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First_Aid_Step2. Hx/PE: Presents with progressive jaundice, pruritus, and fatigue. Dx: is significantly associated with ■ Laboratory findings include ↑ alkaline phosphatase and ↑ bilirubin. ulcerative colitis. MRCP/ERCP show multiple bile duct strictures with dilatations between strictures. Liver biopsy reveals periductal sclerosis (“onion skinning”). Tx: High-dose ursodeoxycholic acid; endoscopic dilation and short-term stenting of bile duct strictures; liver transplantation. Patients are at ↑ risk for cholangiocarcinoma. Liver diseases can be divided into distinct patterns based on LFT results: Hepatocellular injury: ↑ AST and ALT. Cholestasis: ↑ alkaline phosphatase and bilirubin. Isolated hyperbilirubinemia: ↑ bilirubin; normal aminotransferases and alkaline phosphatase.


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First_Aid_Step2. Hepatocellular injury: ↑ AST and ALT. Cholestasis: ↑ alkaline phosphatase and bilirubin. Isolated hyperbilirubinemia: ↑ bilirubin; normal aminotransferases and alkaline phosphatase. Jaundice, which can be seen in any of the patterns outlined above, is a clinical sign that arises when excess bilirubin (> 2.5 mg/dL) is circulating in the blood. Figures 2.6-9 and 2.6-10 summarize the clinical approaches toward cholestasis and isolated hyperbilirubinemia. Hepatocellular injury is described in the section that follows. Inﬂammation of the liver leading to liver cell injury and necrosis. The causes of acute hepatitis include viruses (e.g., HAV, HBV, HCV, HDV, HEV) and drug-induced disease (e.g., alcohol, acetaminophen, INH, methyldopa). The Ductal dilation? FIGURE 2.6-9. Approach to cholestasis. HCV is Chronic. Eighty percent of patients with HCV infection will develop chronic hepatitis. An AST/ALT ratio > 2 suggests alcoholic hepatitis—you’re toASTed.


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First_Aid_Step2. HCV is Chronic. Eighty percent of patients with HCV infection will develop chronic hepatitis. An AST/ALT ratio > 2 suggests alcoholic hepatitis—you’re toASTed. causes of chronic hepatitis include viruses (e.g., HBV, HCV, HDV), alcoholic hepatitis, autoimmune hepatitis, ischemic hepatitis, and hereditary etiologies (e.g., Wilson’s disease, hemochromatosis, α1-antitrypsin deficiency). HAV and HEV are transmitted by the fecal-oral route. HBV and HCV are transmitted by bodily ﬂuids, although the risk of acquiring HCV sexually is very low. Acute hepatitis often starts with a viral prodrome of nonspecific symptoms (e.g., malaise, fever, joint pain, fatigue, URI symptoms, nausea, vomiting, changes in bowel habits) followed by jaundice and RUQ tenderness. Exam often reveals jaundice, scleral icterus, tender hepatomegaly, possible splenomegaly, and lymphadenopathy.


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First_Aid_Step2. Exam often reveals jaundice, scleral icterus, tender hepatomegaly, possible splenomegaly, and lymphadenopathy. Chronic hepatitis usually gives rise to symptoms indicative of chronic liver disease (jaundice, fatigue, hepatosplenomegaly). At least 80% of those infected with HCV and 10% of those with HBV will develop chronic hepatitis. Dramatically ↑ ALT and AST and ↑ bilirubin/alkaline phosphatase are present in the acute form. In chronic hepatitis, ALT and AST are ↑ for > 6 months with a concurrent ↑ in alkaline phosphatase/bilirubin and hypoalbuminemia. In severe cases, PT will be prolonged, as all clotting factors except factor VIII are produced by the liver. The diagnosis of viral hepatitis is made by hepatitis serology (see Table 2.6-8 and Figure 2.6-11 for a description and timing of serologic markers) and by liver biopsy in chronic or severe cases.


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First_Aid_Step2. The diagnosis of viral hepatitis is made by hepatitis serology (see Table 2.6-8 and Figure 2.6-11 for a description and timing of serologic markers) and by liver biopsy in chronic or severe cases. ANA, anti–smooth muscle antibody, and antimitochondrial antibody point to autoimmune hepatitis. Iron saturation (hemochromatosis) and ceruloplasmin (Wilson’s disease) can identify other causes. Treatment is etiology specific; monitor for resolution of symptoms over time. Steroids for severe alcoholic hepatitis. Immunosuppression with steroids and other agents (azathioprine) for autoimmune hepatitis. T AB LE 2.6-8. Key Hepatitis Serologic Markers


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First_Aid_Step2. Steroids for severe alcoholic hepatitis. Immunosuppression with steroids and other agents (azathioprine) for autoimmune hepatitis. T AB LE 2.6-8. Key Hepatitis Serologic Markers HBsAg Antigen found on the surface of HBV; continued presence indicates carrier state. HBsAb Antibody to HBsAg; provides immunity to HBV. HBcAg Antigen associated with core of HBV. HBcAb Antibody to HBcAg; during the window period. IgM HBcAb is an indicator of recent disease. HBeAg A second, different antigenic determinant in the HBV core. An important indicator of transmissibility (BEware!). IgM HAVAb IgM antibody to HAV; the best test to detect active hepatitis A. HBeAb Antibody to e antigen; indicates low transmissibility. IFN-α, lamivudine (3TC), or adefovir for chronic HBV infection; peginterferon and ribavirin for chronic HCV infection. Liver transplantation is the treatment of choice for patients with end-stage liver failure.


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First_Aid_Step2. Liver transplantation is the treatment of choice for patients with end-stage liver failure. ICU management and emergent transplant for fulminant hepatic failure. Important diagnostic tests Incubation Prodrome, The sequelae of chronic hepatitis include cirrhosis, liver failure, and hepatocellular carcinoma. Level of detection F IGU R E 2.6-1 1. Time course of hepatitis B with serologic markers. Alcoholism, chronic hepatitis, and other chronic liver diseases lead to cirrhosis. Gut, butt, and caput—the three anastomoses commonly seen in cirrhosis. Cirrhosis, liver failure, hepatocellular carcinoma (3–5%). Defined as f brosis and nodular regeneration resulting from hepatocellular injury. Etiologies include causes of chronic hepatitis, biliary tract disease (e.g., primary biliary cirrhosis, primary sclerosing cholangitis), right-sided heart failure, constrictive pericarditis, and Budd-Chiari syndrome (hepatic vein thrombosis 2° to hypercoagulability).


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First_Aid_Step2. Presents with jaundice, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy (e.g., asterixis, altered mental status), gastroesophageal varices, coagulopathy, and renal dysfunction. Weakness, anorexia, and weight loss are also seen in advanced disease. Exam may reveal an enlarged, palpable, or firm liver. Stigmata of portal hypertension and signs of liver failure may be present (see Figures 2.6-12 and 2.6-13). Lab studies show ↓ albumin, ↑ PT/PTT, and ↑ bilirubin. Anemia or thrombocytopenia (2° to hypersplenism) may also be seen. Abdominal ultrasound with Doppler can assess liver size, the presence of ascites, and the patency of splenic and hepatic veins. The etiology of ascites can be established through measurement of the serum-ascites albumin gradient (SAAG = serum albumin – ascites albumin); see Table 2.6-9. Obtain hepatitis serologies and autoimmune hepatitis studies.


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First_Aid_Step2. Obtain hepatitis serologies and autoimmune hepatitis studies. Serum ferritin, ceruloplasmin, and α1-antitrypsin may help identify additional causes, such as hemochromatosis, Wilson’s disease, and α1antitrypsin deficiency, respectively. Liver biopsy showing bridging fibrosis and nodular regeneration. Effects of portal hypertension Effects of liver cell failure Loss of sexual hair F IGU R E 2.6-1 2. Presentation of cirrhosis/portal hypertension. (Adapted, with permission, from Chandrasoma P, Taylor CE. Concise Pathology, 3rd ed. Stamford, CT: Appleton & Lange, 1998: 654.) Superior mesenteric v. Gastroesophageal vv. Superior-middle/inferior rectal vv. Gastrorenal-splenorenal vv. Paraumbilical v. IVC Systemic venousPortal venousPortal v. L. gastric v. Retro-peritoneal paravertebral v Splenic v. 1 2 3 4 5 v. F IGU R E 2.6-1 3. Portosystemic anastomoses. 1. Left gastric–azygos → esophageal varices. 2. Superior–middle/inferior rectal → hemorrhoids.


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First_Aid_Step2. F IGU R E 2.6-1 3. Portosystemic anastomoses. 1. Left gastric–azygos → esophageal varices. 2. Superior–middle/inferior rectal → hemorrhoids. 3. Paraumbilical–inferior epigastric → caput medusae (navel). 4. Gastrorenal-splenorenal. 5. Retroperitoneal paravertebral. Aimed at ameliorating the complications of cirrhosis/portal hypertension. Ascites: Sodium restriction and diuretics (furosemide and spironolactone). Noncirrhotic causes of Rule out infectious and neoplastic causes; perform paracentesis to ob- tain SAAG, cell count with differential, and cultures. If possible, treat underlying liver disease. right heart failure, splenic Spontaneous bacterial peritonitis: vein thrombosis, and Presents with fever, abdominal pain, and altered mental status. schistosomiasis. Check peritoneal ﬂuid if there is a possibility of infection. The ﬂ uid is if there are > 250 PMNs/mL or > 500 WBCs.


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First_Aid_Step2. schistosomiasis. Check peritoneal ﬂuid if there is a possibility of infection. The ﬂ uid is if there are > 250 PMNs/mL or > 500 WBCs. Treat with IV antibiotics (e.g., third-generation cephalosporin) to cover both gram-(Enterococcus) and gram-(E. coli, Klebsiella) organisms until a causative organism is identified. T AB LE 2.6-9. Serum-Ascites Albumin Gradient SAAG > 1.1 SAAG < 1.1 Ascites is due to protein leakage: ■Nephrotic syndrome ■Tuberculosis ■Malignancy (e.g., ovarian cancer) Ascites is related to portal hypertension: Presinusoidal: Splenic or portal vein thrombosis, schistosomiasis Sinusoidal: Cirrhosis, massive hepatic metastases Postsinusoidal: Right heart failure, constrictive pericarditis, Budd-Chiari syndrome Spontaneous bacterial peritonitis is diagnosed by > 250 PMNs/mL or > 500 WBCs in the ascitic ﬂ uid. Primary biliary cirrhosis is an autoimmune disease that presents with jaundice and pruritus in middle-aged women.


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First_Aid_Step2. Primary biliary cirrhosis is an autoimmune disease that presents with jaundice and pruritus in middle-aged women. Complications of hepatocellular carcinoma include GI bleeding, liver failure, and metastasis. Hepatorenal syndrome: A diagnosis of exclusion; difficult to treat and often requires dialysis. Hepatic encephalopathy: Due to ↓ clearance of ammonia. Often precipitated by dehydration, infection, electrolyte abnormalities, and GI bleeding. Treat with dietary protein restriction, lactulose, and rifaximin. Esophageal varices: Monitor for GI bleeding; treat medically (β-blockers, octreotide), endoscopically (band ligation), or surgically (portocaval shunt). Consider liver transplantation for patients with advanced disease. An autoimmune disorder characterized by destruction of intrahepatic bile ducts. The disease most commonly presents in middle-aged women with other autoimmune conditions.


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First_Aid_Step2. An autoimmune disorder characterized by destruction of intrahepatic bile ducts. The disease most commonly presents in middle-aged women with other autoimmune conditions. Hx/PE: Presents with progressive jaundice, pruritus, and malabsorption of the fat-soluble vitamins (A, D, E, K). Dx: Laboratory findings include ↑ alkaline phosphatase, ↑ bilirubin, antimitochondrial antibody, and ↑ cholesterol. Tx: Ursodeoxycholic acid (slows progression of disease); cholestyramine for pruritus; liver transplantation. One of the most common cancers worldwide despite its relatively low incidence in the United States. 1° risk factors for the development of hepatocellular carcinoma in the United States are cirrhosis and chronic hepatitis (HCV). In developing countries, af atoxins (in various food sources) and HBV infection are also major risk factors.


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First_Aid_Step2. Patients commonly present with RUQ tenderness, abdominal distention, and signs of chronic liver disease such as jaundice, easy bruisability, and coagulopathy. Cachexia and weakness may be present. Exam may reveal tender enlargement of the liver. Often suggested by the presence of a mass on ultrasound or CT as well as by abnormal LFTs and significantly elevated α-fetoprotein (AFP) levels. Liver biopsy for definitive diagnosis. For small tumors that are detected early, aggressive tumor resection or orthotopic liver transplantation may be successful. Chemotherapy and radiation are generally not effective, although they may be used to shrink large tumors prior to surgery (neoadjuvant therapy). Monitor tumor recurrence with serial AFP levels. Prevent exposure to hepatic carcinogens and vaccinate against hepatitis in high-risk individuals.


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First_Aid_Step2. Monitor tumor recurrence with serial AFP levels. Prevent exposure to hepatic carcinogens and vaccinate against hepatitis in high-risk individuals. Caused by hyperabsorption of iron with parenchymal hemosiderin accumulation in the liver, pancreas, heart, adrenals, testes, pituitary, and kidneys. It is an autosomal-recessive disease that usually occurs in males of northern European descent and is rarely recognized before the fifth decade. 2° hemochromatosis may occur with iron overload and is common in patients receiving chronic transfusion therapy (e.g., for α-thalassemia) as well as in alcoholics (alcohol ↑ iron absorption). Patients may present with abdominal pain or symptoms of DM, hypogonadism, arthropathy of the MCP joints, heart failure, or cirrhosis. Exam may reveal bronze skin pigmentation, pancreatic dysfunction, cardiac dysfunction (CHF), hepatomegaly, and testicular atrophy. ■↑ serum iron, percent saturation of iron, and ferritin with ↓ serum transferrin.


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First_Aid_Step2. ■↑ serum iron, percent saturation of iron, and ferritin with ↓ serum transferrin. Fasting transferrin saturation (serum iron divided by transferrin level) > 45% is the most sensitive diagnostic test. Glucose intolerance and mildly elevated AST and alkaline phosphatase can be present. Perform a liver biopsy (to determine hepatic iron index), hepatic MRI, or HFE gene mutation screen. Weekly phlebotomy; when serum iron levels ↓, perform maintenance phlebotomy every 2–4 months. Deferoxamine can be used for maintenance therapy. Cirrhosis, hepatocellular carcinoma, cardiomegaly leading to CHF and/or conduction defects, DM, impotence, arthropathy, hypopituitarism. ■↓ ceruloplasmin and excessive deposition of copper in the liver and brain due to a deficient copper-transporting protein. Linked to an autosomalrecessive defect on chromosome 13. Usually occurs in patients < 30 years of age; 50% of patients are symptomatic by age 15.


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First_Aid_Step2. Hx: Patients with present hemolytic anemia, liver abnormalities (jaundice 2° to hepatitis/cirrhosis), and neurologic (loss of coordination, tremor, dysphagia) as well as psychiatric (psychosis, anxiety, mania, depression) abnormalities. PE: May reveal Kayser-Fleischer rings in the cornea (green-to-brown deposits of copper in Descemet’s membrane) as well as jaundice, hepatomegaly, asterixis, choreiform movements, and rigidity. Dx: ↓ serum ceruloplasmin, ↑ urinary copper excretion, ↑ hepatic copper. Tx: Dietary copper restriction (avoid shellfish, liver, legumes), penicillamine (a copper chelator that ↑ urinary copper excretion; administer with pyridoxine), and possibly oral zinc (↑ fecal excretion). Wilson’s disease— ABCD Asterixis Basal ganglia deterioration Ceruloplasmin ↓, Cirrhosis, Copper ↑, Carcinoma (hepatocellular), Choreiform movements Dementia


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First_Aid_Step2. Wilson’s disease— ABCD Asterixis Basal ganglia deterioration Ceruloplasmin ↓, Cirrhosis, Copper ↑, Carcinoma (hepatocellular), Choreiform movements Dementia Table 2.6-10 outlines the important features of acute and chronic pancreatitis. Table 2.6-11 lists Ranson’s criteria for predicting mortality associated with acute pancreatitis. T AB LE 2.6-1 0. Features of Acute and Chronic Pancreatitis Treatment Prognosis Complications Can have chronic pain and pancreatic exocrine and endocrine dysfunction. Chronic pain, malnutrition/weight loss, pancreatic cancer.


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First_Aid_Step2. Pathophysiology Leakage of pancreatic enzymes into pancreatic and peripancreatic tissue, often 2° to gallstone disease or alcoholism. Irreversible parenchymal destruction leading to pancreatic dysfunction. Time course Abrupt onset of severe pain. Persistent, recurrent episodes of severe pain. Risk factors Gallstones, alcoholism, hypercalcemia, hypertriglyceridemia, trauma, drug side effects (thiazide diuretics), viral infections, post-ERCP, scorpion bites. Alcoholism (90%), gallstones, hyperparathyroidism, hypercholesterolemia, cystic f brosis. May also be idiopathic. History/PE Severe epigastric pain (radiating to the back); nausea, vomiting, weakness, fever, shock. Flank discoloration (Grey Turner’s sign) and periumbilical discoloration (Cullen’s sign) may be evident on exam. Recurrent episodes of persistent epigastric pain; anorexia, nausea, constipation, f atulence, steatorrhea, weight loss, DM. Diagnosis ↑ amylase, ↑ lipase, ↓ calcium if severe; “sentinel ↑ or normal amylase and


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First_Aid_Step2. episodes of persistent epigastric pain; anorexia, nausea, constipation, f atulence, steatorrhea, weight loss, DM. Diagnosis ↑ amylase, ↑ lipase, ↓ calcium if severe; “sentinel ↑ or normal amylase and lipase, ↓ stool elastase, Removal of the offending agent if possible. Standard supportive measures: IV f uids/electrolyte replacement, analgesia, bowel rest, NG suction, nutritional support, O2, “tincture of time.” IV antibiotics, respiratory support, and surgical debridement if necrotizing pancreatitis is present.


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First_Aid_Step2. loop” or “colon cutoff sign” on AXR. Abdominal ultrasound or CT may show an enlarged pancreas with stranding, abscess, hemorrhage, necrosis, or pseudocyst. Roughly 85–90% are mild and self-limited; 10– 15% are severe, requiring ICU admission. Mortality may approach 50% in severe cases. Pancreatic pseudocyst, fistula formation, hypocalcemia, renal failure, pleural effusion, chronic pancreatitis, sepsis. Mortality 2° to acute pancreatitis can be predicted with Ranson’s criteria (see Table 2.6-11). glycosuria, pancreatic calcifications, and mild ileus on AXR and CT (“chain of lakes”). Analgesia, exogenous lipase/trypsin and medium-chain fatty-acid diet, avoidance of causative agents (EtOH), celiac nerve block, surgery for intractable pain or structural causes. TABLE 2.6-11. Ranson’s Criteria for Acute Pancreatitisa a The risk of mortality is 20% with 3–4 signs, 40% with 5–6 signs, and 100% with ≥ 7 signs.


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First_Aid_Step2. TABLE 2.6-11. Ranson’s Criteria for Acute Pancreatitisa a The risk of mortality is 20% with 3–4 signs, 40% with 5–6 signs, and 100% with ≥ 7 signs. Roughly 75% are adenocarcinomas in the head of the pancreas. Risk factors include smoking, chronic pancreatitis, a first-degree relative with pancreatic cancer, and a high-fat diet. Incidence rises after age 45; slightly more common in men. Presents with abdominal pain radiating toward the back, as well as with obstructive jaundice, loss of appetite, nausea, vomiting, weight loss, weakness, fatigue, and indigestion. Often asymptomatic, and thus presents late in the disease course. Exam may reveal a palpable, nontender gallbladder (Courvoisier’s sign) or migratory thrombophlebitis (Trousseau’s sign). Use CT to detect a pancreatic mass, dilated pancreatic and bile ducts, the extent of vascular involvement (particularly the SMA, SMV, and portal vein), and metastases (hepatic).


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First_Aid_Step2. Use CT to detect a pancreatic mass, dilated pancreatic and bile ducts, the extent of vascular involvement (particularly the SMA, SMV, and portal vein), and metastases (hepatic). If a mass is not visualized, use ERCP or endoscopic ultrasound for better visualization. CA-19-9 is often elevated, but this measure lacks sensitivity and specificity. Most patients present with metastatic disease, and treatment is palliative. Some 10–20% of pancreatic head tumors have no evidence of metastasis or major vessel involvement and may be resected using the Whipple procedure (pancreaticoduodenectomy). Chemotherapy with 5-FU and gemcitabine may improve short-term survival, but long-term prognosis is poor (5–10% five-year survival). The classic presentation of pancreatic cancer is painless, progressive obstructive jaundice. Neutropenia 210 Eosinophilia 211 Transplant Medicine 212 Diseases Associated with Neoplasms 213


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First_Aid_Step2. The classic presentation of pancreatic cancer is painless, progressive obstructive jaundice. Neutropenia 210 Eosinophilia 211 Transplant Medicine 212 Diseases Associated with Neoplasms 213 Bleeding disorders due to platelet dysfunction usually manifest as petechiae, whereas disorders of coagulation factors cause other symptoms, such as hemarthroses. Hemostasis requires the interaction of blood vessels, platelets, monocytes, and coagulation factors. This activates the clotting cascade, as shown in Figure 2.7-1. Heparin: ↑ PTT, activates antithrombin III and affects the intrinsic pathway, and ↓ fibrinogen levels; protamine sulfate is the antidote. Warfarin: ↑ PT, inhibits vitamin K and affects the extrinsic pathway, and is teratogenic, since its small size allows it to cross the placenta. Vitamin K is the antidote. Goal INR of 2.0–3.0 (2.5–3.5 in patients with mechanical valves).


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First_Aid_Step2. Enoxaparin (low-molecular-weight heparin [LMWH]): Inhibits factor Xa and does not have to be monitored; dosing is once or twice daily. Heparin-to-warfarin conversion is necessary because warfarin inhibits proteins C and S before other vitamin K–dependent factors (II, VII, IX, and X), leading to a transient period of paradoxical hypercoagulability before proper anticoagulation. Intrinsic pathway—measured by PTT (initiated by exposure of collagen following vascular trauma) Hemophilia B is characterized by factor IX deficiency. 2 Hemophilia A is characterized by factor VIII deficiency. 3 Thrombin is inactivated by antithrombin III. The rate of inactivation increases in the presence of heparin. * Vitamin K–dependent clotting factors (II, VII, IX, X). Their synthesis is inhibited by warfarin. FIGURE 2.7-1. Coagulation cascade.


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First_Aid_Step2. * Vitamin K–dependent clotting factors (II, VII, IX, X). Their synthesis is inhibited by warfarin. FIGURE 2.7-1. Coagulation cascade. A defciency of a clotting factor that leads to a bleeding diathesis. Subtypes are distinguished on the basis of which factor is lacking (see Table 2.7-1). The condition is usually hereditary but may be acquired through the development of an antibody to a clotting factor. This may occur in patients with autoimmune or lymphoproliferative disease, postpartum, or following a blood transfusion. Patients are nearly always male and may have a family history. Presents with spontaneous hemorrhage into the tissues and joints that, if left untreated, can lead to arthropathy and joint destruction. Spontaneous intracerebral hemorrhages, renal and retroperitoneal bleeding, and GI bleeding may also be seen. Mild cases may have major hemorrhage after surgery or trauma but are otherwise asymptomatic. Evaluate for suspected clotting factor def ciency:


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First_Aid_Step2. Mild cases may have major hemorrhage after surgery or trauma but are otherwise asymptomatic. Evaluate for suspected clotting factor def ciency: PT: Usually normal, but isolated elevations are seen in congenital factor VII deficiency. aPTT: Prolonged (the more prolonged, the more severe the hemophilia). Thrombin time, fbrinogen, bleeding time: Usually normal. Conduct a mixing study: Mix the patient’s plasma with normal plasma; if this corrects the aPTT, a factor deficiency is likely. If the aPTT does not correct, the patient may have a clotting factor inhibitor. Obtain factor assays: Specific factor assays should then be performed for factors VII, VIII, IX, XI, and XII. Hemophilia is characterized according to factor level as follows: Mild: > 5% of normal. Moderate: 1–3% of normal. Severe: ≤ 1% of normal.


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First_Aid_Step2. Mild: > 5% of normal. Moderate: 1–3% of normal. Severe: ≤ 1% of normal. ■Treat bleeding episodes with immediate transfusion of clotting factors (or cryoprecipitate) to at least 40% of normal concentration. Factor VIII has a half-life of 12 hours, so patients should be dosed BID to maintain ad- TABLE 2.7-1. Types of Hemophilia The classic case of hemophilia is the boy (X-linked) from the Imperial Russian family (Recessive) who presents with hemarthroses following minimal or no trauma. Cryoprecipitate consists of factors VIII and XIII, vWF, fibrinogen, and fibronectin. Hemophilia B (factor IX defciency) (9%) X-linked inheritance. Hemophilia C (factor XI defciency) (< 1%) Most common in Ashkenazi Jews. Hemophilia A (factor VIII defciency) (90%) X-linked inheritance; the most common severe congenital clotting def ciency. Factor VII defciency (< 1%) Presents in a milder, likely heterozygous form. DDAVP helps the body release extra factor VIII.


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First_Aid_Step2. DDAVP helps the body release extra factor VIII. ASA ↑ the risk of bleeding in patients with von Willebrand’s disease. Ristocetin cofactor assay measures the ability of vWF to agglutinate platelets in vitro in the presence of ristocetin. Suspect pulmonary embolism in a patient with rapid onset of hypoxia, hypercapnia, tachycardia, and an ↑ alveolar-arterial oxygen gradient without another obvious explanation. equate levels. Factor IX has a half-life of 24 hours, so daily transfusion is needed. The length of treatment varies with the lesion, extending up to several weeks after orthopedic surgery. Mild hemophiliacs may be treated with desmopressin (DDAVP); if so, they should be f uid restricted to prevent the side effect of hyponatremia. It may be necessary to transfuse RBCs, depending on the degree of blood loss.


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First_Aid_Step2. It may be necessary to transfuse RBCs, depending on the degree of blood loss. Fifteen percent of patients who are treated for hemophilia A develop neutralizing IgG antibodies to factor VIII, which precludes further treatment with replacement factor. An autosomal-dominant condition in which patients have deficient or defective von Willebrand’s factor (vWF) with low levels of factor VIII, which is carried by vWF. Symptoms are due to platelet dysfunction and to deficient factor VIII. The disease is milder than hemophilia. vWD is the most common inherited bleeding disorder (1% of the population is affected). Presents with easy bruising, mucosal bleeding (e.g., epistaxis, oral bleeding), menorrhagia, and postincisional bleeding. Platelet dysfunction is not severe enough to produce petechiae. Symptoms worsen with ASA use. Look for a family history of bleeding disorders. Platelet count and PT are normal, but a prolonged aPTT may be seen as a result of factor VIII deficiency.


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First_Aid_Step2. Look for a family history of bleeding disorders. Platelet count and PT are normal, but a prolonged aPTT may be seen as a result of factor VIII deficiency. A ristocetin cofactor assay of patient plasma can measure the capacity of vWF to agglutinate platelets. Bleeding episodes can be treated with DDAVP; menorrhagia can be controlled with OCPs. Avoid ASA and other inhibitors of platelet function. Also called thrombophilias or prothrombotic states, hypercoagulable states is an all-inclusive term describing conditions that ↑ a patient’s risk of developing thromboembolic disease. Causes are multiple and may be genetic, acquired, or physiologic (see Table 2.7-2). Acquired causes are usually 2° to an underlying clinical condition, disease process, or lifestyle. Inherited causes are collectively called hereditary thrombotic disease, of which factor V Leiden (a polymorphism in factor V, rendering it resistant to inactivity by activated protein C, or APC) is the most common.


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First_Aid_Step2. ■ Presents with recurrent thrombotic complications, including DVT, pulmonary embolism, arterial thrombosis, MI, and stroke. Women may have recurrent miscarriages. T AB LE 2.7 -2. Causes of Hypercoagulable States ■Although patients may have no recognizable predisposing factors, they usually have one or more of the causative factors outlined in Table 2.7-2. They may also have a family history. Under ideal circumstances, patients should be diagnosed before they are symptomatic, but this rarely occurs. Prior to workup for hereditary causes, acquired causes of abnormal coagulation values should be ruled out. Confrmation of a hereditary abnormality requires two abnormal values that are obtained while the patient is asymptomatic and untreated, with similar values obtained in two other family members.


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First_Aid_Step2. Workup for hypercoagulability includes lupus antigen/antiphospholipid syndrome, antithrombin III deficiency, protein C and S deficiencies, APC resistance, homocysteine elevation, and prothrombin G20210A mutation. Treatment should address the type of thrombotic event as well as the area of thrombosis. Treat DVT and pulmonary embolism with heparin (unfractionated or LMWH) followed by 3–6 months of oral warfarin anticoagulation for the first event, 6–12 months for the second, and lifelong anticoagulation for subsequent events. Heparin-to-warfarin conversion is necessary (see the “Coagulation Cascade” discussion above). A common disorder among hospitalized patients, second only to liver disease as a cause of acquired coagulopathy. It is caused by deposition of f brin in small blood vessels, leading to thrombosis and end-organ damage. Depletion of clotting factors and platelets leads to a bleeding diathesis. May be associated with almost any severe illness.


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First_Aid_Step2. ■Disorders commonly associated with DIC include obstetric complications, infections with septicemia, neoplasms, acute promyelocytic leukemia, pan- DIC is characterized by both thrombosis and hemorrhage. Petechiae suggest Platelet deficiency. Bleeding into body Cavities or joints suggests Clotting factor deficiency. The three causes of microangiopathic hemolytic anemia are HUS, TTP, and DIC. creatitis, intravascular hemolysis, vascular disorders (e.g., aortic aneurysm), massive tissue injury and trauma, drug reactions, acidosis, and ARDS. ■Presentation varies according to whether the disease is acute or chronic: Acute: Presents with generalized bleeding out of venipuncture sites into organs, with ecchymoses and petechiae. Patients who are in shock may have acral cyanosis. Chronic: Presents with bruising and mucosal bleeding, thrombophlebitis, renal dysfunction, and transient neurologic syndromes. Diagnosed as outlined in Table 2.7-3.


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First_Aid_Step2. Chronic: Presents with bruising and mucosal bleeding, thrombophlebitis, renal dysfunction, and transient neurologic syndromes. Diagnosed as outlined in Table 2.7-3. DIC may be confused with severe liver disease, but unlike liver disease, factor VIII is depressed. Treatment of the underlying illness often results in spontaneous reversal. Patients often require RBC transfusion and shock management. Platelets should be transfused in the event of hemorrhage with a platelet count < 20,000. Part of a spectrum of diseases that includes hemolytic-uremic syndrome (HUS) and HELLP syndrome (see the Obstetrics chapter); thought to be due to platelet microthrombi that block off small blood vessels, leading to end-organ ischemia and dysfunction. RBCs are fragmented by contact with the microthrombi, leading to hemolysis (microangiopathic hemolytic anemia). The cause of initial microthrombus formation is unknown but may be infectious (bacterial toxins), drug related, autoimmune, or idiopathic.


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First_Aid_Step2. A clinical syndrome characterized by f ve signs/symptoms: low platelet count, microangiopathic hemolytic anemia, neurologic changes (delirium, seizure, stroke), impaired renal function, and fever. Diagnosis is largely clinical. It is rare for all signs to be present, but the presence of schistocytes (broken RBCs) on peripheral smear with low platelets and rising creatinine is highly suggestive. Nucleated RBCs are also often seen in the peripheral smear. Hemolytic anemia labs include elevated indirect bilirubin, LDH, and AST along with low haptoglobin. Coagulation factors are normal. TABLE 2.7-3. Laboratory Values in DIC Overlapping conditions are HUS, HELLP syndrome, and DIC. HUS: Characterized by renal failure, hemolytic anemia, and low platelets. Severe elevations in creatinine are more typical of HUS than of TTP. HELLP syndrome: Affects pregnant women, often occurring in conjunction with preeclampsia (see the Obstetrics chapter).


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First_Aid_Step2. HELLP syndrome: Affects pregnant women, often occurring in conjunction with preeclampsia (see the Obstetrics chapter). DIC: Distinguished from TTP by prolonged PT and aPTT. Treat with corticosteroids to ↓ the formation of microthrombi along with plasma replacement and plasmapheresis (the mainstay of severe cases). Rarely, splenectomy is performed with mixed results. Platelet transfusions are contraindicated. A relatively common cause of thrombocytopenia. IgG antibodies are formed against the patient’s platelets. Bone marrow production of platelets is ↑, with ↑ megakaryocytes in the marrow. The most common immunologic disorder in women of childbearing age. May be acute or chronic. Patients often feel well and present with no systemic symptoms. They may have minor bleeding, easy bruising, petechiae, hematuria, hematemesis, or melena. Bleeding is mucocutaneous. Usually there is no splenomegaly.


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First_Aid_Step2. ITP is associated with a range of conditions, including lymphoma, leukemia, SLE, HIV, and HCV. The clinical presentation is as follows: Acute: Abrupt onset of hemorrhagic complications following a viral illness. Commonly affects children 2–6 years of age, with males and females affected equally. Chronic: Insidious onset that is unrelated to infection. Most often affects adults 20–40 years of age; women are three times more likely to be affected than men. A diagnosis of exclusion, as the test for platelet-associated antibodies is a poor one. Once other causes of thrombocytopenia have been ruled out, a diagnosis can be made on the basis of the history and physical, a CBC, and a peripheral blood smear showing normal RBC morphology. Most patients do not require bone marrow biopsy, which would show ↑ megakaryocytes as the only abnormality. Most patients with acute childhood ITP spontaneously remit, but this is rarely the case in chronic ITP.


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First_Aid_Step2. Most patients with acute childhood ITP spontaneously remit, but this is rarely the case in chronic ITP. Treatment is reserved for patients with symptomatic bleeding. Those with platelet counts > 20,000 are generally asymptomatic. Platelet transfusions are of no benefit, as patients’ IgG levels will also lead to destruction of platelets. The main therapies are corticosteroids, high-dose gamma globulin (IVIG), and splenectomy. Most patients respond to corticosteroids, but if Anti-D (Rh) immunoglobulin and rituximab are emerging therapies for ITP. Anti-D (Rh) immunoglobulin and IVIG act as “decoys” so that WBCs will recognize them they cannot be tapered after 3–6 months, splenectomy should be considered. An emerging therapy is anti-D (Rh) immunoglobulin, which binds to RBCs so that they are destroyed instead of the patient’s platelets. Patients will have a drop in their hematocrit. Rhand splenectomized patients should not receive this treatment.


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First_Aid_Step2. In pregnant patients, severe thrombocytopenia may occur in the fetus. instead of IgG on platelets. Figure 2.7-2 illustrates the various blood cell categories and lineages. Anemia is a disorder of low hematocrit and hemoglobin. There are several subtypes, which are classified according to red cell morphology (MCV, RDW, color, shape) and reticulocyte count (see Figure 2.7-3). Once anemia has been diagnosed by a low hemoglobin/hematocrit, the approach starts with the MCV. An MCV < 80 fL indicates microcytic anemia; between 80 fL and 100 fL is normocytic; and > 100 fL is macrocytic. A condition in which iron loss exceeds intake. May occur when dietary intake is insuff cient for the patient’s needs (e.g., when needs are ↑ by growth or pregnancy) or in the setting of chronic blood loss, usually 2° to menstruation or GI bleeding. Toddlers, adolescent girls, and women of childbearing age are most commonly affected. F IGU R E 2.7 -2. Blood cell differentiation. CBC, reticulocyte count


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First_Aid_Step2. F IGU R E 2.7 -2. Blood cell differentiation. CBC, reticulocyte count Retic < 2.5 Retic > 2.5 Iron deficiency anemia in an elderly patient could be due to colorectal cancer and needs to be evaluated to rule out malignancy. Iron deficiency anemia can be due to a hookworm infection. FIGURE 2.7-3. Anemia algorithm. Symptoms include fatigue, weakness, brittle nails, and pica. If the anemia develops slowly, patients are generally asymptomatic. Physical findings include glossitis, angular cheilitis, and koilonychia (“spoon nails”). Bone marrow biopsy looking for evidence of iron stores is the gold standard but is seldom performed. Iron deficiency is often confused with anemia of chronic disease, in which iron use by the body is impaired. Labs can help differentiate the two conditions (see Table 2.7-4). Peripheral blood smear shows hypochromic and microcytic RBCs with a low reticulocyte count.


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First_Aid_Step2. Peripheral blood smear shows hypochromic and microcytic RBCs with a low reticulocyte count. Low serum ferritin reﬂects low body stores of iron and confirms the diagnosis. However, ferritin is also an acute-phase reactant and may thus obscure evidence of iron deficiency. Treat with replacement iron for 4–6 months. Oral iron sulfate may lead to nausea, constipation, diarrhea, and abdominal pain. Antacids may interfere with iron absorption. If necessary, IV iron dextran can be administered but is associated with a 10% risk of serious side effects, including anaphylaxis. Hence, this is usually done only by a hematologist. T AB LE 2.7 -4. Iron Defciency Anemia vs. Anemia of Chronic Disease Most macrocytic anemias are caused by processes that interfere with normal DNA synthesis and replication. B12 deficiency can be due to infection by a tapeworm, Diphyllobothrium latum.


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First_Aid_Step2. Most macrocytic anemias are caused by processes that interfere with normal DNA synthesis and replication. B12 deficiency can be due to infection by a tapeworm, Diphyllobothrium latum. Causes of oxidative stress in G6PD deficiency include infection, metabolic acidosis, fava beans, antimalarials, dapsone, sulfonamides, and nitrofurantoin. Vitamin B12 (cobalamin) and folate def ciency interfere with DNA synthesis, leading to a delay in blood cell maturation. Cobalamin deficiency is due to malabsorption, usually from pernicious anemia (destruction of parietal cells, which produce the intrinsic factor needed for cobalamin absorption). Folate deficiency results from insufficient dietary folate, malabsorption, alcoholism, or use of certain drugs. Drugs that interfere with DNA synthesis, including many chemotherapeutic agents, may lead to megaloblastic anemia. Presents with fatigue, pallor, diarrhea, loss of appetite, headaches, and tingling/numbness of the hands and feet.


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First_Aid_Step2. Presents with fatigue, pallor, diarrhea, loss of appetite, headaches, and tingling/numbness of the hands and feet. Cobalamin deficiency affects the nervous system, so patients lacking that vitamin may develop a demyelinating disorder and may present with symptoms of motor, sensory, autonomic, and/or neuropsychiatric dysfunction, known as subacute combined degeneration of the cord. Peripheral smear shows RBCs with an elevated MCV. Hypersegmented (> 5) granulocytes can also be seen. Bone marrow sample reveals giant neutrophils and hypersegmented mature granulocytes. The Schilling test (ingestion of radiolabeled cobalamin both with and without added intrinsic factor) is classic for measuring absorption of cobalamin but is rarely performed. Serum vitamin levels are poorly diagnostic of deficiencies and are thus used with adjunctive tests, including methylmalonic acid (MMA) and homocysteine levels: B12 def ciency: Elevated MMA and homocysteine.


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First_Aid_Step2. B12 def ciency: Elevated MMA and homocysteine. Folate def ciency: Normal MMA; elevated homocysteine. Address the cause of the anemia, and correct the underlying cause. Occurs when bone marrow production is unable to compensate for ↑ destruction of circulating blood cells. Etiologies include the following: G6PD def ciency: An X-linked recessive disease that ↑ RBC sensitivity to oxidative stress. Paroxysmal nocturnal hemoglobinuria: A disorder in which blood cell sensitivity to complement activation is ↑. Hereditary spherocytosis: An abnormality of the RBC membrane. Autoimmune RBC destruction: Occurs 2º to EBV infection, mycoplasmal infection, CLL, rheumatoid disease, or medications. Sickle cell disease: A recessive β-globin mutation (see the following section). Microangiopathic hemolytic anemia: TTP, HUS, DIC. Mechanical hemolysis: Associated with mechanical heart valves. Other: Malaria, hypersplenism. Presents with pallor, fatigue, tachycardia, and tachypnea.


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First_Aid_Step2. Mechanical hemolysis: Associated with mechanical heart valves. Other: Malaria, hypersplenism. Presents with pallor, fatigue, tachycardia, and tachypnea. Patients are typically jaundiced, with low haptoglobin and elevated indirect bilirubin and LDH. Urine is dark with hemoglobinuria, and there is ↑ excretion of urinary and fecal urobilinogen. Reticulocyte count is elevated. Diagnosed by the history and clinical presentation. High LDH, elevated indirect bilirubin, and ↓ haptoglobin levels are consistent with a diagnosis of hemolytic anemia. Also obtain a reticulocyte count. A Coombs’ test is used to detect autoimmune hemolysis. Treatment varies with the cause of hemolysis but typically includes corticosteroids to address immunologic causes and iron supplementation to replace urinary losses. Splenectomy may be helpful, and transfusion may be necessary to treat severe anemia.


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First_Aid_Step2. A rare condition caused by failure of blood cell production due to destruction of bone marrow cells. It may be hereditary, as in Fanconi’s anemia; may have an autoimmune or a viral etiology (e.g., HIV, parvovirus B19); or may result from exposure to toxins (e.g., drugs, cleaning solvents) or radiation. Patients are typically pancytopenic, with symptoms resulting from a lack of RBCs, WBCs, and platelets—e.g., pallor, weakness, a tendency to infection, petechiae, bruising, and bleeding. The disease may be of sudden or sustained onset and may be of variable severity, depending on the patient’s blood counts. Diagnosed by clinical presentation and CBC; verifed by a bone marrow biopsy revealing hypocellularity and space occupied by fat. The differential includes megaloblastic anemia, as both diseases feature an elevated MCV. The classic case of G6PD deficiency is an African-American male soldier in Vietnam who took quinine.


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First_Aid_Step2. The differential includes megaloblastic anemia, as both diseases feature an elevated MCV. The classic case of G6PD deficiency is an African-American male soldier in Vietnam who took quinine. Indirect Coombs’ tests detect antibodies to RBCs in the patient’s serum. Direct Coombs’ tests detect sensitized erythrocytes. Patients with Fanconi’s anemia may be identified on physical exam by café au lait spots, short stature, and radial/thumb hypoplasia/ aplasia. SCD represents a qualitative defect in the β-globin chain. Patients with SCD classically get osteomyelitis with Salmonella. They are also at ↑ risk of avascular necrosis of the hip. Blood transfusion and stem cell transplantation to replace absent cells; immunosuppression with cyclosporin A and antithymocyte globulin to prevent autoimmune destruction of marrow. Infections are a major cause of mortality and should be treated aggressively.


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First_Aid_Step2. An autosomal-recessive disorder most commonly caused by a mutation of adult hemoglobin (the β chain has glu replaced by val). Signs and symptoms are due to ↓ red cell survival and a tendency of sickled cells to lead to vasoocclusion. Asymptomatic during the first year or two of life; may first present with dactylitis in childhood. Later, hemolysis results in anemia, jaundice, cholelithiasis, ↑ cardiac output (murmur and cardiomegaly), and delayed growth. Vaso-occlusion leads to ischemic organ damage, especially splenic infarction, which predisposes to pneumococcal sepsis, and acute chest syndrome (pneumonia and/or pulmonary infarction). Patients also experience painful crises of unknown etiology. Common triggers for a vaso-occlusive crisis (VOC) include cold temperatures, dehydration, and infection.


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First_Aid_Step2. Other potential complications include splenic sequestration, which occurs in patients who have not infarcted their spleens, and aplastic crisis, which is usually 2° to infection with parvovirus B19. The sickle cell screen is based on a blood smear with sickle cells and target cells. The gold standard is quantitative hemoglobin electrophoresis. Treat with hydroxyurea, which stimulates the production of fetal hemoglobin (hydroxyurea is teratogenic, so it is contraindicated in pregnancy). If hydroxyurea does not prove effective, chronic transfusion therapy, which carries the risk of iron overload, can be tried. Treat cholelithiasis with cholecystectomy. VOCs must be treated with adequate pain management, O2 therapy, IV ﬂuid rehydration, and antibiotics (if infection is suspected to be the trigger).


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First_Aid_Step2. Treat cholelithiasis with cholecystectomy. VOCs must be treated with adequate pain management, O2 therapy, IV ﬂuid rehydration, and antibiotics (if infection is suspected to be the trigger). To prevent VOCs from progressing to acute chest syndrome, initiate aggressive hydration and incentive spirometry, and keep the sickle variant < 40%. This can be done with simple transfusions or, if necessary, exchange transfusion in an ICU setting. Hereditary disorders involving ↓ or absent production of normal globin chains of hemoglobin. α-thalassemia is caused by a mutation of one or more of the four genes for α-hemoglobin; β-thalassemia results from a mutation of one or both of the two genes for β-hemoglobin. Thalassemia is most common among people of African, Middle Eastern, and Asian descent. Disease presentation and prognosis vary with the number of genes missing (see Table 2.7-5).


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First_Aid_Step2. Thalassemia is most common among people of African, Middle Eastern, and Asian descent. Disease presentation and prognosis vary with the number of genes missing (see Table 2.7-5). Diagnosed by hemoglobin electrophoresis evaluation (but note that this is normal in α-thalassemia) and DNA studies. Most patients do not require treatment, but those with β-thalassemia major and hemoglobin H disease are commonly transfusion dependent and should be given iron chelators (deferoxamine) to prevent overload. Erythrocytosis (an abnormal elevation of hematocrit) may be either 1° (due to ↑ RBC production) or 2° (due to ↓ plasma volume and hemoconcentration).


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First_Aid_Step2. Erythrocytosis (an abnormal elevation of hematocrit) may be either 1° (due to ↑ RBC production) or 2° (due to ↓ plasma volume and hemoconcentration). T AB LE 2.7 -5. Differential Diagnosis of Thalassemias β-thalassemia major 0/2 β Patients develop severe microcytic anemia in the frst year of life and need chronic transfusions or marrow transplant to survive. β-thalassemia minor 1/2 β Patients are asymptomatic, but their cells are microcytic and hypochromic on peripheral smear. Hydrops fetalis 0/4 α Patients die in utero. Hemoglobin H disease 1/4 α Patients have severe hypochromic, microcytic anemia with chronic hemolysis, splenomegaly, jaundice, and cholelithiasis. The reticulocyte count elevates to compensate, and one-third of patients have skeletal changes due to expanded erythropoiesis. α-thalassemia trait 2/4 α Patients have low MCV but are usually asymptomatic. Silent carrier 3/4 α Patients have no signs or symptoms of disease.


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First_Aid_Step2. True polycythemia vera is characterized by a high red cell mass. Premedication with acetaminophen and diphenhydramine is sometimes used to prevent transfusion reactions. Hemoglobinuria in hemolytic transfusion reaction may lead to acute tubular necrosis and subsequent renal failure. Characterized by ↑ hematocrit, ↓ tissue blood ﬂow and oxygenation, and ↑ cardiac work. Patients present with “hyperviscosity syndrome,” which consists of easy bleeding/bruising, blurred vision, neurologic abnormalities, plethora, pruritus (especially after a warm bath), hepatomegaly, splenomegaly, and CHF. 1° erythrocytosis is associated with hypoxia (from lung disease, smoking, high altitudes, or a poor intrauterine environment), neoplasia (erythropoietin-producing tumors), or polycythemia vera (PCV), in which there is clonal proliferation of a pluripotent marrow stem cell. 2° erythrocytosis is associated with excessive diuresis, severe gastroenteritis, and burns.


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First_Aid_Step2. 2° erythrocytosis is associated with excessive diuresis, severe gastroenteritis, and burns. Erythrocytosis is diagnosed clinically and by cell counts, with ABGs used to assess hypoxia or imaging to demonstrate neoplasia. Patients with PCV have excess RBCs, WBCs, and platelets. Levels of erythropoietin may be useful in distinguishing PCV, in which levels are low, from other causes of polycythemia. Phlebotomy relieves symptoms of erythrocytosis, but treatment should also address the underlying cause. PCV can be treated with cytoreductive drugs such as hydroxyurea or interferon. Because PCV is prothrombotic, ASA should also be used. With treatment, survival is 7–10 years. Blood transfusion is generally safe but may result in a variety of adverse reactions. Nonhemolytic febrile reactions and minor allergic reactions are the most common, each occurring in 3–4% of all transfusions. Etiologies are as follows:


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First_Aid_Step2. Nonhemolytic febrile reactions: Involve cytokine formation during the storage of blood, and WBC antibodies. Minor allergic reactions: Involve antibody formation (usually IgA) against donor proteins. Usually occur following transfusion of plasma-containing product. Hemolytic transfusion reactions: Entail the development of antibodies against donor erythrocytes. Usually result from ABO incompatibility or from antibody against minor antigens. Nonhemolytic febrile reactions: Present with fever, chills, rigors, and malaise. Symptom onset is 1–6 hours following transfusion. Minor allergic reactions: Characterized by urticaria. Hemolytic transfusion reactions: Present with fever, chills, nausea, ﬂ ushing, apprehension, back pain, burning at the IV site, tachycardia, tachypnea, and hypotension. Symptoms begin following the transfusion of only a small amount of blood. Diagnosed by clinical impression.


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First_Aid_Step2. Diagnosed by clinical impression. Nonhemolytic febrile reactions: Stop the transfusion and control fever with acetaminophen. Rule out infection. Minor allergic reactions: Administer antihistamines. In the setting of a severe reaction, stop the transfusion and give epinephrine +/– steroids. Hemolytic transfusion reactions: Stop the transfusion immediately. Replace donor blood with normal saline; administer vigorous IV ﬂ uids; and maintain good urine output (diuretics and pressors may be used to ↑ renal blood ﬂ ow). The porphyrias are a group of inherited disorders that include acute intermittent porphyria, porphyria cutanea tarda, and erythropoietic porphyria. Some porphyrias are autosomal dominant (e.g., acute intermittent porphyria) and others autosomal recessive (e.g., erythropoietic porphyria). All involve abnormalities of heme production that lead to an accumulation of porphyrins.


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First_Aid_Step2. Signs and symptoms vary with the type of porphyria. In general, however, porphyrias are characterized by a combination of photodermatitis, neuropsychiatric complaints, and visceral complaints that typically take the form of a colicky abdominal pain and seizures. Physical exam reveals tachycardia, skin erythema and blisters, aref exia, and a nonspecifc abdominal exam. Patients with the erythropoietic form present with hemolytic anemia. Acute attacks are associated with stimulants of ↑ heme synthesis such as fasting or chemical exposures; well-known triggers are alcohol, barbiturates, and OCPs. Urine may appear red or brown after an acute attack. Patients may have a family history. Diagnosed by a combination of the history and physical along with labs showing elevated blood, urine, and stool porphyrins. Enzyme assays may also be helpful. Avoidance of triggers of acute attacks; symptomatic treatment during acute episodes.


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First_Aid_Step2. Avoidance of triggers of acute attacks; symptomatic treatment during acute episodes. High doses of glucose may be administered to ↓ heme synthesis during mild attacks, and IV hematin can be given for severe attacks (provides feedback to the heme synthetic pathway). Heme is necessary for the production of hemoglobin, myoglobin, and cytochrome molecules. The telltale sign of porphyria is pink urine. The classic case of porphyria involves a college student who consumes alcohol and barbiturates at a party, and then has an acute episode of abdominal pain and brown urine the next day. Malignant proliferations of hematopoietic cells, categorized by the type of cell involved and their level of differentiation. Leukemias may be acute or chronic, lymphocytic or myelogenous. The four oncologic emergencies: hypercalcemia, spinal cord compression, superior vena cava syndrome, and leukostasis.


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First_Aid_Step2. The four oncologic emergencies: hypercalcemia, spinal cord compression, superior vena cava syndrome, and leukostasis. Acute myelogenous and lymphocytic leukemias are clonal disorders of early hematopoietic stem cells. They are characterized by rapid growth of immature blood cells (blasts), which overwhelms the ability of bone marrow to produce normal cells. Acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL) affect children as well as adults. ALL is the most common childhood malignancy. Disease onset and progression are rapid; patients present with signs and symptoms of anemia (pallor, fatigue) and thrombocytopenia (petechiae, purpura, bleeding). Medullary expansion and periosteal involvement may lead to bone pain (common in ALL). On exam, patients may have hepatosplenomegaly and swollen/bleeding gums from leukemic infiltration and ↓ platelets. Leukemic cells also infiltrate the skin and CNS.


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First_Aid_Step2. On exam, patients may have hepatosplenomegaly and swollen/bleeding gums from leukemic infiltration and ↓ platelets. Leukemic cells also infiltrate the skin and CNS. Based on examination of the patient’s bone marrow, obtained by biopsy and aspiration, or peripheral blood if circulating blasts are present. Marrow that is infiltrated with blast cells (> 20–30%) is consistent with a leukemic process. In AML, the leukemic cells are myeloblasts; in ALL they are lymphoblasts. These cells may be distinguished by examination of morphology, cytogenetics, cytochemistry, and immunophenotyping (see Table 2.7-6). The WBC count is usually elevated, but the cells are dysfunctional, and patients may be neutropenic with a history of frequent infection. If the WBC is very high (> 100,000), there is a risk of leukostasis (blasts occluding the microcirculation, leading to pulmonary edema, CNS symptoms, ischemic injury, and DIC).


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First_Aid_Step2. The type of acute leukemia is further classified according to the FAB system (ALL: L1–L3; AML: M0–M7) and karyotype analysis. Prognosis varies with leukemic cytogenetics. T AB LE 2.7 -6. Myeloblasts vs. Lymphoblasts Size Larger (2–4 times RBC) Smaller (1.5–3.0 times RBC) Amount of cytoplasm More Less Nucleoli Conspicuous Inconspicuous Granules Common, f ne Uncommon, coarse Auer rods Present in 50% of cases Absent Myeloperoxidase ALL and AML are treated primarily with chemotherapeutic agents, although transfusions, antibiotics, and colony-stimulating factors are also used. Patients with unfavorable genetics or those who do not achieve remission may be candidates for bone marrow transplantation. Prior to therapy, patients should be well hydrated, and if their WBC counts are high, they may be started on allopurinol to prevent hyperuricemia and renal insufficiency resulting from blast lysis (tumor lysis syndrome).


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First_Aid_Step2. Leukostasis syndrome may be treated with hydroxyurea +/– leukapheresis to rapidly ↓ WBC count. Indicators of a poor prognosis are as follows: ALL: Age < 1 year or > 10 years; an ↑ in WBC count to > 50,000; the presence of the Philadelphia chromosome t(9,22) (associated with B-cell cancer); CNS involvement at diagnosis; and L3 morphology (associated with Burkitt’s lymphoma). AML: Age > 60 years, CD34+ or MDR1+ phenotype, elevated LDH, mutations in chromosomes 5 or 7, t(6,9), trisomy 8 or a more complex karyotype, FLT3 gene mutation, and FAB M7 (acute megakaryocytic variant). AML type (FAB) M3—acute promyelocytic leukemia (APL)—has a good prognosis because it is responsive to all-trans-retinoic acid (ATRA) therapy. The mutation that causes this form of AML contains the retinoic acid receptor. ATRA is less toxic than conventional chemotherapy.


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First_Aid_Step2. A malignant, clonal proliferation of functionally incompetent lymphocytes that accumulate in the bone marrow, peripheral blood, lymph nodes, spleen, and liver. The most common type of leukemia. A rare form of T-cell CLL exists, but almost all cases involve well-differentiated B lymphocytes. The etiology is unknown, although there is some genetic contribution, as first-degree relatives of patients with CLL are three times more likely than others to develop a lymphoid malignancy. Primarily affects older adults (median age 65); the male-to-female ratio is 2:1. Often asymptomatic, but many patients present with fatigue, malaise, and infection. Common physical findings are lymphadenopathy and splenomegaly. Diagnosed by the clinical picture; may be confirmed by f ow cytometry demonstrating the presence of CD5—normally found only on T cells—on leukemic cells with the characteristic B-cell antigens CD20 and CD21.


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First_Aid_Step2. CBC shows lymphocytosis (lymphocyte count > 5000) with an abundance of small, normal-appearing lymphocytes and ruptured smudge cells on peripheral smear. Granulocytopenia, anemia, and thrombocytopenia are common owing to marrow infiltration with leukemic cells. Abnormal function by the leukemic cells leads to hypogammaglobulinemia. Bone marrow biopsy is rarely required for diagnosis or staging but may provide prognostic information and may help assess response to therapy. A characteristic sign for AML type M3 (APL) is the Auer rod. Eighty-five percent of children with ALL achieve complete remission with chemotherapy. CLL may be complicated by autoimmune hemolytic anemia. The lymphoid equivalent of CLL is small lymphocytic lymphoma. The clinical stage correlates with expected survival (see Table 2.7-7).


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First_Aid_Step2. CLL may be complicated by autoimmune hemolytic anemia. The lymphoid equivalent of CLL is small lymphocytic lymphoma. The clinical stage correlates with expected survival (see Table 2.7-7). Treatment is palliative. The degree of peripheral lymphocytosis does not correlate with prognosis, nor does it dictate when treatment should be initiated. Treatment is often withheld until patients are symptomatic—e.g., when they present with recurrent infection, severe lymphadenopathy or splenomegaly, anemia, and thrombocytopenia. Treatment consists primarily of chemotherapy, especially with alkylating agents, although radiation may be useful for localized lymphadenopathy. Although CLL is not curable, long disease-free intervals may be achieved with adequate treatment of symptoms.


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First_Aid_Step2. Although CLL is not curable, long disease-free intervals may be achieved with adequate treatment of symptoms. Involves clonal expansion of myeloid progenitor cells, leading to leukocytosis with excess granulocytes and basophils and sometimes ↑ erythrocytes and platelets as well. To truly be CML, the BCR-ABL translocation must be present. In > 90% of patients, this is reﬂected by the Philadelphia chromosome t(9,22). CML primarily affects middle-aged patients. With routine blood testing, many patients are diagnosed while asymptomatic. However, typical signs and symptoms are those of anemia. Patients frequently have splenomegaly with LUQ pain and early satiety. Hepatomegaly may be present as well. Constitutional symptoms of weight loss, anorexia, fever, and chills may also be seen. Patients with CML go through three disease phases: Chronic: Without treatment, typically lasts 3.5–5.0 years. Signs and symptoms are as described above. Infection and bleeding complications are rare.


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First_Aid_Step2. Chronic: Without treatment, typically lasts 3.5–5.0 years. Signs and symptoms are as described above. Infection and bleeding complications are rare. Accelerated: A transition toward blast crisis, with an ↑ in peripheral and bone marrow blood counts. Should be suspected when the differential shows an abrupt ↑ in basophils and thrombocytopenia < 100,000. Blast: Resembles acute leukemia; survival is 3–6 months. ■Diagnosed by the clinical picture, including labs; cytogenetic analysis usually reveals the Philadelphia chromosome. TAB LE 2.7 -7. Clinical Staging of CLL (Rai Staging) CBwC shows a very high WBC—often > 100,000 at diagnosis, and sometimes reaching > 500,000. Differential shows granulocytes in all stages of maturation. Rarely, the WBC count will be so elevated as to cause a hyperviscosity syndrome. Leukocyte alkaline phosphatase is low; LDH, uric acid, and B12 levels are elevated.


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First_Aid_Step2. Leukocyte alkaline phosphatase is low; LDH, uric acid, and B12 levels are elevated. Varies with disease phase and is undergoing rapid change, particularly since the introduction of targeted therapies: Chronic: Imatinib. Younger patients can be treated with allogeneic stem cell transplantation if a suitable matched sibling donor is available. Blast: Therapy as for acute leukemia or dasatinib plus hematopoietic stem cell transplant or clinical trial. A malignant disorder of well-differentiated B lymphocytes with an unclear cause. HCL is a rare disease that accounts for 2% of adult leukemia cases and most commonly affects older males. Typically presents with pancytopenia, bone marrow infiltration, and splenomegaly.


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First_Aid_Step2. Typically presents with pancytopenia, bone marrow infiltration, and splenomegaly. Patients complain of weakness, fatigue, petechiae and bruising, infection (especially with atypical mycobacteria such as Mycobacterium avium– intracellulare), abdominal pain, early satiety, and weight loss. Symptoms are similar to those of CLL except that patients rarely have lymphadenopathy. Diagnosed by the history, physical exam, and labs; confirmed through the identification of hairy cells in the blood, marrow, or spleen. Tartrate-resistant acid phosphatase (TRAP) staining of hairy cells, electron microscopy, and f ow cytometry (quantification of ﬂ uorescence on cells with ﬂuorescent-labeled monoclonal antibodies bound to cell-specific antigens) are helpful in distinguishing the pathognomonic hairy cells.


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First_Aid_Step2. CBC usually demonstrates leukopenia (making the name leukemia a misnomer); roughly 85% of the time, a peripheral smear shows hairy cells, or mononuclear cells with abundant pale cytoplasm and cytoplasmic projections. Ten percent of patients have a benign course and never require therapy, but the remainder develop progressive pancytopenia and splenomegaly. The median survival without treatment is five years. Treatment begins when patients are symptomatic or extremely cytopenic. Nucleoside analogs are currently the initial treatment of choice, and effectively induce remission. Other treatment options include splenectomy, which may improve blood counts, and IFN-α. Imatinib (Gleevec) is a selective inhibitor of the BCR-ABL tyrosine kinase. The treatment of high-grade NHL may be complicated by tumor lysis syndrome, in which rapid cell death releases intracellular contents and leads to hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia.


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First_Aid_Step2. Malignant transformations of lymphoid cells residing primarily in lymphoid tissues, especially the lymph nodes. Classically organized into Hodgkin’s and non-Hodgkin’s varieties. NHL represents a progressive clonal expansion of B cells, T cells, and/or natural killer (NK) cells stimulated by chromosomal translocations, most commonly t(14,18); by the inactivation of tumor suppressor genes; or by the introduction of exogenous genes by oncogenic viruses (e.g., EBV, HTLV-1, HCV). There is a strong association between H. pylori infection and MALT gastric lymphoma. Most NHLs (almost 85%) are of B-cell origin. NHL is the most common hematopoietic neoplasm and is five times more common than Hodgkin’s lymphoma. The median patient age is > 50 years, but NHL may also be found in children, who tend to have more aggressive, higher-grade disease. Patient presentation varies with disease grade (see Table 2.7-8).


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First_Aid_Step2. The median patient age is > 50 years, but NHL may also be found in children, who tend to have more aggressive, higher-grade disease. Patient presentation varies with disease grade (see Table 2.7-8). Excisional lymph node biopsy is necessary for diagnosis; the disease may first present at an extranodal site, which should be biopsied for diagnosis as well. A CSF exam should be done in patients with HIV, neurologic signs or symptoms, or 1° CNS lymphoma. Disease staging (Ann Arbor classif cation) is based on the number of nodes and on whether the disease crosses the diaphragm. ■Treatment is based on histopathologic classification rather than on stage. Symptomatic patients are treated with radiation and chemotherapy T AB LE 2.7 -8. Presentation of Non-Hodgkin’s Lymphoma


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First_Aid_Step2. ■Treatment is based on histopathologic classification rather than on stage. Symptomatic patients are treated with radiation and chemotherapy T AB LE 2.7 -8. Presentation of Non-Hodgkin’s Lymphoma Painless peripheral adenopathy. Cytopenia from bone marrow involvement. Fatigue and weakness. Peripheral adenopathy, splenomegaly, hepatomegaly. Adenopathy. Extranodal disease (GI, GU, skin, thyroid, CNS). B symptoms (temperature > 38.5°C, night sweats, weight loss). Mass formation (e.g., abdominal mass with bowel obstruction in Burkitt’s lymphoma; mediastinal mass and SVC syndrome in lymphoblastic lymphoma). Bulky adenopathy, splenomegaly, hepatomegaly. Masses (abdominal, testicular, mediastinal). Skin f ndings. Low Intermediate to high (CHOP: cyclophosphamide [Cytoxan], Adriamycin, Oncovin [vincristine], and prednisone).


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First_Aid_Step2. ■The rule of thumb is for low-grade, indolent NHL to be treated with a palliative approach in symptomatic patients, and for high-grade, aggressive NHL to be treated aggressively with a curative approach. A predominantly B-cell malignancy with an unclear etiology. There is a possible association with EBV. HD has a bimodal age distribution, peaking first in the third decade (primarily the nodular sclerosing type) and then in the elderly at around age 60 (mainly the lymphocyte-depleted type). It has a male predominance in childhood. HD commonly presents as cervical adenopathy, although it may also present as a mediastinal mass; it is usually found above the diaphragm, with infradiaphragmatic involvement suggesting more widely disseminated disease. Patients also have systemic B symptoms, pruritus, and hepatosplenomegaly. Pel-Ebstein fevers (1–2 weeks of high fever alternating with 1–2 afebrile weeks) and alcohol-induced pain at nodal sites are rare signs that are specific for HD.


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First_Aid_Step2. Fine-needle biopsy is usually nondiagnostic, so diagnosis is usually made by excisional lymph node biopsy, which is examined for the classic Reed-Sternberg (RS) cells (giant abnormal B cells with bilobar nuclei and huge, eosinophilic nucleoli, which create an “owl’s-eye” appearance) and for abnormal nodal morphology. Histologic types, in descending order of frequency, include nodular sclerosing, mixed cellularity, lymphocyte predominant, and lymphocyte depleted. Staging is based on the number of nodes, the presence of B symptoms, and whether the disease crosses the diaphragm; staging laparotomy is not recommended. Treatment is stage dependent, involving chemotherapy and/or radiation. Radiation is directed toward the involved lymph node area plus the next contiguous region. Chemotherapy regimens used include ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) and MOPP (mechlorethamine, Oncovin [vincristine], procarbazine, and prednisone).


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First_Aid_Step2. Five-year survival rates are very good and are 90% for stage I and II disease (nodal disease limited to one side of the diaphragm), 84% for stage III, and 65% for stage IV. Chemotherapy and radiation can lead to 2° neoplasms such as AML, NHL, breast cancer, and thyroid cancer. Clonal proliferation of malignant plasma cells at varying stages of differentiation, with excessive production of monoclonal immunoglobulins or immunoglobulin fragments (kappa/lambda light chains). It is commonly believed The combination of anemia and bone pain must always raise suspicion of multiple myeloma. Bone pain at rest should raise concern for malignancy. Hypercalcemia manifests in symptoms of polyuria, constipation, confusion, nausea, vomiting, and lethargy. Because multiple myeloma is an osteoclastic process, a bone scan, which detects osteoblastic activity, may be .


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First_Aid_Step2. Because multiple myeloma is an osteoclastic process, a bone scan, which detects osteoblastic activity, may be . to be a disease of the elderly, with a peak incidence in the seventh decade. Risk factors for disease development include radiation; monoclonal gammopathy of undetermined significance (MGUS); and, possibly, petroleum, pesticides, and other chemicals. Patients present with anemia, plasmacytosis of the bone marrow, lytic bone lesions, hypercalcemia, and renal abnormalities. They are prone to infection and have elevated monoclonal (M) proteins in the serum and/or urine. The classic triad of diagnostic criteria are > 10% plasma cells in the bone marrow and/or histologically proven plasma cell infiltration, M protein in serum or urine, and evidence of lytic bone lesions.


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First_Aid_Step2. The presence of M proteins alone is insuffcient for the diagnosis of multiple myeloma; MGUS is relatively common. Other lymphoproliferative diseases may also result in M proteins, including CLL, lymphoma, Waldenström’s macroglobulinemia, and amyloidosis. Patients should be evaluated with a skeletal survey, a bone marrow biopsy, serum and urine protein electrophoresis, and CBC. Treat with chemotherapy. Common initial treatment involves a combination of melphalan (an oral alkylating agent) and prednisone and other agents. Myeloma cells tend to become resistant to drugs by an MDR gene mechanism, and autologous stem cell transplantation may be used to support more intensive doses of chemotherapy.


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First_Aid_Step2. A clonal disorder of B cells that leads to a malignant monoclonal gammopathy. Elevated levels of IgM result in hyperviscosity syndrome, coagulation abnormalities, cryoglobulinemia, cold agglutinin disease (leading to autoimmune hemolytic anemia), and amyloidosis. Tissue is infiltrated by IgM and neoplastic plasma cells. A chronic, indolent disease of the elderly. Presents with nonspecific symptoms of lethargy and weight loss along with Raynaud’s phenomenon from cryoglobulinemia. Patients complain of neurologic problems ranging from mental status changes to sensorimotor peripheral neuropathy and blurry vision. Organomegaly and organ dysfunction affecting the skin, GI tract, kidneys, and lungs are also seen. As with multiple myeloma, MGUS is a precursor to disease. Labs show elevated ESR, uric acid, LDH, and alkaline phosphatase.


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First_Aid_Step2. As with multiple myeloma, MGUS is a precursor to disease. Labs show elevated ESR, uric acid, LDH, and alkaline phosphatase. Bone marrow biopsy and aspirate are required to establish the diagnosis. Marrow shows abnormal plasma cells, classically with Dutcher bodies (PASIgM deposits around the nucleus). Serum and urine protein electrophoresis and immunofixation are also used. Excess immunoglobulin is removed with plasmapheresis; underlying lymphoma is treated with chemotherapy. A generic term referring to extracellular deposition of protein fibrils. There are many different kinds of amyloidosis, involving different types of deposited fibrils with varying etiologies (see Table 2.7-9). Classically a disease of the elderly.


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First_Aid_Step2. The clinical presentation depends on the type of precursor protein, tissue distribution, and the amount of amyloid deposition. In the two most common forms of systemic amyloidosis, 1° (AL) and 2° (AA), the major sites of clinically important amyloid deposition are in the kidneys, heart, and liver. In some disorders, clinically important amyloid deposition is limited to one organ (e.g., the brain in Alzheimer’s disease). Diagnosed by the clinical picture; confirmed by tissue biopsy with Congo red staining showing apple-green birefringence under polarized light. 1° amyloidosis is treated with experimental chemotherapy to reduce protein burden; in 2° amyloidosis, the underlying condition should be addressed. Transplantation is also used; kidney transplantation may cure dialysis-related amyloid, and liver transplantation may cure heritable amyloid. TABLE 2.7-9. Types of Amyloidosis


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First_Aid_Step2. TABLE 2.7-9. Types of Amyloidosis AL A plasma cell dyscrasia, with deposition of monoclonal light-chain fragments. Associated with multiple myeloma and Waldenstr’s macroglobulinemia. AA Deposition of the acute-phase reactant serum amyloid A. Associated with chronic infammatory diseases (e.g., rheumatoid arthritis), infections, and neoplasms. Dialysis-related Deposition of β2 microglobulin, which accumulates in patients on long-term dialysis. Heritable Deposition of abnormal gene products (e.g., transthyretin, aka prealbumin). A heterogeneous group of disorders. Senile-systemic Deposition of otherwise normal transthyretin. An absolute neutrophil count (ANC) < 1500, where ANC = (WBC count) (% bands + % segmented neutrophils) (0.01). Neutropenia may be due to a combination of ↓ production, sequestration to marginated or tissue pools, and ↑ destruction or utilization. It may be acquired or intrinsic (see Table 2.7-10).


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First_Aid_Step2. Patients are at ↑ risk of infection, which varies inversely with neutrophil count. Acute neutropenia: Associated with S. aureus, Pseudomonas, E. coli, Proteus, and Klebsiella sepsis. Chronic and autoimmune neutropenia: Presents with recurrent sinusitis, stomatitis, gingivitis, and perirectal infections rather than sepsis. Some chronic neutropenias are accompanied by splenomegaly (e.g., Felty’s syndrome, Gaucher’s disease, sarcoidosis). The history and physical exam are the cornerstones of diagnosis. CBC with ANC may be used to follow neutropenia. If thrombocytopenia or anemia is present, bone marrow biopsy and aspirate should be performed. Serum immunologic evaluation, ANA levels, and a workup for collagen vascular disease may be merited. T AB LE 2.7 -1 0. Acquired vs. Intrinsic Neutropenia


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First_Aid_Step2. HEMATOLOGY/ONCOLOGY Acquired Drug induced (e.g., chemotherapy, ethanol, antibiotics, NSAIDs), usually by marrow suppression. Marrow-inf ltrating disorders. Postinfectious. HIV infection. Benign familial leukopenia (seen in Yemenite Jews, West Indians, and people of African descent; due to genetic variation). Chronic idiopathic neutropenia (occurs in infancy and childhood; thought to be due to production of antineutrophil IgG). Autoimmune neutropenia (isolated or 2° to rheumatoid arthritis or SLE). Nutritional def ciency (B12/folate or thiamine def ciency). Metabolic disease (ketoacidosis, hyperglycinuria, orotic aciduria, MMA, hypothyroidism, Gaucher’s disease). Intrinsic Dyskeratosis congenita (X-linked, with integument abnormalities and hypocellular marrow). Kostmann’s syndrome (aka infantile agranulocytosis). Shwachman-Diamond-Oski syndrome (neutropenia, metaphyseal dysplasia, and pancreatic insuff ciency). Chédiak-Higashi syndrome (oculocutaneous albinism, neurologic impairment,


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First_Aid_Step2. agranulocytosis). Shwachman-Diamond-Oski syndrome (neutropenia, metaphyseal dysplasia, and pancreatic insuff ciency). Chédiak-Higashi syndrome (oculocutaneous albinism, neurologic impairment, and giant granules in cells). Fanconi’s anemia.


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First_Aid_Step2. ■Infection management is most important; patients may not be able to mount an inﬂammatory response to infection owing to their lack of neutrophils. Fever in the context of neutropenia should be treated immediately with broad-spectrum antibiotics. Suspected fungal infections should be treated by fungemia. appropriately as well. Hematopoietic stem cell factors such as G-CSF can be used to shorten the duration of neutropenia. In some instances, IVIG and allogeneic bone marrow transplantation may be used. Absolute eosinophil count = (WBC) (% eosinophils) (0.01). Normal levels do not exceed 350. Eosinophilia can be triggered by the overproduction of one or more of three eosinophilopoietic cytokines (IL-3, IL-5, and GM-CSF) or by chemokines that stimulate the migration of eosinophils into peripheral blood and tissues. Eosinophilia may be a 1° disorder, but it usually occurs 2° to another cause (see Table 2.7-11).


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First_Aid_Step2. A travel, medication, atopic, and diet history should be elicited along with a history of symptoms relating to lymphoma/leukemia. Physical exam findings vary. Patients with hypereosinophilic syndrome (HES) may present with fever, anemia, and prominent cardiac findings (emboli from mural thrombi, abnormal ECGs, CHF, murmurs). Other affected organs include the lung, liver, spleen, skin, and nervous system (due to eosinophilic infiltration). ■In addition to a history and physical, a CBC and differential should be obtained, and CSF should be analyzed for eosinophilia, which is suggestive T AB LE 2.7 -1 1. Etiologies of Eosinophilia 1° Hypereosinophilic syndrome: Unknown etiology. Hereditary eosinophilia: Autosomal-dominant inheritance; rare. Eosinophilia-myalgia syndrome: Results from abnormal tryptophan metabolism. 2° Allergic states with elevated serum IgE: The most common cause in the United States. Parasitic diseases: The most common cause worldwide. Other:


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First_Aid_Step2. Allergic states with elevated serum IgE: The most common cause in the United States. Parasitic diseases: The most common cause worldwide. Other: Coccidioidomycosis. Vasculitis (e.g., Churg-Strauss syndrome). Benign or malignant hematologic disorders; also solid tumors. Collagen vascular diseases (e.g., dermatomyositis, PAN). Drug induced (e.g., sulfonamides, iodides, ASA, phenytoin). of a drug reaction or infection with a coccidioidomycosis or a helminth. Hematuria with eosinophilia may be a sign of schistosomiasis. ■Imaging of the lungs, abdomen, pelvis, and brain may demonstrate a focal defect that may be helpful in narrowing down the potential causes. Medication should be tailored to the cause of the eosinophilia. HES is treated with corticosteroid and cytotoxic agents to ↓ the eosinophilia. Tissue transplantation is increasingly used to treat a variety of diseases. Types of transplantation include the following: Autologous: Transplantation from the patient to him/herself.


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First_Aid_Step2. Tissue transplantation is increasingly used to treat a variety of diseases. Types of transplantation include the following: Autologous: Transplantation from the patient to him/herself. Allogeneic: Transplantation from a donor to a genetically different patient. Syngeneic: Transplantation between identical twins (i.e., from a donor to a genetically identical patient). With allogeneic donation, efforts are made to ABO and HLA match the donor and recipient. Even with antigenic matching and immunosuppression, however, transplants may be rejected. There are three types of rejection: hyperacute, acute, and chronic (see Table 2.7-12). Graft-versus-host disease (GVHD) is a complication specific to allogeneic bone marrow transplantation in which donated T cells attack host tissues. It may be acute (occurring < 100 days post-transplant) or chronic (occurring > 100 days afterward).


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First_Aid_Step2. Minor histocompatibility antigens are thought to be responsible for GVHD, which typically presents with skin changes, cholestatic liver dysfunction, obstructive lung disease, or GI problems. Patients are treated with high-dose corticosteroids. T AB LE 2.7 -1 2. Types of Transplant Rejection Timing after transplant Within minutes. Five days to three months. Months to years. Pathomechanism Preformed antibodies. T-cell mediated. Chronic immune reaction causing f brosis. Tissue fndings Vascular thrombi; tissue ischemia. Laboratory evidence of tissue destruction such as ↑ GGT, alkaline phosphatase, LDH, BUN, or creatinine. Gradual loss of organ function. Prevention Check ABO compatibility. N/A N/A Treatment Cytotoxic agents. Confrm with sampling of transplanted tissue; treat with corticosteroids, antilymphocyte antibodies (OKT3), tacrolimus, or mycophenolate mofetil (MMF). No treatment; biopsy to rule out treatable acute reaction.


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First_Aid_Step2. The typical regimen after transplant can include these commonly used drugs: prednisone, MMF, FK506 (tacrolimus), TMP-SMX, ganciclovir, and ketoconazole. A variant of GVHD is the graft-versus-leukemia effect, in which leukemia patients who are treated with an allogeneic bone marrow transplant have significantly lower relapse rates than those treated with an autologous transplant. This difference is thought to be due to a reaction of donated T cells against leukemic cells. Table 2.7-13 outlines conditions that are commonly associated with neoplasms. T AB LE 2.7 -1 3. Disorders Associated with Neoplasms


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First_Aid_Step2. Down syndrome ALL (“We will ALL go Down together”). Xeroderma pigmentosum Squamous cell and basal cell carcinomas of the skin. Chronic atrophic gastritis, pernicious anemia, postsurgical gastric remnants Gastric adenocarcinoma. Tuberous sclerosis (facial angiofbroma, seizures, mental retardation) Astrocytoma and cardiac rhabdomyoma. Actinic keratosis Squamous cell carcinoma of the skin. Barrett’s esophagus (chronic GI ref ux) Esophageal adenocarcinoma. Plummer-Vinson syndrome (atrophic glossitis, esophageal webs, anemia; all due to iron def ciency) Squamous cell carcinoma of the esophagus. Cirrhosis (alcoholic, HBV or HCV) Hepatocellular carcinoma. Ulcerative colitis Colonic adenocarcinoma. Paget’s disease of bone 2° osteosarcoma and f brosarcoma. AIDS Aggressive malignant NHLs and Kaposi’s sarcoma. Autoimmune diseases (e.g., myasthenia gravis) Benign and malignant thymomas. Acanthosis nigricans (hyperpigmentation and epidermal thickening) Visceral malignancy (stomach, lung, breast,


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First_Aid_Step2. sarcoma. Autoimmune diseases (e.g., myasthenia gravis) Benign and malignant thymomas. Acanthosis nigricans (hyperpigmentation and epidermal thickening) Visceral malignancy (stomach, lung, breast, uterus). Dysplastic nevus Malignant melanoma. Immunodefciency states Malignant lymphomas.


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First_Aid_Step2. Infections of the Eyes and Ears 248 INFECTIOUS CONJUNCTIVITIS 248 ORBITAL CELLULITIS 248 OTITIS EXTERNA 249 Some common causes of pneumonia are outlined in Table 2.8-1. May present classically or atypically. Classic symptoms: Sudden onset, fever, productive cough (purulent yellow-green sputum or hemoptysis), dyspnea, night sweats, pleuritic chest pain. Atypical symptoms: Gradual onset, dry cough, headaches, myalgias, sore throat. Lung exam may show ↓ or bronchial breath sounds, rales, wheezing, dullness to percussion, egophony, and tactile fremitus. Elderly patients as well as those with COPD, diabetes, or immunocompromised status may have minimal or atypical signs on physical exam. Workup includes physical exam, CXR, CBC, sputum Gram stain and culture (see Figures 2.8-1 and 2.8-2), nasopharyngeal aspirate, blood culture, and ABG. Tests for specifc pathogens include the following:


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First_Aid_Step2. Tests for specifc pathogens include the following: Legionella: Urine Legionella antigen test (detects only serogroup 1), sputum staining with direct fuorescent antibody (DFA), culture. Chlamydia pneumoniae: Serologic testing, culture, PCR. TABLE 2.8-1. Common Causes of Pneumonia


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First_Aid_Step2. TABLE 2.8-1. Common Causes of Pneumonia Atypical Nosocomial (hospital acquired) Immunocompromised Mycoplasma, Legionella, Chlamydia Gramrods (GNRs), Staphylococcus, anaerobes Staphylococcus, gramrods, fungi, viruses, Pneumocystis jiroveci (with HIV), mycobacteria Aspiration Anaerobes Alcoholics/IV drug users S. pneumoniae, Klebsiella, Staphylococcus Cystic fbrosis (CF) Pseudomonas, Burkholderia, S. aureus, mycobacteria COPD H. inﬂ uenzae, Moraxella catarrhalis, S. pneumoniae Postviral Staphylococcus, H. inﬂuenzae Neonate Group B streptococci (GBS), E. coli Recurrent Obstruction, bronchogenic carcinoma, lymphoma, Wegener’s granulomatosis, immunodefciency, unusual organisms (e.g., Nocardia, Coxiella burnetii, Aspergillus, Pseudomonas) Viruses (RSV) Mycoplasma Chlamydia pneumoniae Streptococcus pneumoniae Mycoplasma C. pneumoniae S. pneumoniae S. pneumoniae H. inﬂ uenzae Anaerobes Viruses Mycoplasma S. pneumoniae Viruses Anaerobes H. inﬂ uenzae Gram-rods Special groups:


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First_Aid_Step2. An adequate sputum Gram stain sample has many PMNs (> 25 cells/hpf) and few epithelial cells (< 25 cells/hpf). FIGURE 2.8-1. S. aureus. These clusters of gramcocci were isolated from the sputum of a patient who developed pneumonia while hospitalized. Mycoplasma: Usually clinical. Serum cold agglutinins and serum Mycoplasma antigen may also be used. Streptococcus pneumoniae: Urine pneumococcal antigen test, culture. Viral: Nasopharyngeal aspirate, rapid tests for pathogens (e.g., inf uenza, RSV), DFA, viral culture. FIGURE 2.8-2. S. pneumoniae. Sputum sample from a patient with pneumonia. Note the characteristic lancet-shaped gramdiplococci. Table 2.8-2 summarizes the recommended initial treatment for pneumonia. Outpatient treatment with oral antibiotics is recommended only in uncomplicated cases.


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First_Aid_Step2. Table 2.8-2 summarizes the recommended initial treatment for pneumonia. Outpatient treatment with oral antibiotics is recommended only in uncomplicated cases. In-hospital treatment with IV antibiotics is recommended for patients > 65 years of age and in those with comorbidity (alcoholism, COPD, diabetes, malnutrition), immunosuppression, unstable vitals or signs of respiratory failure, altered mental status, and/or multilobar involvement. For patients with obstructive diseases (e.g., CF or bronchiectasis), consider adding pseudomonal, staphylococcal, or anaerobic coverage. Infection due to Mycobacterium tuberculosis. Initial infection usually leads to latent TB infection (LTBI) that is asymptomatic. Most symptomatic cases (i.e., cases of active disease) are due to reactivation of latent infection rather TABLE 2.8-2. Treatment of Pneumonia


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First_Aid_Step2. TABLE 2.8-2. Treatment of Pneumonia The PORT criteria (i.e., pneumonia severity index) risk-stratifies patients with pneumonia on the basis of age, comorbidity, and presentation. Note: The PORT criteria do not apply to AIDS patients.


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First_Aid_Step2. Outpatient community-acquired pneumonia, patients ≤ 65 years of age, otherwise healthy S. pneumoniae, Mycoplasma pneumoniae, C. pneumoniae, H. inﬂ uenzae, viral. Macrolide (azithromycin), doxycycline, or f uoroquinolone. Patients > 65 years of age or with comorbidity (COPD, heart failure, renal failure, diabetes, liver disease, EtOH abuse) S. pneumoniae, H. inﬂ uenzae, aerobic GNRs (E. coli, Enterobacter, Klebsiella), S. aureus, Legionella, viruses. Macrolide or f uoroquinolone. Consider adding a second-generation cephalosporin or β-lactam to the macrolide. Community-acquired pneumonia requiring hospitalization S. pneumoniae, H. inﬂ uenzae, anaerobes, aerobic GNRs, Legionella, Chlamydia. Extended-spectrum cephalosporin, β-lactam/β-lactamase inhibitor, or fuoroquinolone. Add a macrolide if atypical organisms are suspected. Community-acquired pneumonia requiring ICU care S. pneumoniae, H. inﬂ uenzae, anaerobes, aerobic GNRs, Mycoplasma, Legionella, Pseudomonas. Fluoroquinolone or


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First_Aid_Step2. if atypical organisms are suspected. Community-acquired pneumonia requiring ICU care S. pneumoniae, H. inﬂ uenzae, anaerobes, aerobic GNRs, Mycoplasma, Legionella, Pseudomonas. Fluoroquinolone or extended-spectrum cephalosporin or β-lactam/β-lactamase inhibitor + macrolide. Institution-/hospital-acquired pneumonia—patients hospitalized > 48 hours or in a long-term care facility > 14 days GNRs (including Pseudomonas and Acinetobacter), S. aureus, Legionella, mixed f ora. Extended-spectrum cephalosporin or β-lactam with antipseudomonal activity or carbapenem. Consider adding an aminoglycoside or a f uoroquinolone for coverage of resistant organisms (Pseudomonas) until lab sensitivities identify the best single agent. Patients who are critically ill or worsening over 24–48 hours on initial antibiotic therapy Methicillin-resistant S. aureus (MRSA). Add vancomycin or linezolid; broader gram-coverage.


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First_Aid_Step2. TB almost always presents with an extended duration (> 3 weeks) of symptoms. than to 1° exposure. Pulmonary TB is most common, but disseminated or extrapulmonary TB should be considered as well. TB can infect almost any organ system, including the lungs, CNS, GU tract, bone, and GI tract. Risk factors for active disease (i.e., reactivation) include immunosuppression (HIV), alcoholism, preexisting lung disease, diabetes, and advancing age. Risk factors for TB exposure include homelessness and crowded living conditions (e.g., prison), immigration/travel from developing nations, working in an allied health profession, and interacting with known TB contacts.


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First_Aid_Step2. Presents with cough, hemoptysis, dyspnea, weight loss, fatigue, night sweats, fever, cachexia, hypoxia, tachycardia, lymphadenopathy, an abnormal lung exam, and a prolonged (> 3-week) symptom duration. TB is a common cause of fever of unknown origin (FUO). HIV patients can present with atypical signs and symptoms and have higher rates of extrapulmonary TB. ■ Active disease: Mycobacterial culture of sputum (or blood/tissue for extrapulmonary disease) is the gold standard but can take weeks to obtain. A sputum acid-fast stain (see Figure 2.8-3) can yield rapid preliminary results but lacks sensitivity. Three A.M. sputum samples for AFB stain and a mycobacterial culture are advised. If the results of the stain are but there is a high degree of clinical suspicion, proceed to bronchoscopy with bronchoalveolar lavage or biopsy. HIV patients have a high rate of sputum stains (i.e., a AFB smear accompanied by a culture).


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First_Aid_Step2. AFB smear accompanied by a culture). The most common fnding among typical hosts is a cavitary inf ltrate in the upper lobe on CXR. HIV patients or those with 1° TB may show lower lobe infltrates with or without cavitation. Multiple f ne nodular F IGU R E 2.8-3. TB organisms are identifed by their red color (“red snappers”) on acid-fast staining. (Reproduced, with permission, from the Pathology Education Instructional Resource Digital Library [ http://peir.net] at the University of Alabama, Birmingham.) densities distributed throughout both lungs are typical of miliary TB, which represents hematologic or lymphatic dissemination. ■LTBI (i.e., previous exposure): Diagnose with a PPD test (see Figure 2.8-4). Immunocompromised individuals with LTBI may not mount a PPD (anergy). Interferon-gamma release assays are now available to diagnose LTBI as well. All cases of LTBI should be evaluated (e.g., with a CXR) to rule out active disease.


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First_Aid_Step2. All cases should be reported to local and state health departments. Respiratory isolation should be instituted if TB is suspected. Treatment is as follows: Active TB: Directly observed multidrug therapy with a four-drug regimen (INH, pyrazinamide, rifampin, ethambutol) × 2 months, followed by four months with INH and rifampin. Administer vitamin B6 (pyridoxine) with INH to prevent peripheral neuritis. Latent TB: For conversion of PPD without signs/symptoms of active disease, initiate therapy with INH × 9 months. Alternative regimens include INH × 6 months or rifampin × 4 months. Viral causes are more common (90% in adults), but it is important to identify streptococcal pharyngitis (group A β-hemolytic Streptococcus pyogenes). Etiologies are as follows: Bacterial: Group A streptococci (GAS), Neisseria gonorrhoeae, Corynebacterium diphtheriae, M. pneumoniae. Viral: Rhinovirus, coronavirus, adenovirus, HSV, EBV, CMV, inf uenza virus, coxsackievirus, acute HIV infection.


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First_Aid_Step2. Viral: Rhinovirus, coronavirus, adenovirus, HSV, EBV, CMV, inf uenza virus, coxsackievirus, acute HIV infection. Typical of streptococcal pharyngitis: Fever, sore throat, pharyngeal erythema, tonsillar exudate, cervical lymphadenopathy, soft palate petechiae, headache, vomiting, scarlatiniform rash (indicates scarlet fever). Atypical of streptococcal pharyngitis: Coryza, hoarseness, rhinorrhea, cough, conjunctivitis, anterior stomatitis, ulcerative lesions, GI symptoms. Rifampin turns body ﬂ uids orange. Ethambutol can cause optic neuritis. INH causes peripheral neuritis and hepatitis.


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First_Aid_Step2. Rifampin turns body ﬂ uids orange. Ethambutol can cause optic neuritis. INH causes peripheral neuritis and hepatitis. PPD is injected intradermally on the volar surface of the forearm. The diameter of induration is measured at 48–72 hours. BCG vaccination typically renders a patient PPD but should not preclude prophylaxis as recommended for unvaccinated individuals. The size of induration that indicates a test is interpreted as follows: ≥ 5 mm: HIV or risk factors, close TB contacts, CXR evidence of TB. ≥ 10 mm: Indigent/homeless, residents of developing nations, IV drug use, chronic illness, residents of health and correctional institutions, and health care workers. ≥ 15 mm: Everyone else, including those with no known risk factors. A reaction with controls implies anergy from immunosuppression, old age, or malnutrition and thus does not rule out TB. FIGURE 2.8-4. PPD interpretation.


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First_Aid_Step2. A reaction with controls implies anergy from immunosuppression, old age, or malnutrition and thus does not rule out TB. FIGURE 2.8-4. PPD interpretation. The Centor criteria for identifying streptococcal pharyngitis are fever, tonsillar exudate, tender anterior cervical lymphadenopathy, and lack of cough (three of four are required). It is important to identify and treat streptococcal pharyngitis in order to prevent rheumatic fever, but overdiagnosis and overtreatment may lead to ↑ cost and antibiotic resistance. Always consider occult sinusitis in febrile ICU patients. Diagnosed by clinical evaluation, rapid GAS antigen detection, and throat culture. With three out of four of the Centor criteria, the sensitivity of rapid antigen testing is > 90%.


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First_Aid_Step2. Diagnosed by clinical evaluation, rapid GAS antigen detection, and throat culture. With three out of four of the Centor criteria, the sensitivity of rapid antigen testing is > 90%. If GAS is suspected, begin empiric antibiotic therapy with penicillin × 10 days. Cephalosporins, amoxicillin, and azithromycin are alternative options. Symptom relief can be attained with fuids, rest, antipyretics, and salt-water gargles. Nonsuppurative: Acute rheumatic fever (see the Cardiovascular chapter), poststreptococcal glomerulonephritis. Suppurative: Cervical lymphadenitis, mastoiditis, sinusitis, otitis media, retropharyngeal or peritonsillar abscess, and, rarely, thrombophlebitis of the jugular vein (Lemierre’s syndrome) due to Fusobacterium, an oral anaerobe.


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First_Aid_Step2. Peritonsillar abscess may present with odynophagia, trismus (“lockjaw”), a muffed voice, unilateral tonsillar enlargement, and erythema, with the uvula and soft palate deviated away from the affected side. Culture abscess fuid and localize the abscess via intraoral ultrasound or CT. Treat with antibiotics and surgical drainage. Refers to infammation of the paranasal sinuses. The maxillary sinuses are most commonly affected. Can be classifed by site, organism, or chronicity. Subtypes include the following: Acute sinusitis (symptoms lasting < 1 month): Most commonly associated with viruses, S. pneumoniae, H. inﬂ uenzae, and M. catarrhalis. Bacterial causes are rare and are characterized by symptoms lasting < 1 week. Chronic sinusitis (symptoms persisting > 3 months): Represents a chronic infammatory process. Often due to obstruction of sinus drainage and ongoing low-grade anaerobic infections. In diabetic patients, mucormycosis should be considered.