or good mood, as well as increased motor activity or uncontrolled emotions. The effects are dose-dependent and can be predicted roughly from the blood alcohol concentration (Fig. 3-8) as follows:
Figure 3-8 Acute alcohol intoxication. The blood concentration depends on the amount of alcohol ingested. The approximate blood alcohol levels for a 70-kg man are shown, using a 120-mL wine glass as a unit. The average alcohol content of wine is 11–13 mg/dL, beer 4–6 mg/dL, and whiskey or other hard liquors 40–45 mg/dL. The alcohol is cleared from the body at the same rate irrespective of the type of drink that was ingested.
Blood alcohol concentration can be reliably predicted from the breath test, which is routinely used by law enforcement to check for alcohol intoxication in drivers. Most of the states define legal intoxication with alcohol as a blood alcohol level of 100 mg/dL (22 mmol/L) in a person driving a motor vehicle.
Alcohol is absorbed in the stomach and small intestine, from which it is transported into the liver. In liver cells alcohol is metabolized through the action of alcohol dehydrogenase in the cytosol, P450 cytochrome (CYP2E) in the smooth endoplasmic reticulum of the microsomal fraction, and catalase in peroxisomes (Fig. 3-9).
Figure 3-9 Three enzymes play a key function in the metabolism of alcohol in liver cells: alcohol dehydrogenase, CYP2E (cytochrome P450 enzyme in the smooth endoplasmic reticulum of the microsomal fraction), and catalase in peroxisomes. Alcohol dehydrogenase is the most important liver enzyme involved in oxidation of alcohol, transforming it into acetaldehyde, which is then oxidized to acetylcoenzyme A (CoA). Nicotine adenine dinucleotide (NAD+) is reduced to NADH in this process, as well as during the action of CYP2E, a toxic metabolite, which is in turn oxidized to acetyl CoA by aldehyde dehydrogenase.
Alcohol dehydrogenase is the most important liver enzyme involved in the oxidation of alcohol. It oxidizes alcohol into acetaldehyde, a toxic metabolite, which is in turn oxidized to acetyl coenzyme A by aldehyde dehydrogenase. Nicotine adenine dinucleotide (NAD+) is the cofactor for both oxidation reactions and in this process is reduced to NADH. An increased ratio of NADH to NAD+ inhibits the NAD+-dependent oxidation of lactate to pyruvate, leading to lactic acidosis. A lack of pyruvate may cause hypoglycemia, which is further exacerbated by poor intake of nutrients in chronic alcoholics. Beta oxidation of fatty acid is reduced and triglyceride formation enhanced, leading to fatty change in liver cells (Fig. 3-10). Hence, alcohol metabolism in the liver ultimately results in the formation of toxic products and metabolic disturbances affecting the function of liver cells. If these changes persist, fatty liver may progress into alcoholic steatohepatitis and finally into cirrhosis.