Semio Book

C.T-scan in some situations may reveal more data concerning complications (e.g. biliar ileus, perforation) or it may bring more information (hepatic tumor) and assist biopsy.

M.R.I and more specifically magnetic resonance cholangiography M.R.C is a non-invasive technique for the evaluation of the biliary tract. M.R.I imaging contrast agent (Primovist) is used for differential diagnosis of focal liver lesions.

Endoscopic or mixt techniques

Echo-endoscopy or endoscopic ultrasound (E.U.S) is an essential diagnostic tool useful for the evaluation of biliary tract and gall bladder.

Endoscopic retrograde cholangiopancreatography (E.R.C.P) is a procedure that combines upper gastrointestinal (G.I) endoscopy and X-rays to diagnose lithiasis of hepatic and pancreatic ducts. It is not only a diagnostic procedure but also a therapeutic procedure as it allows the extraction of gall stones from the biliary main duct for example.

Percutaneous transhepatic cholangiography is an invasive procedure, which also allows biliary drainage.

Other investigation methods

Hepatobiliary scintigraphy is a nuclear imaging technique which uses radiotracers that allows the evaluation of the liver and biliary system.

Bile analysis is nowadays seldomly performed. If there is suspicion of cholangitis bile culture should be performed.

Liver biopsy: a minimally invasive technique which allows the acquisition of histological sampling required for histopathological diagnosis in some liver diseases. It is performed under U.S or C.T guidance.

Laparoscopy is performed only in those cases where the other techniques have failed to establish the diagnosis, and in which tissue sampling for histopathological examination is required for positive or differential diagnosis.

7.5.3.4. Biliary and hepatic syndromes

7.5.3.4.1. Biliary colic

In biliary colic the pain is caused by distension of the gallbladder due to stone migration or spasm of the cystic duct / common bile duct of the biliary tree. It usually occurs a few hours after a meal, especially one rich in fat. Also, trepidations, negative emotions, certain drugs (magnesium sulfate), cold, menstruation, digestive diseases could be triggering factors.

Characteristics of a colic are typically present: pain that "comes and goes", lasting 30 minutes to few hours. Since the pain may be continuous, it seems that in this situation the term colic is not in fact so accurate.

The initial history taking should focus on the location, duration, and character of the symptoms. The patient may have experienced it before.

Typically, pain is in the right hypochondrium or in the epigastrium. There might be atypical pain localization for example in left hypochondrium. Pain radiates "in half belt" on the subcostal ridge straight to the level of the spine, sometimes right interscapulo-vertebral, right humeral region, epigastrium.

Characteristics of pain may overlap that of any colic: tearing, rupture, tension, tightness. In the elderly, or in patients with neuropathies (diabetics) may be perceived as a painful embarrassment. Its intensity varies, being reduced (initially), but persistent and later becoming unbearable and maintaining its intensity in "plateau" until the cessation of the painful crisis (when the parietal edema resolves, or the calculus returns to the gallbladder).

Duration varies between minutes - hours (most frequently). More frequently there is a "timetable" of the onset occurring during night (between 20:00 and 04:00). There is not an antalgic posture, but local heat and antispasmodics may relieve or alleviate the pain. Biliary colic is frequently accompanied by nausea and vomiting.

In uncomplicated biliary colic, patients present frequently only with pain. Typically, patients are afebrile and physical exam is rather scarce with pain or discomfort located on the right upper quadrant or epigastric region, in comparison to acute cholecystitis and cholangitis. If complications develop, the asthenia, sweating, chills, and fever (acute cholangitis), jaundice, hyperchromic urine, paralytic ileus (prolonged colic) and less often cardiovascular symptoms (palpitations, angina) and/or respiratory (cough, dyspnea) may associate. Association of jaundice suggests an obstruction of the main bile duct: stone, inflammation, spasm.

If there is acute cholangitis Charcot's triad is present: combination of fever, abdominal pain (right upper quadrant) and jaundice. A pentad may also be encountered - Reynolds' pentad, in which mental status changes and sepsis (signs/symptoms: low blood pressure, tachycardia) are added to the triad (fig 7.7).

Figure 7.7 summary: A flow chart depicting the complications of classical biliary colic. Biliary colic can lead to acute cholecystitis, acute cholangitis, or pancreatitis. Acute cholecystitis may further progress to complications such as biliary ileus or biliary peritonitis. The diagram serves to map the potential clinical progression from biliary colic to more severe gallbladder and biliary tract conditions.

Investigations

Laboratory testing may reveal leukocytosis with neutrophilia, inflammatory syndrome: elevated C.R.P, E.S.R. If there is a passage of gallstones, or if complication have developed: liver enzymes, cholestasis, jaundice, markers of systemic infection may be elevated.

Imaging techniques, mainly ultrasound can confirm diagnosis, describe the presence of gallstone, edema of the gallbladder walls, dilatation or lithiasis of the main bile duct or presence of complications (fig 7.7 to 7.9).

In emergency rooms, and in certain cases (e.g. morbid obesity), C.T scan is a common technique used especially if there is severe abdominal pain. M.R.I is a highly useful technique for the evaluation of the biliary tract, especially for choledocholithiasis, if the other technique has failed to bring more data.

E.U.S may be needed in patients with prolonged symptoms or alterations of the laboratory testing and E.R.C.P, since it allows the detection and extraction of gall stones from the biliary main duct, may be needed for diagnosing or therapeutic purposes.

Figure 7.8 summary: An ultrasound image of the abdomen showing a bright, echogenic focus in the main bile duct, indicated by a white arrow. This finding depicts lithiasis, or the presence of a stone, within the main bile duct.

7.5.3.4.2. Acute cholecystitis

Acute cholecystitis is one of the causes of the acute pain in the right hypochondrium and may be cause of an acute abdomen. It is the frequent complication of gallstones. Often, there is a specific aliment leading to the acute attack (e.g. fatty foods like sour cream, egg yolk etcetera).

The main symptom is the pain – acute, sharp pain located in right hypochondrium or epigastrium. Pain may irradiate to right shoulder, or interscapular and this may reflect diaphragmatic irritation. Other symptoms that may be present are fever (high fever), chills, tachycardia. If complications have arisen, peritoneal irritation signs may be present (e.g., tenderness in the right hypochondrium or epigastric region, guarding or rebound).

There are certain groups in which acute cholecystitis may present with a different scenario: in elderly (diabetics, neuropathies) – symptoms may be scarce, sometimes only the localized tenderness may raise the suspicion. In these patients the evolution may be rapid towards complication.

Physical examination: superficial and deep palpation may reveal pain or sensibility, and localized abdominal wall edema if there is localized peritonitis (in the right hypochondrium). Murphy's maneuver is positive.

If there is obstruction of the cystic duct by a gallstone the G.B is large, oval, piriform, sensitive, moves with breath – G.B hydrops.

Empyema of the gallbladder is the most severe complication of acute cholecystitis. Symptoms overlap with those of acute cholecystitis. Clinical findings: palpable gallbladder, tender even on superficial palpation.

Patients may present rigors also. Unfavorable evolution towards G.B perforation leads to clinical symptoms and signs of septicemia and localized peritonitis.

Patients may present fever, tachycardia, or hypotension if it progresses to septic shock.

7.5.3.4.3 Portal Hypertension (P.H)

Definition

P.H is a clinical syndrome characterized by an increase of the pressure gradient between the portal vein (P.V) and the inferior vena cava I.V.C above 5 mmHg. It is a consequence of the obstruction in portal blood drainage located sinusoidally (intrahepatic) most frequently in cirrhosis, but also in other conditions, as in pre-and post-hepatic P.H.

Etiology

Etiology of the P.H is resumed in table 7.23.

: Table 7.23 summary: Causes of portal hypertension categorized by their anatomical location. Pre-hepatic causes include malformations, thrombosis, pilephlebitis, and compressions of the portal vein. Intra-hepatic causes are further divided into presinusoidal factors such as sarcoidosis, myeloproliferative diseases, and primary biliary cholangitis; sinusoidal factors including liver cirrhosis, acute hepatitis, Wilson's disease, and hemochromatosis; and postsinusoidal factors like Budd-Chiari syndrome and veno-occlusive disease. Post-hepatic causes include right heart insufficiency, chronic constrictive pericarditis, tricuspid insufficiency, and thrombosis of the inferior vena cava.

Clinical findings

Clinical findings may be divided into three groups of manifestations:

1. signs (and symptoms) due to increased pressure in the portal circulation:

a) the formation of porto-systemic collaterals:

- collateral circulation at the level of the flanks (porto-peritoneal/parietal shunt)

- caput medusae (tortuous collaterals arranged around the navel representing the reopening of the paraumbilical veins, relics of the fetal umbilical circulation)

- rectal varices

- ascites (and umbilical hernia)

Porto-systemic collaterals are divided into 4 groups:

- group Ia: at the level of the cardia (left gastric vein, short gastric veins + azygos vein, diaphragmatic veins): esophageal varices, fundic

Ib: at the level of the rectum (superior hemorrhoidal veins + middle and inferior hemorrhoidal veins): rectal varices

-group two: round ligament, repermeabilization of the umbilical vein ("jellyfish head")

-group three: hepato-diaphragmatic collaterals, hepato-diaphragmatic ligament, lumbar veins, previous post-laparotomy scars

-group four: spleno-renal anastomoses b) portal congestive gastropathy (upper digestive hemorrhage risk)

c) congestive splenomegaly (closely related to the value of pressure in the portal vein)

d) decrease in effective portal flow - manifestations of porto-systemic encephalopathy e) ascites 2. signs (and symptoms) of hyperkinetic circulatory status:

- large pulse

- warm, well-perfused extremities

- arterial hypotension

3. signs (and symptoms) of underlying liver disease (liver cirrhosis)

Complementary examinations have multiple purposes: to establish the diagnosis of P.H and type of P.H, to evaluate liver function and complications:

- abdominal ultrasound: shows suggestive changes for P.H: dilation of the portal venous system (portal vein greater than 13 millimeters, splenic vein, and superior mesenteric vein greater than 10 millimeters) recanalization of the round ligament, dilation of the gastric coronary vein, collaterals in the splenic hilum, etcetera Splenomegaly, collateral circulation, or shunts are also detected.

- digestive endoscopy typically reveals varices: esophageal, gastric, and duodenal varices (upper digestive endoscopy) or rectal varices (colonoscopy). Also, endoscopy has therapeutic roles: in case of upper digestive hemorrhages, in acute setting or for the prophylaxis of variceal bleeding (banding varices).

- C.T, M.R.I: provides data on the existence of collaterals.

Measurement of hepatic venous pressure gradient H.V.P.G is nowadays considered the gold-standard for measurement of portal hypertension.

Splenoportography, transhepatic portography, rectal scintigraphic portography or hepatic vein catheterization are invasive methods, nowadays extremely rare indicated.

7.5.3.4.4. Ascites

It refers to the signs and symptoms as result of the free fluid that may be present in the peritoneal space.

Here we refer to ascites which appears in patients with liver cirrhosis (normal peritoneum). There are also ascites arising from diseases of the peritoneum (by increasing the permeability of subperitoneal and serous capillaries) having for example infectious causes (bacterial, fungal, tuberculosis).

The mechanism that generates the accumulation of the fluids is initially the sequestration of blood at the splanchnic level, with lower effective volume, and in a second step through activation of the renin-angiotensin-aldosterone system leading to hydrosaline retention.

Symptoms of the patient depend on the amount of accumulated fluid and may vary from asymptomatic (small ascites) to multiple symptoms such as: early satiety, abdominal pain, dyspnea, anorexia, vomiting, dyspnea (large ascites).

Physical examination is very important as it may evidence ascites and sometimes its cause.

Inspection may reveal a patient with a bulging abdomen. In a patient with cirrhosis, other findings could also be present – see general physical examination described in this chapter. Ascitic fluid occupies the lowest point in the abdomen, producing initially, bulging of flanks. Depending on the quantity of fluid, the umbilicus may protrude.

In percussion there is typically dullness. If you turn the patient onto one side (lateral decubitus) you'll find one of the characteristics of ascites: the shifting dullness (dullness mobile with the position of the patient).

Palpation may reveal tenderness. Also, another test is a combination of palpation with percussion: "fluid wave" test: ask the patient or an assistant to press the edges of both hands firmly down the midline of the abdomen. This pressure helps to stop the transmission wave through fat tissue.

The association of ascites with other changes may be indicative of the etiology, for example:

- ascites + splenomegaly: cirrhosis, portal vein thrombosis or splenic vein thrombosis

- ascites + pleural effusion: congestive heart failure, cirrhosis, collagen vascular diseases, Demon-Meigs syndrome

- ascites + peripheral edema: congestive heart failure, hypoalbuminemia (nephrotic syndrome, cirrhosis, etcetera)

Cytological and bacteriological analysis of the ascites fluid obtained by paracentesis allows differentiation of a transudate (from P.T.H from the spontaneous bacterial peritonitis, or other type of exudates (infections or collagen diseases or even those neoplastic). Spontaneous bacterial peritonitis is defined as the infection of the ascitic fluid, without an obvious cause, clinically manifested by abdominal pain, fever, ascites resistance to diuretics. Examination of the fluid shows increased cellularity of the ascitic fluid ( greater than 250 P.M.N per millimeter cubed).

7.5.3.4.5. Hepatic Encephalopathy (H.E)

H.E is a reversible syndrome that appears in patients with advanced liver diseases.

H.E appears because of the accumulation of neurotoxic substances in the brain – neurotoxins include ammonia, short-chain fatty acids, mercaptans, false neurotransmitters. One theory is that ammonia-synthesized in the gut and normally detoxified in the liver – enters the systemic circulation and induces its neurotoxic action: alteration of neuronal transmembrane transport and inhibition of postsynaptic potential generation. A second hypothesis is that of "gaba" (gamma-aminobutyric acid). gaba is neuro-inhibitory substance generated at the level of the intestinal tract, that in patients with liver cirrhosis because of a deficient liver metabolism, there is an increase of gaba. gaba may cross the hyperpermeable blood-encephalic membrane and generates the hepatic encephalopathy.

H.E is characterized by a wide spectrum of manifestations neuropsychiatric ranging from subclinical to coma. Symptoms or manifestations frequently seen are confusion, personality changes, disorientation, or inverted sleep-wake patterns.

There are several clinical signs that might be present in these patients which may be suggestive for such as: asterixis, fetor hepaticus, inattention, altered sleep patterns, subtle personality changes or inappropriate behavior, dilated abdominal wall veins or splenomegaly.

H.E may be classified according to the West Haven Criteria (a semi-quantitative grading of mental state) into 4 grades:

- Grade 1: euphoria or anxiety, inattention, altered sleep patterns.

- Grade 2: lethargy or apathy, minimal disorientation, subtle personality changes or inappropriate behavior, asterixis

- Grade 3: somnolence (up to semi-stupor), confusion, gross disorientation

Grade 4: coma

Minimal H.E is encountered in some patients; therefore, we should carefully perform history taking and physical examination. In such patients, if there is cognitive dysfunction can be evidenced with neuropsychological testing.

Investigations:

- ammonia (increased)

- electroencephalography E.E.G

- C.T, M.R.I are used to exclude other intracranial lesions in these patients.

There are some well described favoring factors that may precipitate H.E: infections, transit disturbances (constipation), increased dietary protein intake or excessive administration of diuretics or tranquilizers/sedatives, bleeding (digestive tract).

7.5.3.4.6. Liver failure

Acute liver failure is one of the most complex clinical syndromes that can be encountered in subjects without an underlying chronic liver disease. It is induced by the inability of the liver to perform its functions (metabolic and synthesis) leading to acute fulminant hepatitis. More frequently the etiology is drug-induced liver injury in developed countries, whereas in developing countries viral hepatitis remains the leading cause.

In acute liver failure the triad: coagulopathy (hemorrhagic diathesis, intravascular disseminated coagulopathy), jaundice and hepatic encephalopathy, may be encountered.

Patients typically exhibit an indole/ scathol/ radish smell - "foetor hepaticus", or of fresh liver. This "mousy" odor of breath is due to the volatile compounds. Also, flapping tremor or asterixis may be seen in these patients.

Depending on the time interval between the onset of liver dysfunction and the onset encephalopathy, there is a classification into: fulminant ( less than 7 days), acute (8 to 28 days) and subacute ( greater than 4 weeks).

Also depending on the etiology of the liver failure eg. toxic (alcoholic hepatitis) there could be other signs present such as: Dupuytrén's contracture, jaundice etcetera

History taking is extremely valuable for these patients, each time is possible (the patient may be already in coma!). It may give information regarding previous episodes (patient had same abnormal behavior in the past), or epidemiological data – contact diagnosed with E hepatitis.

Laboratory evaluation should include common blood tests, liver blood tests, I.N.R, renal function, metabolic tests, viral hepatitis serologies, toxicology screening and acetaminophen level, autoimmune markers and arterial blood gas. Ceruloplasmin serum levels should be required if Wilson disease is suspected. If there is a history of travel to tropical sites/endemic areas for specific viral pathogens, additional test should be ordered (eg. for hepatitis E). Abdominal imaging studies - ultrasonography are very important since it allows the detection of various liver diseases. Furthermore, C.T-scans or M.R.I may be needed for detailed characterization of the culprit.

7.5.3.4.7. Jaundice

Jaundice or icterus is a yellowish coloration of the skin and mucosa due to an increased level of bilirubin in the blood above normal values (normal values 0.5 – 1 milligrams %). The yellowish color is visible usually when serum bilirubin reaches 2.5 – 3 milligrams % (50 µmols/l). The term subicterus is used when serum bilirubin is of 1.5 – 2 milligrams% and the jaundice is seen only on mucosas.

Normally, the hepatocytes conjugate the unconjugated bilirubin, turning it and then excreting the conjugated bilirubin into the bile – see figure 7.10 for bilirubin metabolism.

Figure 7.10 summary: A flow diagram of bilirubin metabolism showing the breakdown of red blood cells, cytochromes, and inefficient hematopoiesis into heme. Heme is converted by heme oxygenase into biliverdin, which is then reduced to soluble unconjugated bilirubin. This unconjugated bilirubin can reversibly bind to albumin or be converted by UDP-glucuronosyltransferases and glucuronic acid into water-soluble conjugated bilirubin. The conjugated bilirubin then enters the small bowel, eventually leading to the production of stercobilinogen in the colon and urobilinogen in the urine.

The patient should be examined in natural light preferably, since incandescent bulbs may diminish the intensity of the jaundice – please see volume 1 (general physical examination). Jaundice can be classified as: 1) Pre-hepatic, as result of increased bilirubin production from excessive breakdown of red cells such in hemolysis; 2) hepatocellular (hepatic) resulting from diseases of the liver parenchyma, sometimes referred to as “nonobstructive jaundice”; and 3) posthepatic referred to also as “obstructive” appearing as a consequence from mechanical obstruction of the biliary ducts outside the liver.

In table 7.24 are listed the causes of the jaundice.

Table 7.24 summary: Jaundice is classified into three etiologies based on the location of the cause. Pre-hepatic causes include hemolytic anemias, ineffective erythropoiesis, Bomer anemia, the resorption of big hematomas, and hereditary defects of hepatic conjugation such as Gilbert and Crigler Najjar syndromes. Hepatic causes include acute and chronic hepatitis, ischemic conditions, cirrhosis, pregnancy, intoxication from drugs or mushrooms, drugs like steroids, toxins, and hereditary defects of biliary excretion such as Rotor and Dubin Johnson syndromes. Post-hepatic causes are characterized by extrahepatic cholestasis, including lithiasis, cholangiocarcinoma, PBC, bile duct stenoses, pancreatic neoplasm, chronic pancreatitis, pancreatic pseudocyst, carcinoma of ampulla of Vater, and lymphoma.

Physical examination: shows jaundice or icterus. Please do not forget that even shades of the jaundice may suggest the underlaying cause: pale-yellow (hemolytic jaundice), orange-yellow (hepatocellular jaundice), yellow-green (prolonged obstructive jaundice), and sometimes there could be overlapping causes.

Jaundice can be associated with other symptoms and signs that are relevant for the underlying pathology:

- in cholangitis, secondary to choledochal lithiasis (obstruction) could be encounter Charcot triad: jaundice, fever, pain (painful hepatomegaly).

- presence of jaundice, pruritus, Courvoisier-Terrier sign (palpable distended and nonpainful gall bladder), mid-epigastric pain radiating to the back, significant weight loss, migratory thrombophlebitis (Trousseau sign) – in pancreatic head cancer

- variable jaundice, episodes of upper digestive bleeding, acute pancreatitis and/or acute cholangitis - in carcinoma of ampulla of Vater

- jaundice, pruritus, asthenia, weight loss - in biliary tract neoplasia (in general, the appearance of jaundice in the absence of pain suggests malignant obstruction of the biliary tract)

- jaundice, pruritus, asthenia, xanthelasma, xanthomas - in primary biliary cholangitis.

Investigations

Laboratory testing

In table 7.25 information required for differentiating between the three types of jaundice is synthesized.

: Table 7.25 summary: Differential diagnosis of jaundice based on laboratory testing. Pre-hepatic jaundice, caused by hemolysis, is characterized by mainly unconjugated bilirubin, absent urine bilirubin, increased urine UBG, normal prothrombin time, and hemolysis on blood smear. Hepatocellular jaundice, such as viral hepatitis, shows a mix of unconjugated and conjugated bilirubin, present urine bilirubin, variable urine UBG, abnormal prothrombin time not corrected by Vitamin K, and elevated ALT and AST. Obstructive jaundice, caused by main bile duct lithiasis, features mainly conjugated bilirubin, present urine bilirubin, decreased or absent urine UBG, abnormal prothrombin time that is corrected by Vitamin K, and a marked rise of ALP, usually greater than 3 times the normal range.

In some cases, still C.T-scan, M.R.I, cholangiogram, E.U.S, may be required to establish the diagnosis.

In figure 7.11 is represented an algorithm of complementary investigation of differential diagnosis of the type of jaundice

Figure 7.11 summary: A diagnostic flowchart for laboratory testing of bilirubin in serum and urine. The process branches based on bilirubin levels: normal ranges lead to a diagnosis of pseudojaunice; elevated total and conjugated bilirubin with urine presence leads to conjugated hyperbilirubinemia; and elevated total bilirubin without conjugated bilirubin or urine presence leads to unconjugated hyperbilirubinemia. Conjugated hyperbilirubinemia is further investigated through liver tests, imaging, and biopsies to differentiate between extrahepatic and intrahepatic diseases. The purpose of the diagram is to provide a systematic clinical pathway for diagnosing the cause of jaundice.

2.5.5.3.8 Cholestasis syndrome

- Cholestasis syndrome is defined as all the signs and/or symptoms due to the decrease bile flow due to dysfunction at the level of synthesis, excretion, or biliary drainage.

- Classification of the 2 types of cholestasis, intra-and extrahepatic respectively, and etiology are shown in the table 7.26.

Table 7.26 summary: The etiology of cholestasis is divided into intrahepatic and extrahepatic causes. Intrahepatic causes include ductopenia from conditions like PBC, cholangitis, cholangiocarcinoma, drugs, or toxins, as well as hepatitis, pregnancy, benign recurrent intrahepatic cholestasis, and specific drugs such as steroids, estrogens, contraceptives, carbamazepine, and cimetidine. Extrahepatic causes consist of obstruction of the main bile duct due to lithiasis, tumors, or strictures, and compressions resulting from chronic pancreatitis, pancreatic tumors, or carcinoma of Vater ampulla.

Clinical manifestations

A. by reducing bile transport/ secretion and plasma regurgitation of bile acids, bilirubin, and bile lipids.

- pruritus - itching, dominant symptom - attributed to the increase in the serum and tissue concentration of bile acids. Pruritus can be the first symptom, preceding the onset of jaundice, is predominantly nocturnal or exacerbated during night, disrupting sleep and leading/aggravating insomnia, initially localized (palms and soles), then diffuse, accompanied by grating lesions.

- jaundice is not mandatory, and it is preceded usually by pruritus. Jaundice is of obstructive type (associated with choleric urine and hypo/acholic stools). The combination of jaundice + pain - suggests a subacute obstruction of the bile duct system. Jaundice without pain - suggests malignant obstruction of the biliary tree (especially if it is progressive and associated with anorexia and significant weight loss)!

- xanthelasma and xanthomas are typical in severe and prolonged cholestatic syndromes

- xanthelasma - located on the upper eyelid (inner corner/ half) - and xanthoenas

- tuberous xanthomas – rarer, located at the level of tendon sheaths (extensors of the neck of the hand) and in pressure areas: elbows, knees, buttocks

- perineuronal lipid deposits - xanthomatous neuropathy - manifested by pain and paresthesia, in the hands and feet

- associated: asthenia, fatigue, weight loss (due to anorexia and lipid malabsorption). intolerance to fatty foods, gas dyspepsia, etcetera

B. by decreasing the concentration of bile salts in the intestinal lumen it leads to lipid and fat-soluble vitamins malabsorption:

- lipid malabsorption: steatorrhea

- vitamin A deficiency: hermalopia

- vitamin K deficiency: spontaneous bleeding

- vitamin E deficiency: nervous and sexual disorders

- vitamin D deficiency:

- hepatic osteodystrophy. Vitamin D deficiency is a characteristic of chronic cholestatic syndromes (ex: P.B.C

- osteoporosis (vertebral pain due to compression/vertebral fracture, round kyphosis)

- osteomalacia (bone pain, muscle weakness, fractures).

Investigations are needed to confirm cholestasis and to establish the level of the obstacle. They can be divided as following:

A. to confirm cholestasis syndrome

- increase of cholestasis enzymes: alkaline phosphatase A.L.P, gamma-glutamyl transferase G.G.T, 5-nucleotidase 5-N.T

- increased serum bilirubin (predominantly direct/conjugated; in association with bilirubinuria)

- hyperlipemia

- prolongation of prothrombin time (correctable by parenteral administration of vitamin K.1 – positive Koller test).

B. to establish the site of cholestasis (intra-or extrahepatic)

- U.S (usually first examination) - visualizes: gallbladder, bile ducts, liver parenchyma (focal lesions)

- E.U.S or magnetic resonance cholangiopancreatography for better characterization of bile ducts

- C.T scans: in patients when E.U.S or I.R.M cannot be performed (patients that have various devices I.R.M incompatible, patients that are not eligible for E.U.S), C.T scan allows a better evaluation of the anatomy of the biliary tree

- E.R.C.P - of choice for lithiasis of the main bile duct and pancreatic tumors; besides having disadvantages (invasive, irradiating) it has also multiple advantages - allows sphincterotomy, extraction of choledochal calculus, placement of stents, dilatation of strictures and a very good visualization of the bile ducts.

7.6. Semiology of the pancreas

The pancreas is involved in the alimentary activity, secreting enzymes for digestion; at the same time, the pancreas is also an endocrine organ, with special function in the homeostasis of blood glucose.

7.6.1. History taking

Age: Some congenital malformations, like cystic fibrosis (mucoviscidosis), pancreas divisum, start having clinical manifestations in young people. In children, the pancreas can be affected during infectious diseases (parotitis, measles, chicken pox), as well as in cystic fibrosis.

In adults, pancreatic pathology is dominated by acute and chronic pancreatitis and tumors of the pancreas (95% being adenocarcinomas). Acute biliary pancreatitis is also more common in adults (between 50 to 70 years).

In the elderly, pancreatic cancer is increasing in frequency.

Gender

Acute and chronic pancreatitis are more common in men (80% of cases of chronic pancreatitis occur in men), as well as pancreatic cancer (male: female ratio 1.5:1), while in women biliary pancreatitis is more frequent (female: male ratio 2:1). Family history

Cystic fibrosis has an autosomal recessive transmission.

Pancreatic cancer, especially cases with early onset (before 50 years), can have familial aggregation, as well as chronic autoimmune pancreatitis.

Personal pathological history

In case of pancreatitis, the conditions that can cause this disease should be investigated. Thus, gallstones (especially small, multiple stones) are very frequently responsible for the etiology of acute pancreatitis (40% of cases). The rare causes of acute pancreatitis also should be searched: malformations (pancreas divisum, choledochal cyst), severe hypertriglyceridemia ( greater than 1000 milligrams/dl), hypercalcemia, trauma, invasive interventions (endoscopic retrograde cholangiopancreatography-E.R.C.P), surgical interventions (surgery of the bile ducts, pancreas or stomach), ischemia (arteritis, embolic conditions), acute porphyrias (can increase the susceptibility of patients to develop acute pancreatitis, especially secondary to the consumption of certain drugs, such as such as statins), viral infections (H.I.V, herpes virus, hepatitis viruses, Ebstein-Barr, herpes viruses, cytomegalovirus) or parasitic infections (toxoplasmosis).

Sjögren's syndrome, inflammatory bowel diseases, annular pancreas, posttraumatic pancreatic ductal scars represent risk factors for chronic pancreatitis.

Certain pancreatic lesions (mucinous cystadenoma, papillary mucinous intraductal neoplasia), diabetes mellitus, and chronic pancreatitis are risk factors for pancreatic cancer.

Lifestyle and occupational risk factors

Acute pancreatitis often begins after a heavy, often high-fat meal.

Smoking is a risk factor for pancreatic cancer, with active smokers having a 3-fold increased risk of developing pancreatic adenocarcinoma compared to nonsmokers. The role of smoking in chronic pancreatitis remains controversial, especially since smoking and alcohol consumption are frequently associated in the same patient.

Alcohol consumption is a major etiological factor for both acute pancreatitis (30% of cases) and chronic pancreatitis (causes 60 to 90% of cases).

Rarely, some drugs can cause acute pancreatitis: thiazide diuretics, estrogens, azathioprine, glucocorticoids, valproic acid, etcetera

7.6.2. Symptoms

pain is the most common symptom in acute pancreatitis. Its characteristics are:

- sudden onset (often after heavy meals, rich in fat, protein and accompanied by alcohol consumption)

- felt in the upper abdominal area, typically being known as pain "like a belt" (the pain is in the epigastrum, with radiation to the right and left upper quadrant, and posteriorly to the lumbar region, below the ribs); irradiation can also be "transfixingly" in the back; some patients complain of pain in the entire abdomen or predominantly in one of the upper quadrants

- reaches a maximum intensity in 30 to 60 min, after which it remains constant for 2 to 3 days, then slowly subsides

- the intensity is very high, generating shock and requiring the administration of major analgesics

- increases in the supine position and after eating

- is relieved in a sitting position, in the "egg" position (anteflexion of the body on the thighs and the thighs on the abdomen, with the knees bent) and after administration of analgesics

Cave! Quick differential diagnosis with acute surgical abdomen (cavitary organ perforation, intestinal occlusion) is required.

Associated symptoms are:

- nausea and especially vomiting are the second most frequent symptoms, initially being alimentary, then bilious and even faecal (ileus); they are constant, appear early, are persistent and do not relieve pain

- important abdominal distension may be accompanied by cessation of faecal and gas transit (secondary to paralytic/dynamic ileus induced by intense pain)

- shock in acute pancreatitis with respiratory distress, (a rare situation). It is explained by the marked inflammatory syndrome, with the release of cytokines and by the loss of fluids in the retroperitoneal "third space".

- paralytic ileus

The Dieulafoy's triad: pain, vomiting, shock is pathognomonic for the diagnosis of acute pancreatitis.

Pain in chronic pancreatitis is explained by increased intraductal pressure (maintenance of secretory capacity in the presence of ductal obstructions) and by the discharge of nociceptive substances through chronic inflammation. The pain diminishes or disappears parallel to the onset of pancreatic exocrine insufficiency and the decrease in secretory flow, so the absence of pain does not exclude the diagnosis of chronic pancreatitis. Three phases of chronic pancreatitis are described:

1. In the first 5 years: chronic pain, with exacerbations. Complications are pseudocysts and compression of the common bile duct. Painful terms can last from a few hours to 2 weeks and alternate with long painless periods, are unpredictable and are generally triggered by alcohol consumption. There are also patients who have almost continuous pain.

2. Between 5 and 10 years: rare exacerbations pancreatitis, still risk of developing pseudocysts (especially retention) and compression of the common bile duct (frequency increasing linearly over time).

3. After 10 years of evolution: decreased pain incidence and risk of surgical complications, increased risk of pancreatic cancer. Manifestations of exocrine pancreatic insufficiency and diabetes predominate.

Characteristics of pain in chronic pancreatitis are the following:

- location: usually in the left epigastrium or hypochondrium, with radiation to the lumbar area. Less often, the pain is felt periumbilically, with radiation throughout the abdomen, or transfixing posteriorly at the level of vertebrae D.10 to D.12

- continuous, lasting for several days (differential diagnosis: biliary colic) and forces the patient to stop eating

- occurs after drinking alcohol (within 12 to 24 h), but also late postprandial

- high intensity (but less than in acute pancreatitis)

- character: distension or pressure

Associated, patients with chronic pancreatitis complain of anorexia, nausea, sometimes vomiting, flatulence, diarrhea. Over time, after 15 years from onset, the malabsorptive syndrome develops (steatorrhea, weight loss, etcetera) and secondary diabetes occurs. After 10 to 20 years of evolution, exocrine pancreatic insufficiency sets in, being manifested (when pancreatic parenchyma is reduced by more than 90%): steatorrhoeic stool (voluminous, pastyligoid, discolored -clay yellow, shiny, with a rancid smell, may float on the surface of toilet water) due to maldigestion and malabsorption of lipids; inhomogeneous appearance of lienteric stool (food residues are macroscopically identifiable), also a consequence of the malabsorption syndrome.

Other symptoms are secondary to complications: gastric outlet syndrome (nausea, postprandial vomiting, marked weight loss) by duodenal compression (by hypertrophy, fibrosis, cephalic pseudocyst, or cystic dystrophy of the duodenal wall); transit disorder-mechanical ileus (meconium ileus as an early sign of cystic fibrosis), fever in mesenteric venous thrombosis; choledochal compression (due to fibrosis or pseudocysts) usually develops with asymptomatic anicteric cholestasis.

Pancreatic neoplasia pain is a chronic, dull one, initially of low intensity, later becoming more severe, located in epigastrium. In cancers of the tail of the pancreas, the pain is localized to the left hypochondrium. In corporeal tumors, pain is felt in the epigastrium and lumbar region. The pain is increased during night and in the supine position. Steatorrhea may occur due to exocrine pancreatic In severe acute necrotic-hemorrhagic pancreatitis, the diffusion of pancreatic enzymes can cause necrosis of adipose tissue, with the appearance of periumbilical ecchymosis (Cullen's sign) or in the flanks (Grey-Turner's sign).

Palpation of the abdomen if pancreatic disease is suspected will be done gently, as the patient usually presents with severe abdominal pain.

In acute pancreatitis, skin hyperesthesia may be present in the semibelt, in an area starting at the anterior midline, continuing to the left hypochondrium and posterior to the vertebral column (D.10 to D.12). Also in acute pancreatitis, when palpating the region in the epigastric area, the feeling of throbbing caused by the marked peripancreatic inflammation can be perceived (without contracture or muscular defense occurring as in digestive perforations).

The painful areas at palpation are:

-pancreatico-choledochian area (Chauffard's triangle): pancreatitis, the cephalic neoplasia; the area is bounded by the xipho-umbilical line, the right costal border and a line that joins the umbilicus to it, at an angle of 45 degrees to the xiphouumbilical line

- pancreatic point: chronic pancreatitis; located 5 to 6 centimeters from the umbilicus, on the line between the umbilicus and the right armpit

- left costo-muscular point, located in the angle created by the 12th rib and the paravertebral muscles (Mayo-Robson's sign).

- the Mallet-Guy point: at the meeting of the left rib edge with the external border of the rectus abdominis and is the place to palpate the tail of the pancreas, with little clinical value. The Mallet-Guy maneuver consists in compressing the tail of the pancreas in the patient in the right lateral decubitus.

Pancreatic tumors are accessible to palpation only when they are already very large, and especially if they are located cephalically; consistency is different: hard (adenocarcinoma), elastic (pseudocyst) or fluctuating (abscess); neoplasias are immobile with breathing in the epigastric region and against the surrounding tissues.

Prolonged choledochal obstruction (caused by neoplasm of the head of the pancreas) is associated with dilation of the extrahepatic and intrahepatic bile ducts and marked distension of the gallbladder (vesicular hydrops) that becomes palpable. A pear-like mass will be palpated under the lower edge of the liver, elastic and mobile with respiratory movements (Courvoisier-Terrier's sign). This sign can also occur in other situations of chronic choledochal obstruction, for example Vater's ampulloma or chronic hypertrophic cephalic pancreatitis.

Percussion

Percussion is of little use in exploring the pancreas. Percussion is useful, however, to highlight the abdominal hypertimpany secondary to paralytic ileus (acute pancreatitis) or the abdominal dullness (ascites) in acute pancreatitis or advanced pancreatic cancer (shifting dullness with position) (corresponding to the so-called sentinel loop, dilated loop due to paralytic ileus).

Left pleural effusion may be present in severe acute pancreatitis (sign of severity) and in chronic pancreatitis (caused by a fistulized pseudocyst in the pleural cavity). In these situations, during the physical examination of the respiratory system, left basal dullness will be present.

Auscultation

Abdominal auscultation is important if dynamic ileus associated with acute pancreatitis is suspected - the hydro-aeric sounds will be absent. Rarely, murmurs can be heard in the epigastrium caused by the compression of some arterial trunks (splenic or mesenteric artery) by pancreatic tumors.

7.6.4. Investigations

Functional exploration of the pancreas

Faecal fat/24-hour dosing (steatorrhea) is a noninvasive method of assessing lipid use, values greater than 7g/day being pathological.

Faecal pancreatic elastase assay assesses the degree of exocrine pancreatic insufficiency. Values greater than 200 µg/g faecal matter are considered normal, values between 100 to 200 µg/g are uncertain but may suggest a mild/ moderate pancreatic insufficiency, and values less than 100 µg/g are found in severe pancreatic insufficiency.

Serum trypsin less than 20 ng/ml is specific for chronic pancreatitis, but with high sensitivity only in the advanced forms.

On microscopic examination of faeces - undigested muscle fibers, neutral fats and extracellular starch can be observed.

Serum amylase is mainly secreted by the pancreas and salivary glands, in the form of two isoenzymes. It has a relatively low specificity for acute pancreatitis, increasing also in other pancreatic conditions, but also in extrapancreatic conditions (bile duct diseases, esophageal rupture, peritonitis or intestinal-mesenteric infarction, perforated ulcer, acute appendicitis, tubal-ovarian abscess, ruptured ectopic pregnancy, advanced renal failure). Macroamylasemia is characterized by serum pancreatic amylase values 6 to 8 times normal, but with amylazuria within normal limits, in a patient without clinical manifestations of acute pancreatitis.

It is determined by the presence of a macromolecule that is not eliminated renally. Salivary amylase increases in salivary gland diseases (epidemic parotiditis, inflammation, ductal obstruction by lithiasis, irradiation).

In acute pancreatitis, amylase increases rapidly in 3 to 6 hours, reaches maximum values in 24 to 48 hours, and returns to normal in 3 to 5 days. Normal values are less than 100 U/l. Amylasemia values must increase at least 3-fold to support the diagnosis of acute pancreatitis.

Urinary amylase increases in parallel with amylasemia (after 6 to 10 hours after the elevation in serum amylase), and returns to normal more slowly, after 10 days. The normal value is less than 400 U/l. The measurement of urinary amylase is useful in pancreatic pseudocyst diagnosis because urinary amylase persists for several weeks after normalization of serum amylase.

Serum lipase is involved in the hydrolysis of triglycerides, having a higher specificity in the diagnosis of pancreatic diseases compared to serum amylase. Values exceeding 3 times normal are suggestive of acute pancreatitis. Lipase persists for a longer period in serum (7 to 10 days) but can also increase in Wirsung duct obstruction (by compressive cyst or tumor), cholecystitis, peritonitis, mesenteric venous thrombosis, ileus, liver cirrhosis, chronic renal failure. Normal values are less than 60 U/l.

Other laboratory investigations

In acute pancreatitis

- inflammatory syndrome with leukocytosis (10.000 to 30.000/mm cubed), increase of C.R.P (C-reactive protein)

- an increase in A.L.T greater than 80 U/L suggests biliary etiology of pancreatitis

- dosage of serum triglycerides, calcium - with the aim of identifying the etiology of acute pancreatitis

A number of these parameters help assess the severity of acute alcoholic pancreatitis in the first 48 h by calculating the Ranson score. The monitored parameters at admission are:

1. leukocytosis greater than 16000/mm cubed

2. glycemia greater than 200 milligrams/dl

3. L.D.H greater than 350 U/L,

4. A.S.T greater than 250 U/L

5. age over 55 years

and after 48 hours:

1. decrease of hematocrit by greater than 10%

2. increase of urea by greater than 5 milligrams/dL

3. P a O 2 less than 60 mmHg

4. serum Ca less than 8 milligrams/dl (4 mEq/dL)

5. base deficit greater than 4 mEq/L

6. fluid retention greater than 6 L (clinically assessed).

The presence of three criteria predicts a complicated evolution of acute pancreatitis. Serum tumor markers (Ca ^{19 to 9} , C.E.A are of rather limited utility given their low sensitivity and specificity.

Imaging

Abdominal ultrasound (U.S) is the most frequent method used, it can highlight changes in the structure and volume of the pancreas, as well as the possible etiology of acute pancreatitis by revealing gallstones. Thus, in acute edematous pancreatitis, the pancreas becomes more hypoechoic; in severe forms, intra-and peripancreatic collections appear, forming pseudocysts. In chronic pancreatitis, the presence of parenchymal calcifications, ductal dilatations and cystic images are highly suggestive for the diagnosis. Pancreatic adenocarcinoma usually appears as a poorly delimited hypoechoic mass.

Computed tomography (C.T) is an extremely useful examination, offering information about the morphology and the presence of focal lesions (assessing the existence of necrosis in acute pancreatitis, and of tumor vascularization in neoplasia). It allows establishing the severity of an acute pancreatitis (Balthazar score), the presence of intrapancreatic necrosis, complications (pseudocysts, abscesses, retroperitoneal fusae), as well as the staging of the pancreatic neoplasm. It is the most sensitive method for highlighting pancreatic calcifications (pathognomonic for chronic pancreatitis).

Magnetic resonance imaging (M.R.I) has the same accuracy as C.T.

Echoendoscopy (E.U.S) allows the visualization of the pancreatic parenchyma, the choledocus and the adjacent vascular structures, in addition allowing the puncture-aspiration biopsy. It is an essential examination in the pre-therapeutic assessment (local staging) and follow-up of pancreatic cancer.

Endoscopic retrograde cholangiopancreatography (E.R.C.P), being an invasive method, is used less for diagnostic purposes (in chronic pancreatitis or pancreatic cancer). However, it is the method of choice in acute pancreatitis of biliary etiology, allowing desobstructing of the common bile duct and placement of pros-thee-seez in Wirsung's stenosis and choledochal tumor obstruction.

7.6.5. Syndromes

7.6.5.1. Acute pancreatitis

Acute pancreatitis represents the acute inflammation of the pancreatic tissue due to alcohol abuse (35%), biliary obstruction (40%), medication (10%) such as diuretics, betablocker, A.C.E-inhibitors, estrogens, glucocorticoids, antibiotics, N.S.A.I.D's, citostatics, genetics or other rare reasons (severe hypertriglyceridemia, hypercalcemia, autoimmune, abdominal trauma, viral infections, malformation-pancreas divisum, transplanted pancreas).

Figure 7.12 summary: A CT scan showing the pancreas with extensive bright, white deposits. These high-density areas indicate chronic calcific pancreatitis, where calcium deposits have formed within the pancreatic tissue.

There are 2 forms: a) edematous (mild) pancreatitis. b) necrotic-hemorrhagic (severe) pancreatitis

Symptomatology: sudden onset with acute abdominal pain upper abdomen (as described above), nausea, vomiting, (sub)ileus, bloating, fever, shock

Physical exam: paralytic ileus, ascites, jaundice, periumbilical hematomas (Cullen sign) or in the flancs (Grey-Turner sign), left pleural effusion.

Complications: bacterial infections of necrotic areas, sepsis, shock, pancreatic abscess, pseudocysts, acute renal failure.

Laboratory data show: elevated serum lipase (there is no direct correlation between its value and the severity!) and amylase at least 3 times the normal level; inflammatory syndrome (C.R.P, L.D.H, leucocytosis)

Unfavorable prognostic represents hypocalcemia less than 2 millimoles/l, increase of creatinine, L.D.H greater than 350 U/l and hyperglycaemia.

Imaging:

Ultrasound (fig 7.13, 7.13): increased and flu delimited pancreatic area (edema), necrosis, abscesses, pleural effusion, ascites, extrahepatic cholestasis, and gallbladder stones (biliary etiology)

clinical relief after 3 to 5 days

E.R.C.P - if obstruction of choledocus is suspected.

Figure 7.13 summary: An ultrasound image of the abdomen showing a large, heterogeneous mass with mixed echogenicity in the region of the pancreas. The image depicts the structural changes associated with chronic calcific pancreatitis.

Diagnosis is established by history taking+ lipase level+ U.S; in biliary etiology: + cholestasis and cytolysis, stones (E.U.S/U.S, MRCP/E.R.C.P)

7.6.5.2. Chronic pancreatitis

Chronic pancreatitis is a chronic disease with progredient loss of exocrine and endocrine function of the pancreas; 80% are caused by chronic alcohol abuse, the rest of 20% belonging to other different etiologies, such as: ereditary and autoimmune pancreatitis, idiopathic, smoking, medication, hyperparathyroidism.

Symptomatology: often oligosymptomatic; recurrent upper abdominal pain (90%) in the guiding complaint, lasting sometimes days, “like a belt”; intolerance for fatty meals (nausea, vomiting, dyspepsia); maldigestion (weight loss, steatorrhoea, diarrhea), secondary diabetes mellitus

Physical exam: pain at deep palpation of the upper abdomen; reccurent jaundice (if there is compression on choledocus)

Complications: pancreatic pseudocysts and carcinoma; thrombosis of v.lienalis or porta; stenosis of pancreatic ducts, duodenum or choledocus; pancreatic lithiasis. Laboratory data: low elastase levels in stool.

Imaging: U.S and Endoscopic ultrasound (E.U.S)-pancreatic calcifications (especially in alcoholic etiology); dilatations alternating with stenosis of pancreatic ducts; pseudocysts.

Contrast enhanced C.T (fig 7.14, 7,15)-pancreatic calcifications, irregular pancreatic ducts, pseudocysts.

Figure 7.14 summary: An axial CT scan of the abdomen showing the pancreas with multiple bright, high-density spots. These areas of calcification within the pancreatic tissue are characteristic of chronic calcific pancreatitis.

E.R.C.P, M.R.C.P-stenosis of pancreatic, choledocus ducts and duodenum. U.S-guided puncture of suprainfected necrotic areas.

Diagnosis is established by proof of repeated acute pancreatitis episodes (Cave: normal lipase levels do not exclude a chronic pancreatitis!), of exocrine pancreatic insufficiency (low elastase levels in stool-most sensitive method) and by imaging: morphological changes (pancreatic calcifications; irregular pancreatic ducts; pancreatic lithiasis), complications (pseudocysts, stenosis of choledocus, duodenum)

Figure 7.15 summary: An axial CT scan of the abdomen showing the pancreas with extensive calcifications. This imaging is used to demonstrate the characteristic findings of chronic calcific pancreatitis.

7.6.5.3. Pancreatic carcinoma

Pancreatic carcinoma is the most common form among digestive neoplasms, after colon and stomach. It is diagnosed and treated with difficulty and has a bad prognosis. The exact cause in unknown, but smoking, heavy drinkers, obesity, chronic pancreatitis, and cystic tumors of pancreas are involved. Adenocarcinomas are the most frequent encountered form.

Symptomatology: early symptoms are missing! The clinical picture is similar with the one in chronic pancreatitis (unspecific upper abdominal pain, nausea, loss of weight and appetite); jaundice (tumors of head of pancreas in 90% in late stages), back pain (often).

Physical exam: - jaundice (early sign in 25% of head tumors)

- Courvoisier-Terrier sign (palpable painless hydrops with jaundice) due to compression on the choledocus

- migratory thrombophlebitis

Complications: local invasion of mesenteric vessels and generalized metastases Laboratory data show:

- new diagnosed diabetes mellitus/pathological oral glucose tolerance test

- tumoral markers (Ca 19 to 9, C.A.50: for postoperative follow-up Imaging: U.S: flu, hypoechoic, inhomogeneous mass

E.U.S with fine-needle-biopsy (to be avoided if tumor seams operable) sensitive in tumors less than 1 centimeters, assesses the regional staging(invasion)

Contrast enhanced M.R-best method.

Diagnostic laparoscopy: if operability is doubtful.

Diagnosis is established by corroborating imaging with clinical picture.

7.6.5.4. Endocrine insufficiency

Pathology of the endocrine pancreas is dominated by diabetes mellitus (D.M), a very common condition and a component of the metabolic syndrome. At the level of the pancreas, several other hormones are also secreted (glucagon, V.I.P, somatostatin, etcetera). Disturbance of their secretion is usually secondary to some secreting pancreatic endocrine tumors, that will cause specific clinical syndromes.

Diabetes Mellitus (D.M)

D.M represents chronic hyperglycemia determined by the absolute/relative lack of insulin, or by factors that prevent the normal activity of this hormone.

History taking

Age: Type 1 D.M occurs mostly in children and young people, before the age of 40. Type 2 D.M occurs in adults and the elderly.

Gender

D.M type 2 has a higher prevalence in men (male: female ratio 2:1). Family history

Genetic factors are clearly involved in the occurrence of D.M type 2.

Maturity-onset diabetes of the young mody type D.M secondary to a genetic defect of B-cell function, is transmitted autosomal dominantly.

Pancreatic endocrine tumors can be hereditary, being part of the multiple endocrine neoplasia M.E.N syndrome type I, which is usually transmitted in an autosomal dominant manner.

Personal pathological history

Gestational diabetes (glucose intolerance manifested during pregnancy, in the second or third trimester), has the following risks: of developing D.M later (mother) and abortion, fetal macrosomia, respiratory distress (fetus).

Different conditions can complicate over time with secondary D.M, such as pancreatic diseases (acute, chronic pancreatitis, pancreatic cancer, cystic fibrosis, hemochromatosis), endocrinopathies (Cushing's syndrome, acromegaly, glucagonoma) pr infections (epidemic parotiditis, Coxsackie B, rubella, C.M.V Lifestyle and professional risk factors

Sedentaryism and excessive food intake (causing obesity) are the major environmental factors involved in the pathogenesis of type 2 D.M. It is important to obtain qualitative and quantitative data about daily food intake.

Some drugs may lead to secondary D.M: glucocorticoids, alpha/beta blockers, thiazide diuretics, antiretroviral nucleoside analogues and antiproteases (H.I.V), hydantoin, nicotinic acid, etcetera

W.H.O's etiological classification of D.M is presented in (Table 7.27).

Table 7.27 summary: The etiological classification of diabetes mellitus, categorized into four main groups. DM type I is divided into immunologically mediated Type I A and idiopathic Type I B. DM type II and Gestational DM are listed as distinct categories. Specific types of DM encompass a wide range of causes, including genetic disorders of beta cell function like MODYdiabetes, genetically determined changes in insulin action such as lipoatrophic diabetes, diseases of the exocrine pancreas, endocrinopathies like Cushing's syndrome, drug-induced cases from glucocorticoids or thiazides, infections, rare immunological forms, and other genetic syndromes including Down, Turner, and Prader-Willi.

Clinical manifestations

Symptoms:

-the classic triad (typical for D.M type I, in type 2 it may be incomplete/lacking):

1. Polyuria (consequence of glycosuria (which occurs at blood glucose values greater than 180 milligrams/dl, when the tubular glucose reabsorption capacity is exceeded).

2. polydipsia (due to: hyperosmolar state, that causes intense thirst; osmotic polyuria, which leads to intracellular dehydration)

3. polyphagia, which tends to compensate for caloric losses

- none: D.M type 2, is usually discovered incidentally during a biological assessment of a cardiovascular condition or preoperatively.

- asthenia (caused by loss of glucose, therefore of energy, muscle protein catabolism, hypokalemia)

- marked weight loss, despite a normal/increased appetite

- manifestations of an acute metabolic complication (ketoacidosis, hyperosmolar hyperglycemic state, etcetera).

Some clinical characteristics of the two main types of D.M are presented in Table 7.28.

Table 7.28 summary: Diabetes Mellitus type II is significantly more frequent than type I, accounting for 90 percent of cases compared to 5 to 10 percent for type I. Type I is an autoimmune disease involving the destruction of B cells in the islets of Langerhans, typically appearing suddenly in thin individuals under 30 years old. In contrast, type II is secondary to insulin resistance, typically appearing insidiously in overweight or obese adults over 40 years old, often with a family history of the disease or a history of fetal macrosomia. While type I is usually diagnosed in symptomatic patients presenting with a classic triad or complication, type II is frequently discovered incidentally during biological assessments while the patient is asymptomatic.

Physical exam:

Changes in the skin

- face: diabetic rubeosis

- lower limbs: dry, atrophic, shiny, pink-violet

- in hypoglycemia: cold, pale, and moist

- occurring skin infections resistant to treatment (pyoderma, mycoses)

- lipoid necrobiosis or migratory necrolytic erythema (hard papules on the lower limbs with evolution towards areas of atrophy with a waxy yellow center, surrounded by an erythematous rim)

- ulcerations, bedsores, gangrene (due to diabetic angiopathy)

- plantar ulcer ("mal perforant plantaire") - painless, atonic, round, deep ulcer, with sharp, insensitive edges, located on the plantar side of the metatarsophalangeal joints - increased risk of infection, sepsis, and the main cause of amputation

- insulin lipodystrophy at the site of insulin injection (atrophy of the subcutaneous tissue at the injection site, causing the appearance of depressed areas)

Subcutaneous cellular tissue

- obesity in D.M type 2, especially abdominal obesity

- edema of the foot (through vasodilatation, increased capillary permeability)

Osteoarticular changes

- the deformed, "widened" Charcot foot, with hammer toes is a neurotrophic arthropathy (alteration of sensory or proprioceptive innervation) - the neuropathic foot

Neurological changes

- osteotendinous hyporeflexia (diabetic neuropathy)

- seizures in K.A.D, hyperosmolar hyperglycemic state, hypoglycemia

Disturbances of the state of consciousness - described above, in the context of acute metabolic complications.

Signs of intracellular dehydration are:

- dryness of mucosa and skin

- intense thirst

- fever

-confusional syndrome, convulsions, coma

Signs of extracellular dehydration are:

- persistent skin fold

- eyeballs sunken into the orbits

- tachycardia, orthostatic hypotension, arterial hypotension

Diagnosis of D.M:

1. Two fasting glucose levels greater than 126 milligrams/dl (on different days) or one glucose level

greater than 200 milligrams/dl at any time of the day

2. O.G.T.T: glycemia at 2 hours greater than or equal to 200 milligrams/dl

A. Acute Complications of D.M:

1. evolving with hyperglycemia (table 7.29):

a) Diabetic ketoacidosis (K.A.D), the major complication of type 1 D.M, is the consequence of absolute insulin deficiency. It can be the first manifestation of type 1 D.M. The definition of K.A.D is biological: the association of hyperglycemia with glycosuria and ketonemia with ketonuria, under conditions of acidosis.

b) Hyperosmolar hyperglycemic state is typical for D.M type 2, being a state of marked dehydration secondary to severe hyperglycemia.

c) Lactic acidosis is a rare complication during treatment with oral antidiabetics of the biguanide type (metformin).

Table 7.29 summary: Clinical and laboratory distinctions between three acute hyperglycemic complications of diabetes mellitus: Ketoacidosis (KAD), Hyperosmolar hyperglycemic state, and Lactic acidosis. KAD is characterized by glycemia over 250 mg/dl, pH under 7.3, and intensely positive ketonic bodies, with clinical signs including Kussmaul breathing and the smell of acetone. Hyperosmolar hyperglycemic state presents with much higher glycemia, over 600 mg/dl, pH over 7.3, and absent or slightly increased ketonic bodies, featuring more severe dehydration than KAD. Lactic acidosis, often linked to Metformin overdose, is identified by severe hyperventilation, severe acidosis with pH under 7.3, and serum lactate levels over 5 mmol/L, while glycemia can be normal, high, or low.

Hypoglycemia (blood glucose less than 60 milligrams/dl)

Clinical symptoms of hypoglycemia are:

- Neuropsychiatric (secondary to neuroglycopenia): headache, visual disturbances (even diplopia), slurred speech/aphasia, marked asthenia or restlessness, anxiety, confusional state, seizures, amnesia, coma, muscle spasms, perioral paresthesia

- Vegetative: palpitations, tachycardia, sweating, tremor

- Others: nausea, vomiting, feeling hungry

Diabetic patients, either on insulin or on oral hypoglycemic agents, are at risk of developing hypoglycemia. Severe, untreated hypoglycemia can progress to coma, so it is very important to know its manifestations. Sometimes the appearance of hypoglycemia is favored by intense physical exertion, alcohol consumption or reduced food intake.

Whipple's triad is characteristic for hypoglycemia (regardless of the cause):

1. History of symptoms of hypoglycemia.

2. Fasting blood sugar less than 40 milligrams/dl.

3. Rapid improvement of symptoms after administration of glucose.

B. Chronic Complications of D.M:

a) macroangiopathy, responsible for complications such as coronary artery disease stroke, renal artery stenosis, and arteriopathy obliterans of the lower limbs.

b) microangiopathy, will cause diabetic nephropathy, diabetic retinopathy (ophthalmological and fundus examination), diabetic neuropathy.

c) susceptibility to infections (urinary, skin and E.N.T

d) diabetic foot

e) neuropathy can be vegetative or somatic (peripheral) sensorimotor. The manifestations of vegetative neuropathy are:

- urogenital - impotence, micturition difficulties due to bladder paresis (neurogenic bladder), causing bladder stasis and favors urinary infections

- digestive: dyspeptic syndrome (nausea, bloating, postprandial fullness) due to diabetic gastroparesis, postprandial or nocturnal diarrhea alternating with constipation

- cardiovascular - orthostatic hypotension (systolic blood pressure drops by more than 30 mmHg while standing and/or diastolic blood pressure by more than 15 mmHg) which is manifested by dizziness, fainting, fatigue, and blurred vision, when standing up suddenly.

- thermoregulatory function disorders – distal anhidrosis, heat intolerance

Peripheral neuropathy includes symmetric distal polyneuropathy, isolated peripheral neuropathy, and painful diabetic neuropathy. Symmetrical distal polyneuropathy is the most common manifestation. It is characterized by the appearance of "glove" or "sock" symptoms, symmetrical, distal, bilateral, more frequently in the lower limbs.

Initially, sensory symptoms appear (pain, paresthesias, hypoesthesia, decreased perception of vibrations, temperature), later motor symptoms (muscle weakness). Secondary to sensitivity disorders, over time the risk of plantar ulcers and Charcot foot increases.

In diabetic patients, the annual balance of the target organs is essential, for the early detection of complications.

Laboratory data

1. Basal serum (fasting) glycemia (normal values between 60 to 110) mg/dl This analysis is also used to monitor the response to treatment, values considered acceptable between 90 to 130 milligrams/dl.

2. Postprandial blood glucose is useful in monitoring response to diet and treatment. Postprandial blood glucose values at 1 hour less than 180 milligrams/dl, and at 2 hours less than 150 milligrams/dl are considered "acceptable".

3. Oral glucose tolerance test (O.G.T.T) is performed when there is a suspicion of a glycoregulation disorder (when glycemia 110 to 126 milligrams/dl). The test consists of collecting a basal glucose, then administering 70 g of pulvis glucose dissolved in 250 ml of water within 5 minutes. Blood glucose is repeated after 2 hours. During the 2 hours, the patient is asked not to consume food, liquids and not to smoke. In the last 3 days before testing, the patient must consume at least 150 to 200 g of carbohydrates/day. Medicines that can affect this test are glucocorticoids, diuretics, contraceptives, phenytoin, and niacin, so they should be stopped in the previous days. Starting from the glycemia at 2h, we can distinguish the following terms (D.M and pre-diabetes conditions):

- D.M greater than or equal to 200 milligrams per deciliter

- reduced glucose tolerance=140 to 200 milligrams/dl

- impaired fasting glucose less than 140 milligrams/dl, and fasting glycemia is 100 to 126 milligrams/dl; these patients have an increased risk of developing D.M.

4. Glycosuria occurs when blood sugar greater than 180 milligrams/dl.

5. Ketonuria appear in K.A.D when accompanied by metabolic acidosis (pH less than 7.3 and bicarbonate less than 24 mEq/L), but also in starvation states.

6. The dosage of glycosylated hemoglobin H.b.A.1.c (normal values 4 to 6%) allows monitoring the balance of D.M over a period of 3 to 4 months prior to collection. In D.M, values less than 6.5% indicate good glycemic control. The higher the H.b.A.1.c values, the poorer the glycemic balance was in the previous months.

7. Dyslipidemia:

- D.M 1: High L.D.L cholesterol and triglycerides; these values decrease with the correction of the glycemia.

- DM2: High triglycerides (300 to 400 milligrams/dl), reduction in H.D.L cholesterol ( less than 30 milligrams/dl) and a qualitative change in L.D.L (more atherogenic)

8. Microalbuminuria ( greater than 30 milligrams/24 hours) allows early detection of diabetic nephropathy. It represents the first sign of kidney damage in a diabetic patient.

7.7. Acute abdomen

Definition: a sudden onset of severe abdominal pain of less than 24 hours duration.

Acute surgical abdomen has several recognized causes as:

- Peritonitis syndrome

- Bowel obstruction

• Digestive bleeding

- Acute necrotic-hemorrhagic pancreatitis

- Entero-mesenteric infarction

7.7.1. History taking

The main symptom - abdominal pain - may install abruptly. Evolution can be fast, requiring emergency assessment, or repeated evaluation.

The characteristics of the pain are of great importance as they may offer elements for the cause. Using the systematic Socrates approach, we can reduce the lack of information that in emergency may be omitted. Any severe pain can be accompanied by nausea, sweating and weakness from the vagal and sympathetic response.

Age

In new-born meconial ileus, while in children intussusception could be the cause for an A.A. In adults, acute hemorrhage, or acute pancreatitis are more frequent while in the elderly obstructive colon cancer.

Gender

While genital-urinary causes are more frequently in females, in male's acute pancreatitis or acute intestinal infarction are more frequent. In females is very important to recall general data - see volume 1, especially if we suspect a potential pregnancy, or a potential complication: for example ectopic pregnancy, or the presence of “mittelschmerz” – a unilateral pain, located in the iliac fossa typically, which is seen a reproductive age females related to ovulation, which is sometimes excruciating thus leading the patient to emergency.

Lifestyle

In certain patients (e.g. hypertriglyceridemia) consumption of ethanol and lipids may be the triggering factor for acute pancreatitis.

Acute intermittent porphyria may be the cause of A.A.

Personal history

Atherosclerosis promotes aortic atherosclerosis, which facilitates the occurrence of abdominal ay-or-tuh aneurysms; atherosclerosis of the mesenteric artery exposes to intestinal-mesenteric infarction; repeated abdominal surgical procedures cause the appearance of adhesion bands that produce episodes of intestinal occlusion; intestinal diverticula.

7.7.2. Physical examination

General physical examination can guide further assessment of the patient. There are numerous differences regarding pain in adults versus children, and in females, or in the elderly for example. We refer here dominantly of A.A in adults.

We may find an anxious patient with a suffering face, ill-looking, in search for an anti-pain position. Physical examination may be limited since the patient is anxious. Certain peculiarities guide the diagnosis towards a cause of acute abdomen, for example a patient with a colic pain may change its position.

Fever typically suggests infection, though there are subgroups of patients that do not develop fever for example: immunocompromised patients.

Overweight and obese subjects are at higher risk of biliary colic, acute pancreatitis.

“Zygomatic” facies is suggestive for a duodenal ulcer in acute phase, with complications. Hippocratic facies “facies Hippocratica” – a morbid faces: “a sharp nose, hollow eyes, sunken temples, cold ears” suggesting that “the end is at hand”, may be encountered in peritonitis.

In an elderly patient with atherosclerosis, A.A probably has a vascular cause; a very pale patient may suggest that hemorrhage has occurred. A smoker's face or an alcoholic's rhinophyma may suggest a duodenal or an active gastric ulcer. An emaciated patient may have a digestive neoplasm which causes the acute abdomen. A patient presenting fever, sweaty teguments may indicate septic peritonitis, usually through perforated organs: gall bladder, appendix, stomach-duodenum, intestinal diverticulum.

Tachycardia and orthostatic hypotension suggest hypovolemia (e.g. hemorrhage may be the cause!)

The physical examination allows the diagnosis to be more oriented according to the site of the pain on the surface.

Though some data obtained during general physical examination may orientate towards the cause, physical examination of the abdomen will provide the most important data.

Inflammation of the parietal peritoneum or peritonitis is a cause for A.A.

Inspection of the abdomen may reveal a distended abdomen such as in an intestinal occlusion. Sometimes intermittent peristaltic waves are visible on the surface of the abdomen suggesting a dynamic occlusion. These visible peristaltic waves may be associated with abdominal distention and hyperactive bowel sounds, Scars on the abdomen may indicate previous surgeries, therefore adhesions could be suspected as the culprit for an acute ileus.

A rigid abdomen which restricts the palpation occurs in peritonitis.

Though signs such as rigidity and rebound tenderness are suggestive for an A.A, are nonspecific.

Auscultation should be performed prior to percussion and palpation. Lack of intestinal bowel sounds is suggestive for intestinal occlusion. We should be cautious when interpreting the presence of bowel sounds, since here are data that indicate that bowel sounds decreased or absent in only one quarter of cases. The presence of a murmur (e.g. renal artery) indicates stenosis.

When patient coughs, we could identify where the cough produces pain. Then we pass to palpate gently, the area where he described pain. We should search for signs of guarding, rigidity, and rebound tenderness.

Physical examination should be repeated each time when a change of the characteristic of the pain appears.

Physical examination in peritonitis includes a positive cough test, guarding, rigidity, rebound tenderness, and percussion tenderness.

Guarding can be diffuse or localized, and it refers to tension of the abdominal wall when we perform palpation. It can be involuntary (referred as rigidity) or voluntary. Patients with anxiety, or if the examiner's hands are cold, can induce this response.

Cough test is a simple test that can be performed in conscious patients: by coughing, there will be an increase intra-abdominal pressure and of the pain, in case of peritonitis.

Blumberg's sign or "rebound tenderness" is a sign useful in clinical practice if we suspect peritonitis: by performing a palpation - pain at the removal of pressure of the abdomen (pain appears when we remove the hand, not when we press the abdomen!). Another sign of irritation of the peritoneum is "bell sign" or "Mendel sign": percussion with the fingertips around the umbilicus reveals intense pain.

Physical examination will be then centered on the quadrant corresponding to the site where the pain is the most intense. For example, if we suspect an appendicitis there are several clinical signs which are very useful: check for involuntary rigidity, rebound tenderness, a Rovsing sign, or a positive psoas or obturator sign.

At the end, physical examination should be ended with the rectal digital examination which may show rectal bleeding and an impacted fecaloma. Intense pain "Douglas cry" is suggestive for peritonitis.

Causes of acute abdominal pain

Right hypochondrium: cholecystitis, biliary colic, liver abscess, acute hepatitis, pancreatitis, perforated duodenal ulcer, retrocecal appendix, basal pneumonias, pleurisy, Herpes zoster, acute congestive hepatopathy.

Epigastrium: pancreatitis, peptic ulcer, acute myocardial infarction, gastritis, esophagitis, aortic aneurysm rupture.

Left hypochondrium: splenic infarction/rupture/abscess, gastritis, peptic ulcer, basal pneumonias, pleurisy, herpes zoster.

Flanks: kidney stones, nephrolithiasis.

Right iliac fossa: appendicitis, diverticulitis (Meckel's also), intestinal inflammation (terminal ileitis), inflammatory bowel diseases, irritable bowel syndrome, salpingitis, strangulated hernias, ectopic pregnancy, psoas abscess, ovarian torsion. Left iliac fossa: diverticulitis, salpingitis, strangulated hernias, irritable bowel syndrome, inflammatory bowel disease, ectopic pregnancy, abscess psoas, ovarian torsion.

Hypogastrium: cystitis, endometritis, salpingitis, testicular torsion, ectopic pregnancy, pelvic inflammatory diseases, intestinal inflammation, appendicitis.

There are numerous causes that can lead to an acute abdomen. There are medical and surgical causes that are recognized – see table 7.30.

Table 7.30 summary: Causes of acute abdomen divided into abdominal and extra-abdominal origins. Abdominal causes include trauma from closed and open injuries, vascular issues like abdominal aortic aneurysm rupture, and obstructive causes such as intestinal occlusion from parietal or extraparietal sources. Inflammatory causes are split between those with perforation, such as acute appendicitis and peptic ulcers, and those without perforation, including acute pancreatitis and liver abscess. Gynecological causes include ovarian torsion and rupture of ectopic pregnancy. Extra-abdominal causes span several systems, including cardiac issues like congestive heart failure, thoracic conditions such as basal pneumonias and pulmonary embolism, and metabolic triggers like diabetic ketoacidosis and chronic renal failure. Other extra-abdominal origins include neurological causes such as shingles, toxic causes like lead poisoning, hematological causes such as sickle cell anemia, and immunological causes like vasculitis.

7.7.3. Investigations

Laboratory testing

Complete blood count is mandatory if we suspect an infection or blood loss. It may reveal leukocytosis with neutrophilia in acute infection or inflammation. Erythrocyte sedimentation rate or C reactive protein might be elevated also. Though leukocytosis is typically present in acute appendicitis, nearly one in four patients with appendicitis does not have an elevated white blood cell count.

In patients with pain located in the upper abdomen, amylase and lipase should be determined especially if we suspect pancreatitis. More specifically if there is available, we should ask for pancreatic amylase if lipase is not available. Other useful tests are transaminases A.L.A.T and A.S.A.T), alkaline phosphatase, gamma glutamyltranspeptidase, bilirubin – for hepatobiliary causes. L.D.H, A.S.A.T can be elevated also in intestinal infarction or ischemia. If we suspect an inferior myocardial infarction, myocardial necrosis enzymes should be determined. Renal function should also be assessed, not only in cases where we foresee the need for a C.T scan with contrast agent.

Urinalysis should be performed in all patients, not just in those presenting hypogastric pain or renal symptoms.

In females, pregnancy tests may be helpful and are needed prior to performing radiological procedures. Also, in some cases chlamydia and gonorrhea testing might be needed if there is a genitourinary infection or a sexually transmitted infection.

Imaging studies

Imaging studies are recommended based on the location of the pain.

Ultrasonography (U.S) is recommended usually when a patient presents right upper quadrant pain. For example, it may detect the cause for an acute right upper quadrant as a calculous cholecystitis as seen in figure 7.16.

Also, U.S is very important in children and in pregnant females. U.S is generally recommended for evaluation of left lower quadrant pain in women of reproductive age and in pregnant patients, and in some cases endovaginal ultrasound may offer relevant information.

Frequently the first examination to be performed still is a plain radiography of the abdomen. It is a largely available examination since devices are available in almost every setting and less expensive than ultrasonography or C.T. It is very helpful in several circumstances. In an upright position it can detect free air under the diaphragm, indicating perforation of a cavitary organ. Also, can detect calcifications (kidney stones, and appendicoliths) and may raise the suspicion of a bowel obstruction when dilated loops of the bowel and air-fluid levels are described.

Computed tomography (C.T) with intravenous contrast agent is acknowledged to have higher sensitivity and specificity and is recommended in adults with acute right lower quadrant pain.

For left upper quadrant pain endoscopy might be indicated.

Special categories, like children, pregnant females, or females of reproductive age, may pose more difficulties, especially regarding choosing imaging studies.

In selected cases, if there is hemodynamic instability exploratory laparoscopy may be indicated.

Figure 7.17 summary: An ultrasound image showing distended loops of the small bowel. Within these loops, there is a visible separation between liquid and semisolid contents, along with a small amount of free peritoneal fluid. The image depicts signs of a bowel obstruction.

7.7.4. Peritoneal syndrome – Acute peritonitis

Peritoneal syndrome may occur due to:

- bacterial contamination (perforated organs, inflammatory diseases)

chemical contamination (perforated peptic ulcer, pancreatitis, perforated cholecystitis)

It starts suddenly with an intense pain, initially pain may be localized pointing to the cause (cholecystitis). Then – the ileus (suspension of transit for gas and feces) – may follow. Later, vomiting will appear. Not only that now we have symptoms and signs for peritoneal syndrome, but symptoms and signs for occlusive syndrome are present, therefore there is an overlapping symptoms/ physical finding that are seen in these patients.

Peritonitis can be classified as:

primary: hematogenous spread of bacteria; spontaneous (cirrhosis), tuberculosis, pneumococcal

- secondary: direct inoculation or transmural necrosis/ translocation: postoperative, trauma, necrosis (transmural)

- tertiary (occult): occult, in immunocompromised patients, patients that have not healed from secondary peritonitis.

Physical examination

Inspection may reveal a patient with a suffering appearance, eyes retracted into the orbits and prominent zygomatic bones - peritoneal facies.

Auscultation may reveal lack of intestinal bowel sounds, suggestive for intestinal occlusion – if a paralytic ileus is associated.

Palpation of the abdomen is very painful in peritonitis, palpation of the abdominal wall, shows initially guarding limited to the affected area, and later diffuse guarding.

Percussion with the fingertips revealing peritoneal sensitivity, called “bell sign” or “Mendel sign” are typical present. Also, the Blumberg sign is typically present.

Maneuvers for pain provocation – elicitation of pain:

- the McBurney point - on the line that joins the umbilicus and the anterior superior iliac spine where third external extremity joins the middle of this line: acute appendicitis.

- psoas sign/ maneuver (Jaworski's - Lapinski) - right iliac fossa is compressed and the right lower limb is raised, if there is accentuation of the pain is suggestive of acute appendicitis. obturator sign – stretching of the internal obturator muscle by internal rotation of the hip, the patient being positioned in dorsal decubitus with the right thigh flexed, with the knee bent, suggestive of acute appendicitis.

Murphy's sign – see acute cholecystitis.

- Rovsing sign/ maneuver - progressive palpation of the colon, starting from the left iliac fossa to the cecum, if pain produced by distension of the cecum appears is suggestive of inflammation of the ileo-cecal region rectal examination and, in women, a pelvic examination – intense pain in the Douglas pouch, may indicate a ruptured extrauterine pregnancy or a rupture of the ovary (normal/ pathological – tumor).

Later, palpation of the abdomen will reveal a "wooden" abdomen.

Rectal digital examination may reveal: rectal bleeding/ impacted fecaloma. Intense pain “Douglas cry” is suggestive for peritonitis.

Complementary examinations

Laboratory work-up are needed to assess the patient, to detect complications: blood count, serum electrolytes, renal function, urinary testing must be determined in all patients. We may find:

- dehydration (elevated/ normal Hematocrit, hydro electrolytic imbalances)

- hemorrhage (anemia)

- infection/ inflammation (leukocytosis, elevated C reactive protein)

- renal function may show acute renal failure, renal function and are needed further on if contrast agents are required for radiological examinations

- urinary infection (bacteriuria, leukocyturia)

- decompensated diabetes (glycosuria).

Other tests useful are:

- amylase and lipase in case of suspicion of acute pancreatitis (amylase increases in case

- of intestinal ischemia and in perforated ulcer)

- transaminases

- alkaline phosphatase, gamma-glutamyl-transpeptidase, bilirubin: hepatobiliary diseases

- cardiac enzymes if inferior myocardial infarction is suspected.

- in female patients (fertile) a urinary pregnancy

Abdominal ultrasound can be performed typically in emergency, and it is the first examination usually: it may detect the cause of the acute abdomen (acute pancreatitis, occlusion, organ perforation, ascites - peritonitis, gynecological emergencies) or it may give information useful for differential diagnosis (renal colic that can be confused with acute abdomen)

Abdominal X-ray shows the hydro-aeric levels "gas-fluid level" in ileus and pneumoperitoneum in perforation of cavitary organs.

Chest X-ray may play a role in the differential diagnosis, as some patients may have pulmonary embolism, pneumonia, which may present with pain and alteration general status.

Abdominal C.T is frequently the examination of choice that provides more information and establishes the cause, where ultrasound has failed to do this.

In case of doubt, exploratory laparoscopy is required, and after the identification of the cause in the second step it can be sanctioned by surgery.

7.7.5. Bowel obstruction

Occlusive syndrome or bowel obstruction is characterized by the triad of pain with hyper�ristalsis, vomiting, lack of transit for feces and gases. The higher the occlusion, the earlier the vomiting appears. Low occlusions are better tolerated for a longer time and vomiting occurs usually after a few hours. The pathognomonic vomiting has a fecaloid odor and contains intestinal chillum or even feces, according to the level of occlusion. Pain from occlusion it is intermittent, returning after a few minutes or hours.

It can be classified as: mechanical or functional obstruction. Mechanical obstruction recognizes various causes such as: tumors (intrinsic or by extraluminal compression), volvulus, hernias, inflammation, adhesions, infarction. Functional ileus, also referred to as paralytic ileus, can appear after surgery - postsurgical ileus, can be induced by drugs or it may be associated to other diseases, for example severe form of pancreatitis (necrotic-hemorrhagic).

If there is no intervention, complications arise: perforation, peritonitis. Attention! Although the occlusion typically is accompanied by transit suspension, it may happen that, in incomplete bowel obstruction or even complete bowel obstruction, if the intestinal content below the obstruction can be evacuated, the presence of bowel transit to be wrongly interpreted and therefore may distract attention towards the occlusion!

Symptoms: abdominal pain, abdominal distension, vomiting – see general description.

Physical examination: abdominal distension (more obvious in distal obstructions), hyperactive bowel sounds (early), or reduced/absent bowel sounds (later). In evolution, signs of peritonitis install. It is important to look for potential causes of obstruction such as: hernias, at the end of the physical examination it is mandatory to perform digital rectal examination.

Investigations – see the investigations in this chapter.

7.7.6. Intestinal infarction

Intestinal infarction, intestinal-mesenteric infarction, acute bowel ischemia, acute mesenteric ischemia are interchangeable names that are frequently used.

Bowel ischemia can be classified as small bowel ischemia, commonly referred to as mesenteric ischemia, whereas for large bowel ischemia colonic ischemia is the term frequently encountered.

Usually, acute intestinal ischemia appears if there is a reduction of intestinal perfusion of at least 75%.

Etiologies of acute intestinal ischemia can be arterial embolism, intestinal hypoperfusion or nonocclusive ischemia, arterial thrombosis, and venous thrombosis. Arterial embolism is typically encountered in patients with cardiovascular diseases: mitral stenosis, cardiac arrhythmias. Arterial thrombosis can be encountered in patients with an advanced age, and/or peripheral artery disease.

Venous thrombosis is typically encountered in hypercoagulability status. Nonocclusive ischemia can be found in patients in shock (septic, hypovolemic).

Main symptom is represented by pain. History taking and physical examination may orientate towards the type of infarction. While in colonic infarction symptoms are milder, in small bowel infarction pain is severe, frequently accompanied by nausea and vomiting.

Differential diagnosis of chronic mesenteric ischemia should be considered in the elderly, known with atherosclerotic diseases. Pain in chronic mesenteric ischemia appears typically after shortly after eating, especially after larger meals and it can cause patients to lose weight.

Physical examination may be compatible with that of the intestinal occlusion – physical examination may reveal findings of the occlusive syndrome.

Complementary examinations are needed to detect the site of occlusion and the repercussion: Doppler ultrasound, C.T angiography (examination of choice In unstable patients, exploratory laparoscopy may identify the lesion and, in the second time it allows to perform treatment.

7.8. References:

Chapter 8. Semiology of the hematological system

8.1.1. History taking

8.1. Semiology of the spleen

Disorders affecting the spleen can range from benign conditions to life-threatening diseases. An enlarged spleen, known as splenomegaly, can be a sign of various underlying medical conditions including liver cirrhosis, malignancy, viral infections, or hemolytic anemia.

Symptoms

Splenic disorders may manifest with a variety of clinical features, necessitating a comprehensive approach. Common symptoms include left upper quadrant abdominal pain or discomfort, which may radiate to the left shoulder (Kehr's sign) due to irritation of the diaphragm. Patients might also report a feeling of fullness or bloating in the abdomen, particularly after meals, which can be attributed to splenomegaly.

Hematologic manifestations, such as easy bruising, petechiae, or prolonged bleeding, may signify underlying splenic dysfunction affecting platelets. Additionally, anemia may result from splenic sequestration of red blood cells R.B.C's or hemolysis. It is imperative to inquire about constitutional symptoms like fever, night sweats, and unintended weight loss, as these may indicate an underlying infectious or neoplastic process affecting the spleen.

Medical history

It is essential to investigate any pre-existing medical conditions, chronic illnesses, or hematologic disorders, as certain conditions predispose individuals to splenic complications. Chronic liver diseases, such as cirrhosis, can lead to portal hypertension and subsequent splenomegaly. A history of infectious diseases, especially mononucleosis caused by the Epstein-Barr virus, is relevant, as it can lead to splenomegaly with an increased risk of splenic rupture.

Inquiring about prior trauma, such as abdominal injuries or surgeries, is essential, as these events may contribute to splenic pathology. Furthermore, a history of blood transfusions or exposure to potential infectious sources, like endemic areas for certain parasitic infections, aids in the diagnostic process.

A thorough exploration of the patient's family history is imperative in identifying potential genetic predispositions or hereditary conditions associated with splenic disorders. Some genetic disorders, such as hereditary spherocytosis or thalassemia, may manifest with splenomegaly and hematologic abnormalities. Additionally, a family history of autoimmune disorders, hematologic malignancies, or chronic liver diseases may contribute valuable insights into the patient's risk profile. Inherited coagulopathies, such as hemophilia or von Willebrand disease, may be associated with a higher propensity for bleeding and hematoma formation, which can affect the spleen.

Life conditions, lifestyle, diet

Lifestyle factors can also influence the risk of developing splenic disorders. Alcohol abuse is associated with an increased risk of liver cirrhosis, characterized by hepatomegaly and splenomegaly. Exposure to certain infectious agents, such as parasites, can also cause splenomegaly.

Occupational exposures to toxic substances or infectious agents may be relevant, particularly in industries with known associations to hematologic disorders. Travel history is essential, especially in regions endemic for parasitic infections like malaria or schistosomiasis.

8.1.2. Physical examination

The general physical examination can provide several signs that are associated with splenomegaly:

- weight loss: leukemias, lymphomas

- skin and mucous pallor: anemias, leukemias, lymphomas; sometimes with jaundice (Biermer's anemia)

- redness of the face: polycythemia vera

- petechiae: thrombocytopenic purpura

- palmar redness, stellate angiomas: liver cirrhosis

- abdominal collateral circulation: liver cirrhosis

- superficial, firm, persistent adenopathy: lymphomas, leukemias

- fever: undulating (Hodgkin's lymphoma), intermittent (malaria, septicemia), in the plateau (typhoid fever), recurrent (brucellosis) or irregular (leukemia).

Physical examination of the spleen

Inspection

Bulging of the abdomen at the level of the left hypochondrium, in case of splenomegaly. Giant splenomegaly can also produce bulging of the left flank, even the entire abdomen.

Normal spleen is not palpable. A normal sized spleen can be palpated, only in the case of visceroptosis. In this case, it must be differentiated from the left kidney ptosis (for the spleen the lienal incision is recommended and for the kidneys the lumbar contact and posterior location).

Palpation of the spleen from the right side of the patient

It is the preferred palpation method. This technique can be performed with the patient in the supine position or in the right lateral position, with the knees partially bent to relax the muscles of the abdominal wall. The doctor, standing to the right of the patient, places his hand right at the level of the patient's left hypochondrium, at the level of the anterior axillary line (tangent at the front edge of the axillary fossa), in the direction of the armpit, with the fingers insinuated slightly below the costal edge and the left hand at the level of the patient's left lumbar region, which he will lift slightly, exerting at the same time a pressure with his right hand of the left hypochondrium in the direction of the armpit, trying to feel the lower pole of the spleen when the patients perform a deep inspiration (fig 8.1). As the patient inspires, the edge of an enlarged spleen descends to the examiner's fingertips. Identification of the spleen is based on the palpatory characters: hard consistency, sharp and crenulated edge, painless smooth anterior and external surface, and active mobility with respiratory movements.

Figure 8.1 summary: A photograph showing a person's torso with a hand pressing into the upper abdomen. This image depicts a clinical examination technique used to assess for abdominal tenderness or organ enlargement.

Palpation of the spleen from the left side of the patient, "by hooking"

The patient is in the right lateral decubitus, with the knees semi-flexed and the limb upper left raised above head. With the fingertips of both his hands, the doctor is sitting in the left side of the patient and is using the fingertips of both his hands. He will palpate the edge anterior edge of the lower pole of the spleen towards the end of inspiration (when the spleen is pushed far forward and down by the diaphragm) (fig 8.2).

Figure 8.2 summary: Two photographs showing a person's hand and arm in the first image, and a close-up of a human ear in the second. These are illustrative images with no data or analytical results to report.

An enlarged spleen, highlighted by palpation, requires an appreciation of the dimensions, consistency, anterior surface, anterior margin, sensitivity, and respiratory mobility.

Splenomegaly is defined as an enlarged spleen. In this condition the spleen expands anteriorly, downward, and medially, often replacing the tympany of stomach and colon with the dullness of a solid organ. In case of splenomegaly, the spleen becomes palpable below the costal margin. Percussion and palpation can confirm the enlargement.

Regarding consistency, splenomegaly can be hard (leukemia, polycythemia vera), semi-hard (cirrhosis of the liver), soft (septicemia, typhoid fever, malaria), fluctuating (splenic abscess), elastic (splenic hydatid cyst). The anterior surface of the spleen can be irregular (splenic tumors) and smooth in the other situations that evolve with splenomegaly. Tenderness to palpation is present in splenic infarction, or traumatic rupture of the spleen. Respiratory mobility of the spleen is present in all splenomegaly, except for the giant ones.

Percussion

It must be coupled with palpation, especially when the spleen does not exceed significantly the left costal rim. Anatomical features of the normal spleen: oval shape, vertical diameter 6 centimeters, its projection at the level of the left lateral hemithorax with the following limits: 9th rib (superior), 11th rib (inferior), mid axillary line (anterior).

The patient is placed in the right lateral decubitus position, with the upper left limb on top head and knees bent. For the upper limit the percussion starts down from lung sonority, on the middle axillary line, then on the anterior one. Where lung sonority turns into dullness, corresponds projection of the upper limit and the level where dullness is replaced by tympanic indicates the lower limit.

The posterior limit cannot be determined percussively (interposition of the dullness of the kidney). When the vertical diameter of the splenic opacity, determined by the previously described percussion, is greater than 9 centimeters and when the anterior pole of the spleen is before the mid-axillary line, we consider splenomegaly.

8.1.3. Investigations

Laboratory tests

Complete Blood Count (C.B.C)

In patients with splenic disorders, alterations in red blood cell parameters, such as anemia is indicative of sequestration or hemolysis, thrombocytopenia suggestive of hypersplenism, or leukocytosis reflecting an underlying infectious process, can be identified.

peripheral blood smear

Peripheral blood smears may also be examined for morphological abnormalities, aiding in the diagnosis of certain hereditary disorders or infections affecting the spleen. Spherocytes are present in hereditary spherocytosis or schistocytes suggestive of microangiopathic hemolytic anemia. Additionally, the presence of Howell-Jolly bodies may suggest functional asplenia or hyposplenia, emphasizing the importance of splenic function assessment.

Liver Function Tests L.F.T's

Given the intimate relationship between the liver and spleen, L.F.T's play a crucial role in evaluating hepatic function and identifying conditions that may contribute to splenic disorders. Elevated levels may indicate liver cirrhosis, hepatic congestion in right ventricular failure.

Imaging

Abdominal ultrasound

Ultrasound represents a non-invasive and readily available imaging modality for assessing the spleen. It provides valuable information regarding the size, contour, and echotexture of the organ. Splenomegaly, focal lesions, or cystic changes can be identified through ultrasound (fig 8.3, 8.4). Doppler studies may aid in evaluating blood flow within the splenic vasculature, offering insights into conditions such as portal hypertension or splenic artery aneurysms.

Figure 8.3 summary: An ultrasound image of a normal spleen, with two white circles highlighting the typical homogeneous echo texture of the organ. The image serves as a clinical reference for the appearance of a healthy spleen.

Computed tomography (C.T) scan

C.T scans offer a more detailed anatomical assessment of the spleen and surrounding structures (fig 8.5). Contrast-enhanced C.T imaging facilitates the visualization of vascular abnormalities, parenchymal lesions, and the overall architecture of the spleen. It is particularly valuable in detecting neoplastic conditions, abscesses, or traumatic injuries that may affect the spleen.

Figure 8.5 summary: Two CT scan images comparing a normal spleen (left) to a case of splenomegaly (right). The spleen in the right image is significantly larger in size and occupies more of the abdominal cavity than the spleen in the left image. The point is to illustrate the visual difference between a normal-sized spleen and an enlarged one.

Figure 8.4 summary: An ultrasound image showing an enlarged spleen, known as splenomegaly. The image serves as a clinical example of this condition.

Magnetic Resonance Imaging (M.R.I)

M.R.I, with its superior soft tissue contrast, is a valuable tool for evaluating splenic disorders, especially in cases where further characterization of lesions or clarification of unclear findings on C.T scans is required. Additionally, M.R.I can provide functional information, such as perfusion studies, aiding in the differentiation of benign from malignant lesions. The absence of ionizing radiation makes M.R.I particularly suitable for pregnant patients or those with contraindications to C.T scans.

Functional assessments

Technetium-99m sulfur colloid scan

This nuclear medicine techniques enables the quantification of splenic function by evaluating the uptake and clearance of radiolabeled particles by the reticuloendothelial system. Reduced uptake may indicate functional asplenia or hyposplenia, impacting the patient's susceptibility to infections and guiding prophylactic measures, such as vaccination against encapsulated bacteria.

Indium-111 labeled white blood cell scan

In cases of suspected splenic abscess or infection, the indium-111 labeled white blood cell scan proves valuable. It provides functional information beyond anatomical imaging, facilitating precise diagnosis and guiding therapeutic interventions.

Histopathological evaluation

Fine Needle Aspiration (F.N.A) Biopsy

For focal lesions identified on imaging studies, F.N.A biopsy offers a minimally invasive means of obtaining tissue for histopathological examination. This procedure aids in differentiating between benign and malignant conditions, providing essential information for treatment planning. F.N.A biopsy is particularly useful in the assessment of splenic masses, such as lymphomas or metastatic lesions.

Core needle biopsy

In cases where a larger tissue sample is required for a more comprehensive evaluation, core needle biopsy may be employed. This technique allows for the extraction of a cylindrical tissue specimen, facilitating detailed histopathological analysis. Core needle biopsy is often utilized when F.N.A biopsy yields inconclusive results or in the presence of diffuse splenic abnormalities requiring a more extensive tissue assessment.

8.1.4. Spleen syndromes

Splenomegaly - defined as an enlargement of the spleen, is a clinical manifestation stemming from a myriad of underlying causes. The primary causes encompass hematologic, infectious, infiltrative, and neoplastic pathology (table 8.1).

Table 8.1 summary: The etiologies of splenomegaly categorized by the underlying mechanism of splenic enlargement. Causes of increased demand for splenic function include hematological conditions such as nutritional anemias, hemoglobinopathies, hemolysis, spherocytosis, sequestration crisis, and elliptocytosis; infectious agents including viral EBV, HIV, and CMV, bacterial endocarditis and tuberculosis, and parasitic malaria, histoplasmosis, and leishmaniasis, as well as fungal infections; and inflammatory conditions like SLE, sarcoidosis, Felty syndrome, and Still's disease. Congestive causes include cirrhosis, portal HTN, portal vein obstruction, and splenic vein thrombosis. Infiltrative causes are divided into non-malignant types, such as benign metaplasia, cysts, amyloidosis, sarcoidosis, hamartomas, vascular abnormalities, and lysosomal or glycogen storage diseases, and malignant types, including leukemia (CML, CLL), lymphoproliferative disease (CLL, HL), MPNs (CML, MF), and metastatic tumors.

Abbreviations: C.M.L, chronic myelogenous leukemia, C.L.L: chronic lymphocytic leukemia, H.L: Hodgkin's lymphoma, M.F: myelofibrosis.

Hematologic etiology includes disorders such as chronic myeloid leukemia, lymphomas, and hemolytic anemias, wherein splenomegaly arises due to increased cellular turnover or abnormal blood cell sequestration.

Infectious etiology, notably viral infections like infectious mononucleosis (Epstein-Barr virus) and bacterial infections such as brucellosis, may induce splenomegaly through direct splenic involvement or immune-mediated mechanisms.

Infiltrative disorders, exemplified by amyloidosis or Gaucher disease, result in splenomegaly due to the accumulation of abnormal substances within the spleen.

Neoplastic causes, inclusive of metastatic disease or primary tumors arising within the spleen, contribute to splenomegaly through space-occupying lesions.

Management of splenomegaly hinges on the identification and treatment of the underlying cause. In cases where an underlying pathology is not immediately apparent, a comprehensive diagnostic workup, including imaging studies, laboratory investigations, and potentially invasive procedures like biopsy, is recommended.

Splenomegaly can be:

- isolated: primitive tumors, hydatid cyst, splenic vein thrombosis

- associated with other symptoms and signs (mentioned previously)

Complications of splenomegaly

1. Splenic rupture, a critical medical emergency, involves the sudden disruption of the spleen's structural integrity, often resulting from trauma or underlying pathological conditions. Blunt abdominal trauma, notably in motor vehicle accidents or sports injuries, poses a significant risk. In nontraumatic cases, underlying pathology such as infectious mononucleosis or neoplastic processes may weaken the spleen's capsule, predisposing it to rupture. Clinical manifestations include acute abdominal pain, hypovolemic shock, and left shoulder pain (Kehr's sign). Prompt diagnosis through imaging studies is crucial, and emergent splenectomy is often warranted to address life-threatening hemorrhage.

2. Splenic infarction, a vascular event, entails the ischemic necrosis of splenic tissue due to ischemia. It can be caused by thromboembolic events, myeloproliferative disorders, thromboembolic or hypercoagulable states including malignancy and antiphospholipid syndrome, and splenomegaly. Clinical presentation includes left upper quadrant pain, fever, and leukocytosis. Diagnosis relies on imaging modalities, with contrast-enhanced C.T being pivotal.

Depending upon the cause, the enlarged spleen may return to normal size and function when the underlying disease is treated or resolved. Commonly, in infectious mononucleosis, the spleen returns to normal as the infection is efficiently treated.

Hypersplenism

Hypersplenism is defined as an overactive spleen that removes too many blood cells. Splenomegaly refers strictly to spleen enlargement, and is distinct from hypersplenism, which connotes overactive function by a spleen of any size. Splenomegaly and hypersplenism should not be confused. Each may be found separately, or they may coexist. Hypersplenism is characterized by peripheral blood cytopenia, sometimes pancytopenia (anemia, leukopenia, thrombocytopenia) and medullary hyperplasia, for this reason, frequently splenectomy is recommended. After the splenectomy is performed, the pancytopenia is no longer present.

The hypersplenism triad: splenomegaly, peripheral cytopenia due to premature destruction of blood cells and normocellular bone marrow.

Primary hypersplenism: The cause is unclear. The diagnosis process is complicated and comprehensive investigations are performed to establish the diagnosis of primary splenic hyperplasia (exclusion diagnosis).

Secondary hypersplenism: The cause is clear. The most common hypersplenism is secondary to post-viral chronic hepatitis and liver cirrhosis.

- infections: viral hepatitis, brucellosis, mononucleosis syndrome and malaria.

- chronic diseases: chronic alcohol abuse, portal hypertension, liver cirrhosis, portal vein thrombosis

- granulomatous inflammation: systemic lupus erythematosus, rheumatoid arthritis, Felty's syndrome, and sarcoidosis.

- malignancies: splenic lymphosarcoma, leukemia, and cancer metastasis

- myeloproliferative disorders: polycythemia vera, chronic myeloid leukemia, and myelofibrosis

- chronic hemolytic diseases: hereditary spherocytosis, autoimmune hemolytic anemia, and thalassemia

- lipidosis: Gaucher's disease, and Niemann-Pick disease

- other diseases: splenic cyst, splenic artery aneurysm, and cavernous hemangioma.

Hyposplenism or asplenia - indicates the decrease or absence of spleen functions. It occurs after splenectomy, congenital absence of the spleen, multiple splenic infarctions (sickle cell disease).

8.2. Semiology of the hematological disorders

8.2.1. History taking

Chief complaint

In hematology, common presenting symptoms include fatigue, dyspnea, pallor, easy bruising, and bleeding tendencies. A meticulous exploration of the onset, duration, progression, and severity of these symptoms provides critical insights into potential hematologic abnormalities.

Medical history

A detailed exploration of past illnesses, surgeries, transfusions, aids in uncovering genetic predispositions and identifying potential risk factors. The clinician should also inquire about medication history, particularly pharmacologic therapy that may impact coagulation and hematopoiesis.

Family history

The genetic background is relevant in disorders such as sickle cell anemia, hemophilia, and thalassemia. About 10% of cases of leukemia and myelodysplastic syndromes are caused by genetic factors.

Life conditions, lifestyle, diet

Occupational exposures, dietary habits, alcohol, and substance abuse can significantly influence hematologic parameters. Certain industries or environments may expose individuals to toxins that can adversely affect the bone marrow, leading to hematological disorders.

Past blood transfusions and transplant history

A meticulous inquiry into past blood transfusions is essential. This information aids in assessing potential complications, such as transfusion reactions or alloimmunization, which may impact future transfusions. Blood transfusion is a risk factor for viral hepatitis (B and C hepatic viruses) leading to liver cirrhosis. Patients with a history of hematopoietic stem cell transplantation require special attention, as they may experience long-term complications affecting hematologic parameters.

Vaccination history

Immunization history is important, particularly in patients with hematologic disorders. Some disorders, such as sickle cell disease, predispose individuals to infections, making vaccinations a vital aspect of preventive care.

8.2.2. Symptoms present in hematological diseases

a) Bone pain

Bone pain is a notable and often distressing symptom encountered in various hematological disorders. The skeletal system serves as a dynamic hematopoietic organ, and disturbances in blood cell production, infiltration, or bone structure can manifest as bone pain (table 8.2).

Leukemic infiltration: leukemias, especially acute leukemias, can infiltrate the bone marrow and bone tissue.

- Lymphomatous involvement: lymphomas (Hodgkin and non-Hodgkin) may infiltrate lymph nodes and bone marrow.

- Multiple Myeloma: bone pain due to lytic lesions, fractures, and bone marrow infiltration.

- Myeloproliferative Neoplasms: polycythemia vera, essential thrombocythemia, and myelofibrosis (bone pain due to marrow hyperplasia and fibrosis).

Sickle Cell Disease: vaso-occlusive crises can lead to ischemia in bone tissue, causing acute and recurrent bone pain.

The bone marrow is a primary site for hematopoiesis, responsible for producing blood cells, including red blood cells, white blood cells, and platelets. Disruptions in normal hematopoiesis can lead to increased pressure within the bone marrow, causing bone pain.

The infiltration of malignant cells (leukemia, lymphoma, multiple myeloma) may infiltrate the bone marrow and adjacent bones, causing pain. The bone marrow expansion (myeloproliferative neoplasms, hemolytic disorders) can lead to excessive bone marrow expansion, resulting also in bone pain.

b) Joint pain

Joint pain present in the following hematological disorders

- Myeloproliferative Disorders: polycythemia vera, essential thrombocythemia, and myelofibrosis can cause joint pain due to increased cell production in the bone marrow.

- Hemophilia: joint pain can occur due to bleeding into the joints.

- Leukemia: joint pain may be present, particularly in cases where the disease infiltrates the joints or affects bone marrow function.

- Multiple Myeloma: plasma cell disorder manifested with joint and bone pain.

c) Fatigue: non-specific symptoms can be indicative of various hematologic malignancies and other blood disorders. Anemia can lead to decreased oxygen delivery to tissues, causing fatigue. Malignant infiltration or hyperplasia in the bone marrow can disrupt normal hematopoiesis, contributing to a general sense of malaise.

d) Weight loss: increased metabolic demands due to abnormal hematopoiesis or rapid cell turnover in hematological disorders can contribute to weight loss.

e) Dyspnea: expression of anemia-induced reduced oxygen-carrying capacity, altered blood viscosity or pulmonary infiltrates in malignancies with compromised oxygen exchange.

f) Infectious disease symptomatology: frequent infections in hematological disorders are associated with a compromised immune system. Conditions such as leukemia or lymphomas disrupt normal white blood cell production, impairing the body's ability to combat pathogens. Additionally, treatments like chemotherapy may further suppress the immune system, leaving individuals more susceptible to recurrent infections and inefficient antibiotic therapy. The presence of abnormal cells or dysregulated immune responses in hematological malignancies can trigger systemic inflammation and fever.

Infiltration or disruption of the bone marrow by malignant cells may lead to an inflammatory response and fever. For this reason, continuing or recurrent fever can be a significant indicator of an underlying hematological disorder.

g) Abdominal discomfort or diffuse abdominal pain: enlarged spleen or liver explain those symptoms.

8.2.3. Physical examination

Inspection

Cutaneous manifestations often play a pivotal role in the identification, evaluation, and management of various hematological conditions. Below we enumerate the most important manifestations:

Pallor: a clinical hallmark of anemia, manifests as a generalized paleness of the skin, mucous membranes, and conjunctiva. The reduction in circulating red blood cells and hemoglobin compromises oxygen-carrying capacity, resulting in a visibly pallid complexion.

Petechiae and ecchymosis: Petechiae, non-blanching, red or purple pinpoint spots, and ecchymosis, larger subcutaneous hemorrhages presenting as purplish discolorations, signify disturbances in platelet function or a decreased platelet count. Present in immune thrombocytopenic purpura, aplastic anemia, and leukemia.

Jaundice: cirrhosis, hemolytic anemias (sickle cell disease, hereditary spherocytosis) and malignancies affecting the liver, such as lymphomas and infiltrative disorders.

Livedo reticularis manifests as a mottled, net-like pattern on the skin, particularly observed in the extremities. This cutaneous finding is associated with underlying thrombotic disorders, including antiphospholipid syndrome and myeloproliferative neoplasms, where compromised blood flow in small vessels contributes to the development of this type of skin modification.

Erythema nodosum presents as painful, erythematous nodules, typically on the anterior surface of the lower extremities. This cutaneous manifestation is observed in hematological disorders such as lymphoma, myelodysplastic syndromes, and sarcoidosis, where it may represent an immune-mediated response to the underlying hematological pathology.

Vasculitic lesions resulting from inflammation of blood vessels, present as palpable purpura, or ulcers. Hematological disorders associated with vasculitic lesions include cryoglobulinemia, immune complex vasculitis, and vasculitis related to myeloproliferative neoplasms.

Hemorrhagic manifestations include:

-Hematoma localized collections of blood outside blood vessels, resulting in skin discoloration and swelling. Coagulation disorders, including hemophilia and von Willebrand disease, as well as thrombocytopenia or platelet dysfunction, contribute to easy bruising and hematoma formation.

-Mucosal bleeding—such as the gums, nose, or gastrointestinal tract, manifests as a common hemorrhagic presentation. Hematologic disorders affecting platelet function, or the coagulation cascade often manifest with mucosal bleeding. Von Willebrand disease and hemophilia are notable examples.

-Purpura - purple palpable or not lesions resulting from bleeding into the skin, signifies small-vessel bleeding. Thrombocytopenic purpuras and vasculitis may manifest with purpura.

-Bleeding at venipuncture sites - prolonged bleeding or oozing at venipuncture or injection sites is indicative of impaired clot formation (coagulation disorders).

-Hemarthrosis - bleeding within joint spaces, resulting in pain, swelling, and restricted joint movement. Hemophilia, particularly hemophilia A and B, is characterized by recurrent hemarthrosis. Recognition of this specific manifestation directs clinicians toward a focused evaluation of coagulation factors and aids in differentiating hemophilic joint bleeds from other joint-related pathologies.

-Gastrointestinal (G.I) bleeding -chronic or recurrent G.I bleeding can result in iron-deficiency anemia, with associated fatigue, weakness, and pallor. Patients with hematologic disorders may manifest G.I bleeding through various clinical presentations including melena, hematemesis, or hematochezia.

Palpation

In Medical Semiology Volume 1, pages 125 to 129 provide comprehensive information on the palpation of lymph nodes. The evaluation of lymph nodes involves a comprehensive assessment of their distribution, size, consistency, tenderness, and mobility (table 8.3). Lymphomas, marked by malignant lymphocytes, often cause generalized lymphadenopathy. The tenderness and warmth of palpable nodes may herald inflammatory or infectious processes, distinguishing them from the insidious nature of malignancies. The pattern and distribution of lymphadenopathy become diagnostic signposts, guiding clinicians toward specific hematological entities.

Table 8.3 summary: Key clinical differences between malignant and benign causes of lymphadenopathy. Malignant nodes are typically larger than 2 centimeters, feel hard, firm, or rubbery, and are fixed or attached to surrounding tissues due to invasion. They generally persist for more than a few weeks and are usually non-tender. In contrast, benign nodes are smaller than 2 centimeters, feel soft or fluctuant, are mobile and not attached to surroundings, typically last less than 2 weeks, and are usually tender.

The acronym "A.L.L Ages can be used to remember the points to consider in differentiating benign vs malignant cause of lymphadenopathy (table 8.4).

Table 8.4 summary: The acronym ALL AGES serves as a mnemonic for malignant lymphadenopathy. Each letter corresponds to a specific clinical factor: A for Age, L for Location, L for Length of the time present, A for Associated Symptoms and signs, G for Generalized Lymphadenopathy, E for Extra nodal association, and S for Splenomegaly and Fever.

8.2.4. Investigations

8.2.4.1. Complete Blood Count (C.B.C)

The cornerstone of hematological investigations, the C.B.C, provides a comprehensive overview of red blood cells R.B.C's, white blood cells W.B.C's, and platelets P.L.T's (table 8.5).

Table 8.5 summary: Normal reference values and definitions for complete blood count tests. For red blood cells, normal RBC counts range from 4.0 to 5.2 times 10 to the 12th per liter for females and 4.4 to 5.7 for males, with hemoglobin levels between 123 and 157 grams per liter for females and 130 to 170 for males. Hematocrit ranges from 37 to 46 percent in females and 38 to 50 percent in males. Other red cell indices include MCV at 80 to 100 femtoliters, MCH at 27 to 34 picograms, MCHC at 32 to 36 percent, and RDW at 11.5 to 14.5 percent. The reticulocyte count is 20 to 84 times 10 to the 9th per liter, and the ESR is less than 10 millimeters per hour for females and less than 6 for males. White blood cell counts range from 4 to 10 times 10 to the 9th per liter, with a differential including lymphocytes at 1.0 to 4.0 and segmented neutrophils at 2 to 7 times 10 to the 9th per liter, while band neutrophils, basophils, eosinophils, and monocytes are typically lower. Finally, the platelet count is 130 to 400 times 10 to the 9th per liter, with a mean platelet volume of 7.2 to 11.7 femtoliters.

a) R.B.C's

Elevated R.B.C parameters, such as polycythemia, may indicate erythropoietin-producing disorders or lung diseases, while decreased values, such as anemia, suggest iron deficiency, vitamin deficiencies, or blood loss.

Size. The mean corpuscular volume (M.C.V) is a measure of the average volume of a red blood corpuscle: microcytic (M.C.V less than 80 fL), normocytic (M.C.V = 80 to 100 fL), macrocytic (M.C.V greater than 100 fL).

Color. The mean corpuscular hemoglobin M.C.H, or "mean cell hemoglobin", is the average mass of hemoglobin per red blood cell in a sample of blood. R.B.C's are either normochromic or hypochromic.

b) Reticulocytes

Reticulocytes are immature erythrocytes and are markers of erythrocyte production and are very good indicator for regenerative and non-regenerative anemia

c) W.B.C's

White blood cells are classified into five main types: neutrophils, lymphocytes, monocytes, eosinophils, and basophils.

d) Platelets

Low platelet counts, thrombocytopenia, may indicate bleeding disorders, autoimmune diseases, or bone marrow dysfunction, while elevated counts, thrombocytosis, can suggest myeloproliferative disorders or certain inflammatory conditions.

8.2.4.2. Blood film interpretation

Blood films, thin smears of blood spread onto a glass slide and stained with special dyes, serve as invaluable tools in the diagnosis and management of hematological disorders. By examining the morphology and distribution of red blood cells R.B.C's, white blood cells W.B.C's, and platelets, experienced hematologists can identify subtle abnormalities that point to underlying pathologies.

Red blood cell morphology

R.B.C's should exhibit consistent size and shape. Abnormalities in R.B.C morphology can provide clues to various hematological conditions.

Anisocytosis, the presence of R.B.C's of varying sizes, is a common finding in anemia, particularly iron deficiency anemia. Poikilocytosis, characterized by R.B.C's of abnormal shapes, is associated with various disorders, including thalassemia, sickle cell anemia, and megaloblastic anemia.

Erythrocyte abnormalities extend beyond size and shape. Howell-Jolly bodies, remnants of nuclear material, suggest splenic dysfunction, while schistocytes, fragmented R.B.C's, are indicative of microangiopathic hemolytic anemia.

White blood cell differential

White blood cell differential provides information about the types and amounts of W.B.C's and is performed as part of a C.B.C, measures the amounts of the five normal white blood cell types – neutrophils, lymphocytes, monocytes, eosinophils, and basophils – as well as abnormal cell types if they are present and provides a detailed breakdown of these cell types, allowing for the identification of specific infections, inflammatory conditions, or malignancy.

The test can be performed by an automated analyzer or manually, by examining blood smears under a microscope. The manual differential can identify cell types that are not counted by automated methods and detect clinically relevant changes in the appearance of W.B.C.

Blast cells are immature cells that are normally found in the bone marrow, where they develop into mature cells (hematopoiesis). When present in the blood smear, blast cells are an abnormal finding and may be indicative of acute leukemia or other serious blood disorders. They can be identified by their large overall size, deep blue cytoplasm, and large nucleus with fine chromatin and prominent nucleoli.

Platelet morphology

Large platelets (megathrombocytes) suggest bone marrow dysfunction, while small platelets, termed microthrombocytes, are associated with immune-mediated platelet destruction. Platelet clumping, observed when platelets form aggregates, can indicate platelet dysfunction or anticoagulant therapy.

8.2.4.3. Bone marrow aspiration and biopsy

Bone marrow biopsies and aspirates, obtained by specialized procedures, provide a direct view of bone marrow cellularity and morphology. Aspiration takes a fluid marrow sample for cellular morphology, flow cytometry, cytogenetics, molecular studies, and microbiology (acid-fast bacilli smear, culture, P.C.R. Biopsy takes a sample of intact bone marrow to assess histology (architecture) and immunohistochemistry. These procedures are realized in the posterior iliac crest/spine, sternum (aspiration only).

Indications

• unexplained C.B.C abnormalities

• diagnosis of infiltrating cancers: plasma cell disorders, leukemias, and solid tumors

• diagnosis and staging of lymphoma or solid tumors

• suspected deposition and storage disease (e.g. amyloidosis, Gaucher's disease)

· fever of unknown origin

• unexplained splenomegaly

8.2.4.4. Other tests

Coagulation tests

The complex balance of coagulation is assessed by a battery of tests, including prothrombin time P.T, activated partial thromboplastin time (A.P.T.T), and thrombin time T.T. These tests evaluate the function of various clotting factors, assisting in the diagnosis of bleeding and clotting disorders.

Cytogenetics and molecular techniques

Advances in molecular biology have transformed hematological investigations, enabling the identification of genetic abnormalities and molecular markers associated with various blood disorders. Cytogenetic analysis, involving the study of chromosomes, detects chromosomal abnormalities that underlie leukemias, lymphomas, and other malignancies. Molecular techniques, such as polymerase chain reaction (P.C.R, fluorescent in situ hybridization fish, and gene expression profiling, provide insights into specific gene mutations and molecular alterations that characterize various blood disorders.

Imaging studies

Ultrasound, C.T, and M.R.I play a complementary role in hematological investigations. These techniques can visualize abnormalities in the bone marrow, spleen, and other organs involved in blood production and circulation.

History taking

Age

8.2.4. Hematological Syndromes

8.2.4.1. Erythrocyte Syndromes

Neonatal Rh incompatibility is the cause for fetal erythroblastosis with jaundice and occurs in the first days after birth. Severe neurological symptoms are present in this case. Infants fed with cow's milk and not diversified in the right time (6 months) can develop iron deficiency anemia.

In childhood, the first manifestations of hemolytic anemias (congenital (hereditary spherocytosis, hemoglobinopathies) appear. In adults, posthemorrhagic anemias are more common. Biermer's anemia and simple chronic anemias occur more frequently in elderly people.

Gender

Iron-deficiency anemia and Biermer's anemia are more frequently present in females. Pregnancy and breastfeeding accentuate the pre-existing iron deficiency anemia.

Family history

Hereditary transmission for congenital hemolytic anemia (hereditary spherocytosis, thalassemia, glucose-6-phosphate deficiency dehydrogenase). In 20% of the patients with Biermer's anemia, other members of their family have this type of anemia.

Personal history

In the antecedents of patients with iron deficiency anemia we can encounter repeated episodes of bleeding (epistaxis, hematemesis, melena, hemoptysis, hematuria or metrorrhagia). Uncontrolled consumption of N.S.A.I.D's is common in the history of patients with acute or chronic posthemorrhagic anemia.

It is mandatory to note the presence of infections (pneumonia, pyelonephritis, chronic infections, intestinal parasites, malaria), diseases characterized by chronic inflammation or lead poisoning. Infections can determine anemias by hemolytic mechanism or by disrupting the use of iron. Chronic inflammatory diseases evolve with microcytic anemia by sequestering iron in the reticulohistiocytic system. Cardiovascular diseases (heart failure, chronic pulmonary heart, diseases chronic pulmonary disease) lead to secondary polyglobulia. Mechanic valve pros-thee-seez can cause hemolytic anemia by mechanical destruction of red blood cells.

Life conditions, lifestyle, diet

Inadequate diet (vegetarian diet, vegan diet, extreme poverty) can lead to iron deficiency anemia. Exposure to lead generates toxic/hemolytic anemias and the consumption of drugs can generate aplastic anemias (chloramphenicol), marrow toxicity with anemia and pancytopenia (cytostatic therapy). Smokers and people living at altitude will present secondary polyglobulia. This can also occur because of the increased consumption of androgenic hormones.

Symptoms

Anemia:

a. neurosensory (the consequence of hypoxia at the level of nervous structures): headache, dizziness, asthenia, drowsiness, decreased ability to concentrate, visual disturbances (decreased visual acuity), ear noises; these can occur in any type of anemia.

b. cardiovascular: dyspnea, palpitations, precordial pain (angina-like) - can be found frequently in any type of anemia.

c. symptoms specific to certain types of anemia:

- neurological symptoms characteristic of Biermer's anemia: decreased muscle strength at the level of the lower limbs - characterizes the funicular myelosis that appears because of damage to the posterior and lateral cords of the spinal cord and demyelination of the peripherals nerves)

- digestive symptoms characteristic of Biermer's anemia: glossodynia or a nonspecific dyspeptic syndrome (anorexia, nausea, vomiting).

- specific symptoms of iron deficiency anemia: dysphagia (Plummer-Vinson syndrome), pica (ingestion of abnormal substances: earth, chalk, etcetera, due to perversion of taste, disorder with unknown mechanism)

Polyglobulia (polycythemia):

a. neurosensory: headache, hypoacusis, sometimes confusing states or even hallucinations, paresthesia at the level of the pulp of the fingers b. cardiovascular: attacks of angina pectoris or intermittent claudication (frequent in polycythemia vera).

Physical examination

The mongoloid (oriental) facies and the exaggerated development of the skull in relation to the facial massif, with the realization of the skull "in a tower" or the "Olympic forehead" is found in hereditary microspherocytosis (congenital hemolytic anemia). In this type of anemia, we can also encounter skin manifestations such as chronic lower limb ulcer. Dwarfism and infantilism can be seen in congenital hemolytic anemias.

Physical signs, present in all types of anemia: pallor of the skin and mucous membranes, brittle, streaked nails, lackluster hair with a tendency to fall out, low-grade tran-zee-unt heart murmurs in all focuses of auscultation, tachycardia, arterial hypotension, heart failure.

Signs specific to certain types of anemia:

- Hunter's glossitis (tongue of color bright red, painful, atrophy of the papillae) in Biermer's anemia

- nails deformed with concavity upwards ("spoon-shaped" nails) are characteristic of iron deficiency anemia (severe forms)

- ulcerations and sores at the corners of the lips are specific to iron-deficiency anemia (angular stomatitis) and chronic atrophy of the nasal mucosa associated with fetid crusts (ozena)

- specific neurological signs of funicular myelosis in Biermer's anemia: disappearance of deep sensitivity, ataxic gait, hyporeflexia osteotendinous.

- splenomegaly occurs in hemolytic anemias, in Biermer's anemia and polycythemia vera.

The skin and mucous membranes have a red-violet color (reddish cyanosis), evident on the extremities and on the lingual and conjunctival mucous membranes. In the case of secondary polyglobula, the signs are obvious on physical examination causative diseases (ex: chronic obstructive pulmonary disease). Part of the cases with polyglobulia evolves with arterial hypertension.

8.2.4.1.1. Anemia

Anemia is defined as a syndrome characterized by a decrease in the number of R.B.C's which may result from blood loss, increased destruction of R.B.C's (hemolysis), or decreased production of R.B.C's. The classification of anemia using M.C.V is presented in table 8.6.

: Table 8.6 summary: Anemia classification based on Mean Corpuscular Volume, or MCV. Low MCV, defined as less than 80 cubic micrometers, includes conditions such as iron deficiency anemia, chronic bleeding, anemia of chronic disease, sideroblastic anemia, lead poisoning, and thalassemia. High MCV, defined as greater than 100 cubic micrometers, is split into megaloblastic causes, like vitamin B12 or folate deficiency and certain drugs, and non-megaloblastic causes, such as liver disease, alcoholism, and hypothyroidism. Normal MCV, between 80 and 100 cubic micrometers, is categorized by reticulocyte levels. High reticulocyte counts suggest inherited or acquired hemolysis, or acute bleeding. Low reticulocyte counts suggest pancytopenia, including aplastic anemia, leukemia, or bone marrow infiltration, as well as non-pancytopenia causes like anemia of chronic disease.

8.2.4

Anemia is normocytic when the R.B.C's are of normal size and the M.C.V is 80 to 100 fL. When determining the underlying cause of the normocytic anemia, reticulocyte count is essential. A high reticulocyte count signifies that bone marrow processes are normal, a low reticulocyte count would signify there is a pathologic process at the level of the bone marrow, which produces the stem cells. Acute blood loss would result in a high reticulocyte count, as bone marrow processes are normal, and the bone marrow responds accordingly to the body's deficiency of R.B.C's.

Etiology

- acute loss of blood of a significant volume (posthemorrhagic anemia)

- decreased production of normal R.B.C's (chronic disease, aplastic anemia)

- increased production of HbS (sickle cell disease)

- increased destruction or loss of R.B.C's (hemolysis, hypersplenism)

- uncompensated increase in plasma volume (pregnancy, fluid overload)

- Vitamin B.2 (riboflavin) or vitamin B.6 (pyridoxine) deficiency

- a mixture of conditions producing microcytic and macrocytic anemia

Blood loss and hemolysis represent the most frequent cases of normocytic anemia. In blood loss, morphologic findings are generally unremarkable, except after 12 to 24 hours when polychromasia appears. Hemolysis will often demonstrate poikilocytes specific to a cause or mechanism, including:

- oxidative hemolysis - bite cells and/or blister cells

- pyruvate kinase deficiency or McLeod phenotype - acanthocytes

- sickle cell anemia - sickle cells.

- immune-mediated hemolysis or hereditary spherocytosis - spherocytes

- hereditary elliptocytosis - elliptocytosis

- intravascular hemolysis - schistocytes

Aplastic anemia

Definition: destruction of hematopoietic cells of the bone marrow causing pancytopenia and hypocellular bone marrow

Clinical Features

• symptoms of anemia, thrombocytopenia, infection

• splenomegaly and lymphadenopathy

Investigations

- C.B.C: pancytopenia, decreased reticulocytes.

- Excluding other causes of pancytopenia is mandatory.

- Blood film: decreased number of normal R.B.C's.

- Bone marrow biopsy is the most precise investigation and shows aplasia or hypoplasia of cells with adipose tissue replacement.

Hemolytic anemia

Definition: anemia due to decreased circulating R.B.C survival, usually defined as less than 100 days.

Etiology

Hemolytic anemia could be hereditary and acquired (immune and non-immune).

The hereditary causes are related to

- abnormal membrane (spherocytosis, elliptocytosis)

- abnormal enzymes (pyruvate kinase deficiency, g6pd deficiency)

- abnormal Hb synthesis (hemoglobinopathies)

The acquired immune forms of hemolytic anemia could have autoimmune (acquired hemolysis caused by the host's immune system acting against its own red cell antigens. Consequent complement activation can impact the clinical picture. Sometimes a trigger is found, such as a drug, an infection, or an autoimmune condition, eg. systemic lupus erythematosus) or alloimmune mechanisms (hemolytic disease of the fetus/newborn and post-transfusion).

The non-immune hemolytic anemia appears in march hemoglobinuria (exertional hemolysis), snake venoms, mechanical heart valves, thrombotic microangiopathies or infections that can cause hemolysis in intravascular (Clostridium), extravascular, or both (malaria) territory.

Clinical features

- jaundice

- dark urine (hemoglobinuria, bilirubinuria)

- cholelithiasis (pigment stones)

- potential for an aplastic crisis (i.e. bone marrow suppression in overwhelming infection)

- iron overload with extravascular hemolysis.

- iron deficiency with intravascular hemolysis.

Specific investigations for hemolytic anemia are detailed in Table 8.7.

Table 8.7 summary: Specific investigations for hemolytic anemia are categorized by their diagnostic purpose. General screening tests include increased LDH, decreased haptoglobin, increased unconjugated bilirubin, increased urobilinogen, and reticulocytosis. For intravascular hemolysis, specific tests include the presence of schistocytes on blood film, free Hb in serum, methemalbuminemia, immediate hemoglobinuria, and delayed hemosiderinuria, the latter being the most sensitive. For extravascular hemolysis, the Direct Antiglobulin Test detects IgG or complement on the RBC surface and is indicated for AIHA, hemolytic transfusion reaction, and hemolytic disease of the newborn. The Indirect Antiglobulin Test detects antibodies in the serum and is used for cross-matching donor RBCs, atypical blood groups, AIHA, and blood group antibodies in pregnant women.

8.2.4.1.1.2. Microcytic anemia

Microcytic anemia is characterized by smaller than normal R.B.C's. When the M.C.V is less than 80 fL, the red cells are described as microcytic. In microcytic anemia, the R.B.C's contain less hemoglobin and are usually also hypochromic (paler) and low M.C.H.C is found. For this reason, anemia of this category is described as "microcytic, hypochromic anemia".

Etiology

- Iron deficiency anemia: the most common cause of anemia in general and of microcytic anemia in particular.

- Anemia of chronic disease

- Thalassemia

- Rare hereditary causes: sideroblastic anemia, hereditary hypotransferrinemia, hereditary aceruloplasminemia, erythropoietic protoporphyria, iron-refractory iron deficiency anemia, Lepore syndrome).

- Rare, acquired causes: lead poisoning, zinc deficiency, copper deficiency.

The presence of two or more causes of anemia can distort the typical clinical picture and the laboratory test, for this reason, other causes that are typically causing normocytic anemia or macrocytic anemia must also be considered.

Iron deficiency anemia

The etiology of iron deficiency anemia is detailed in table 8.8.

Table 8.8 summary: The etiology of iron deficiency anemia is categorized into three primary drivers. Increased demand occurs during physiological states such as pregnancy. Decreased supply results from dietary deficiencies, malnutrition, specific restrictive diets like cow's milk for infants or tea and toast for the elderly, and absorption imbalances caused by conditions such as celiac disease, post-gastrectomy, or autoimmune atrophic gastritis, as well as eating disorders like anorexia nervosa and bulimia. Increased losses are driven by hemorrhage, including obvious causes like abnormal uterine bleeding and gastrointestinal bleeds, or occult causes like peptic ulcer disease and gastrointestinal cancer, as well as hemolysis from conditions such as paroxysmal nocturnal hemoglobinuria and cardiac valve RBC fragmentation.

Clinical Features

- iron deficiency may cause fatigue before clinical anemia develops

- general symptoms of anemia: fatigue, headache, light-headedness, malaise, weakness, decreased exercise tolerance, dyspnea, palpitations, dizziness, tinnitus, and syncope

- brittle hair, nail changes (brittle, koilonychia)

- pica (appetite for non-food substances, for example ice, paint, and dirt)

- restless leg syndrome

Blood tests:

- Low iron saturation.

- Low hemoglobin (Hg) and hematocrit (Hct)

- Low mean cellular volume (M.C.V)

- Low ferritin and low serum iron F.E

- High transferrin or total iron-binding capacity T.I.B.C

Peripheral Blood Film

- Hypochromic microcytosis: R.B.C's have low Hb levels due to lack of iron

- Pencil forms, anisocytosis

Anemia of chronic disease

Etiology

- Infection, malignancy, inflammatory, and rheumatologic disease

- Chronic renal disease

- Chronic liver disease

- Endocrine disorders (diabetes mellitus, hypothyroidism, hypogonadism, hypopituitarism)

Pathophysiology

- R.B.C's underproduction due to impaired iron utilization.

- hepatic hepcidin production is increased in inflammatory processes, trapping iron in enterocytes and macrophages.

- reduced plasma iron levels make iron relatively unavailable for new Hb synthesis.

- marrow unresponsive to normal or slightly elevated erythropoietin.

Investigations

• diagnosis of exclusion

• associated with elevation in acute phase reactants (E.S.R, C.R.P, fibrinogen, and platelets)

· peripheral blood

- mild: usually normocytic and normochromic

- moderate: may be microcytic and normochromic

- severe: may be microcytic and hypochromic

- absolute reticulocyte count is frequently low, reflecting overall decrease in R.B.C production

- low serum iron

- low total iron-binding capacity

- low to normal percent transferrin saturation

- elevated ferritin

Bone Marrow Biopsy: normal or increased iron stores and decreased or absent staining for iron in erythroid precursors.

8.2.4.1.1.3. Macrocytic anemia

A macrocytic class of anemia in which the R.B.C's are larger than their normal volume (macrocytosis). In macrocytic anemia, the larger red cells are always associated with insufficient numbers of cells and insufficient hemoglobin content per cell, resulting the opposite effect of larger cell size, to finally result in a low total blood hemoglobin concentration.

Etiology (table 8.9)

Mnemonic: A.B.C.D.E.F

- Alcoholism (liver disease)

- B.12 deficiency

Compensatory reticulocytosis

Drugs (cytotoxic, azidothymidine)/Dysplasia

• Endocrine (hypothyroidism)

Folate deficiency/Fetus (pregnancy)

Table 8.9 summary: The etiology of vitamin B12 deficiency is categorized into four primary groups: diet, gastric issues, intestinal absorption problems, and genetic factors. Dietary causes include strict veganism, vegetarianism during pregnancy, and general malnutrition. Gastric-related causes involve mucosal atrophy leading to gastritis or autoimmune conditions, pernicious anemia, and post-gastrectomy states. Intestinal absorption issues encompass malabsorption from conditions like Crohn's Disease, Celiac sprue, pancreatic insufficiency, H. pylori, and stagnant bowel conditions such as blind loop or stricture. Other intestinal factors include fish tapeworm, resection of the ileum, and the use of specific drugs like Neomycin, biguanides, proton pump inhibitors, metformin, or N2O anesthesia. Finally, genetic causes are identified as Transcobalamin II deficiency and IF receptor defects.

Pernicious Anemia (Biermer's anemia)

- auto-antibodies produced against gastric parietal cells leading to achlorhydria and lack of intrinsic factor (I.F) secretion.

- I.F is a glycoprotein produced by the parietal cells (oxytic cells) located at the gastric body and fundus and plays a crucial role in the transportation and absorption of the vital micronutrient vitamin B.12 (cobalamin) by the terminal ileum.

- decreased I.F leads to decreased ileal absorption of B.12.

- most common in Northern European Caucasian populations

Clinical features

- peripheral neuropathy with variable reversibility and usually symmetrical, affecting lower limbs more than upper limbs

- posterior columns: decreased vibration sense, paresthesia

- pyramidal tracts: spastic weakness, ataxia

- cerebral (common, reversible with B.12 therapy): confusion, delirium, and dementia

Investigations

- M.C.V greater than 110 fL

- serum cobalamin (Vitamin B.12) less than 200 nanograms per liter

- presence of anti-I.F antibodies

- I.F is either absent or markedly decreased.

- elevated unconjugated bilirubin and L.D.H due to breakdown of cells in B.M

- elevated methylmalonic acid and homocysteine presented. Blood Film: oval macrocytes, hypersegmented neutrophils

Bone Marrow Biopsy

- hypercellularity

- nuclear-cytoplasmic asynchrony in R.B.C precursors (less mature nuclei than expected from the development of the cytoplasm).

- Schilling test: the purpose of the test is to determine how well a patient can absorb B.12 from their intestinal tract. Today is rarely performed.

Gastroscopy: atrophic gastritis associated with achlorhydria

Folate deficiency anemia

Folate deficiency (vitamin B.9 deficiency results in a macrocytic anemia called folate deficiency anemia. The clinical features are often subtle, and the first stages of the disorder might be asymptomatic. Not consuming enough folate can lead to folate deficiency within a few months. Folate is commonly found in green, leafy vegetables, and fortified cereals.

Etiology of the folate deficiency anemia is detailed in table 8.10.

Table 8.10 summary: The causes of folate deficiency are categorized into four primary etiologies. Diet and deficiency include alcohol use disorder, substance misuse, poor intake, and the needs of elderly patients or infants. Malabsorption occurs in conditions such as Celiac sprue, IBD, infiltrative bowel disease, and short bowel syndrome. Drug-induced deficiency is associated with anti-folates like methotrexate, anticonvulsants such as phenytoin, and oral contraceptives. Finally, increased demand is seen during pregnancy, hemolysis, prematurity, hemodialysis, and exfoliative dermatitis or psoriasis.

Clinical features

Symptoms may include fatigue, heart palpitations, dyspnea, syncope, open sores on the tongue, loss of appetite, changes in the color of the skin or hair, irritability, and behavioral changes. Temporary reversible infertility may occur. During pregnancy it can be the cause of low weight birth premature infants and infants with neural tube defects.

Investigations

- serum folate levels less than 2 nanograms per milliliter are considered deficient,

- borderline levels between 2 to 4 nanograms per milliliter warrant further confirmation by measurement of methylmalonic acid (normal) and homocysteine (low0 levels.

- C.B.C

- blood film

- serum Vitamin B.12 - normal

8.2.4.2. White blood cells disorders

Distinguishing malignant from benign modifications of the W.B.C is an essential step which will further initiate a different decision tree. Below we present the modifications of the W.B.C's in benign conditions:

1. Leukopenia = low number of W.B.C

- The decrease in the number of leukocytes below 4000/mm cubed is generally achieved by decreasing one of its components:

a) Neutropenia - below 3000 neutrophils/mm cubed can be observed in: -bacterial infections: typhoid fever, tuberculosis

-viral infections: flu, acute viral hepatitis, measles

-immune diseases: Systemic lupus erythematosus, Felty syndrome

- drugs: cytostatic therapy, non-steroidal anti-inflammatory drugs, anticonvulsants. - bone marrow diseases: Biermer's anemia, aplastic anemia, leukemias

- Agranulocytosis: the decrease in the number of neutrophils below 1000/mm cubed . It is a rather rare condition and occurs especially after the consumption of certain drugs (amidopyrine, thiouracil, gold salts, sulfonamides, phenylbutazone). It evolves with necrotic lesions of the oral cavity and oropharynx.

b) Lymphopenia - below 1000/mm cubed lymphocytes, present in: -congenital or acquired immunodeficiency syndromes (H.I.V infection)

- treatment with corticosteroids, cytotoxic drugs

- postirradiation

- S.L.E, sarcoidosis, advanced Hodgkin's disease

2. Leukocytosis: increased number of leukocytes = (over 10,000/mm cubed). Generally achieved by increasing one of its components:

a) Neutrophilia - increase in the number of neutrophils making up over 70% of the total number of leukocytes (over 7000/mm cubed). It is generally accompanied by a deviation to the left of the leukocyte formula by the appearance of circulating young elements. Appears in:

- physiological conditions: stress, pregnancy, lactation

- acute bacterial infections (pyogenic in particular)

- acute inflammatory diseases

- metabolic disorders: uremia, diabetic ketoacidosis, thyrotoxicosis

- posthemorrhagic or posthemolytic

- necrosis (myocardial infarction, gangrene).

b) Eosinophilia - eosinophils over 3% of the total number of leukocytes or over 300/mm, occurs in:

- parasitic infestations: ascaridosis, trichinosis, filariasis, hydatid cyst.

- allergic diseases: bronchial asthma, urticaria, Quincke's edema.

- dermatitis: eczema, psoriasis, pemphigus

-collagenases: polyarteritis nodosa, fasciitis with eosinophils, etcetera

Under the name hypereosinophilic syndrome are grouped the clinical manifestations associated with the significant increase in the number of eosinophils, sometimes anemia and thrombocytopenia. Clinical features include fever, night sweats, weight loss, splenomegaly, cardiac (eosinophilic infiltration, endocardial and subendocardial necrosis and fibrosis), pulmonary, and nervous system lesions.

c) Lymphocytosis-increase in the number of lymphocytes over 30% of the total leukocytes or over 3000/mm cubed. Appears in: -viral infections: infectious mononucleosis, cytomegalovirus infection, measles, rubella, chicken pox, acute viral hepatitis.

-bacterial infections: tuberculosis, whooping cough, syphilis

Malignant hematologic disorders, notably leukemia, intricately involve W.B.C's in their pathogenesis. Leukemic transformation results in uncontrolled proliferation and impaired functionality of W.B.C's. Highly elevated W.B.C counts are specific for leukemia and distinct subtypes, such as acute myeloid leukemia (A.M.L) or chronic lymphocytic leukemia (C.L.L), exhibit characteristic alterations in W.B.C profiles. Monitoring these quantitative and qualitative changes in W.B.C's is essential for disease classification, prognostication, and tailoring targeted therapeutic approaches in the realm of malignant hematologic disorders

8.2.4.2.1. Leukemia

Leukemias are malignant diseases of the bone marrow, consisting in the replacement of normal cells with precursors of the hematopoietic cells, leading to infiltration of organs and tissues.

The classification relies on the type of cells (lymphocytic and myeloid), these categories presenting both as acute and chronic forms.

History taking

Age

In children up to the age of 5, acute leukemias are more common. Chronic myeoloid leukemia (C.M.L) is common in adults, and chronic lymphatic leukemia (C.L.L) and multiple myeloma (M.M) are more common in the elderly.

Gender

Family history

Familial aggregation has been found in some forms of leukemia. In leukemias with genetic involvement, the presence of chromosomal abnormalities was also found (Philadelphia chromosome appears in 90% of patients with chronic granulocytic leukemia).

Personal history

Repeated radiological examinations or radiation therapy are risk factors for white series malignancies. Chronic use of certain drugs (chemotherapy, chloramphenicol, anti-inflammatory, analgesics, antithyroid) can cause leukopenia or even agranulocytosis.

Lifestyle and professional factors

Radiologists and radiology nurses, after a prolonged number of years of exposure to X-rays, are prone to white cell proliferative diseases. Prolonged handling of toxic substances (benzene, insecticides, detergents) exposes to the same leukemogenic risk.

8.2.4.2.1.1. Acute leukemia

Clinical manifestations are related directly to the rapid infiltration of the marrow and organs with immature cells.

8.2.4.2.1.1.1. Acute Lymphoid Leukemia (A.L.L)

Symptoms include:

- fever (even in absence of infection)

- infections

- abdominal pain (especially left upper quadrant) due to splenomegaly

- bone pain

- general symptoms (asthenia, lack of appetite)

- due to anemia: fatigue, dizziness, palpitations, dyspnoea

- due to leukostasis (leucocytes greater than 100.000 cells/μl) and hyperviscosity syndrome: altered mental status, drowsiness, coma, papillary edema, respiratory failure

- due to thrombocytopenia: hemorrhage

- meningeal syndrome (cranial nerve paralysis)

- infiltration of the gonads, salivary and lacrimal glands (Mickulicz syndrome)

Physical examination

skin and mucous membranes: pallor; due to anemia (concomitant or secondary damage to erythropoiesis or hemolysis).

- purpura, petechiae, ecchymoses

- superficial lymphadenopathies (A.L.L greater than A.M.L)

- blastic meningitis

oral hemorrhages or ulcerations (A.L.L), erythematopultaceous angina (infectious mononucleosis) or ulceronecrotic (agranulocytosis)

- splenomegaly

- innocent systolic heart murmurs

- manifestations of renal failure (hyperuricemia)

8.2.4.2.1.1.2. Acute Myeloid Leukemia (A.M.L)

A.M.L represent infiltration with greater than 30% blasts (myeloblasts, promyelocites, monoblasts, pro-monocytes) in the bone marrow

Symptoms include:

- due to thrombocytopenia: manifestations of disseminated intravascular coagulation hemorrhage (A.M.L greater than A.L.L)

- same symptoms like in A.L.L

Physical examination

- massive splenomegaly

- oral cavity and pharynx: gingival hypertrophy (A.M.L)

- skin and mucous membranes: pallor; due to anemia (concomitant or secondary damage to erythropoiesis or hemolysis)

- purpura, petechiae, ecchymoses

- superficial lymphadenopathies (A.L.L greater than A.M.L)

- innocent systolic heart murmurs

- manifestations of renal failure (hyperuricemia)

Complementary investigations in acute leukemias:

1. complete blood count: leucocytes increased (moderate - 50,000/mm cubed)/normal/ low (less often), anemia, thrombocytopenia

2. Peripheral blood smear: blast cells greater than 30%; leukemic hiatus - the presence of only leukemic and mature cells, with the absence of intermediate forms

3. Increased L.D.H

4. Blood culture (in case of fever, signs of infection)

5. Bone marrow aspiration and biopsy (mandatory!)

6. Immunophenotyping (differential diagnosis A.M.L-A.L.L)

7. Cytogenetic tests

8. Imaging tests (deep lymph nodes, mediastinum assessment): Chest-X-ray, C.T

9. E.C.G (before chemotherapy)

8.2.4.2.1.2. Chronic leukemia

Clinical manifestations are related directly to the slow infiltration of the marrow and organs with relative mature, but abnormal white blood cells.

8.2.4.2.1.2.1. Chronic Lymphocytic Leukemia (C.L.L)

Symptoms include:

- asymptomatic/mild fatigue

- weight loss

- excessive sweating

- leukostasis and hyperviscosity syndrome

- frequent infections

Physical examination

- generalized adenopathies

- malignant infiltration of skin (diffuse redness and violet nodules)

- lymphocytic infiltration of the lacrimal and salivary glands (Mikulicz face), tonsils, central nervous system

- hepatomegaly, splenomegaly

Complementary investigations:

1. complete blood count: leucocytosis greater than 10.000/mm cubed and lymphocytosis

2. peripheral blood smear: nuclear Gumprecht shadows; smudge, large, atypical, cleaved cells, prolymphocytes

3. low immunoglobulins

4. bone marrow aspiration and biopsy: hypercellularity, expansion of lymphoid cell line

5. Imaging tests (hepatosplenomegaly, deep lymph nodes, mediastinum assessment): abdominal U.S, C.T (thorax, abdomen, pelvis)

8.2.4.2.1.2.2. Chronic Myeloid Leukemia (C.M.L)

- initial chronic phase (years), then transitional, unstable, accelerated (months) and final aggressive (blast crisis), fatal phase

Symptoms include:

- insidious onset with general symptoms: asthenia, sweating, weight loss, pallor, discomfort in the left upper quadrant

- weight loss

- excessive sweating

- leukostasis and hyperviscosity syndrome

- frequent infections

- hemorrhagic manifestations (mainly in blast crisis)

Physical examination

- important splenomegaly (dominant)

- hepatomegaly

- polymicroadenopathies

- gingival hypertrophy

Complementary investigations:

1. complete blood count: leucoerythroblastic aspect, increased basophils and eosinophils; leukocytosis greater than 100,000/mm cubed with left deviation of leukocyte formula up to myeloblast; thrombocytopenia; normochromic and normocytic anemia

2. Peripheral blood smear: early myeloid cells

3. hyperuricemia

4. high B.12 vitamin-binding protein

5. Bone marrow aspiration and biopsy: hypercellularity, expansion of myeloid cell line

6. Cytogenetic tests: P.h.1 chromosome present

8. Imaging tests (hepatosplenomegaly, deep lymph nodes, mediastinum assessment): abdominal U.S, C.T (thorax, abdomen, pelvis)

8.2.4.2.2. Lymphoma

Lymphomas are malignant tumors of cells of the immune system (B and T lymphocytes), located in different tissues. Usually, proliferation begins at the level of cells in the structure of lymphoid organs (ganglions, spleen, Waldeyer's ring, etcetera) with generalization in follow-up.

There are 2 major forms of lymphomas:

a) Hodgkin's lymphoma (H.L) - the onset is frequent with laterocervical and supraclavicular lymphadenopathy (grouped nodes, of increased consistency, painless, of large or medium size, deforming the respective region).

b) non-Hodgkin lymphomas (N.H.L) with nodal or extranodal onset (gastrointestinal, hepatic, splenic, bone lymphomas, etcetera)

History taking

Age

In children up to 5 years of age, lymphocytic lymphoma is more common.

H.L is common in young adults and people over 55 years, while N.H.L and multiple myeloma are more common in elderly.

Gender

Lymphomas are more common in men.

Personal history

In some patients with H.L and N.H.L, infection with the H.I.V or E.B.V (Burkitt-lymphoma) was highlighted. Long term infection with Helicobacter pylori is involved in the gastric malt-lymphoma. Immundefficiencies (genetic, acquired) as well as irradiation are risk factors for N.H.L.

Lifestyle and professional factors

Immunosuppressive therapy and toxic substances (wood protective substances, dilution substances) are cofactors involved in H.L. Ionizing irradiation for solid tumors or exposure to radiation, pesitcids are risk factors for M.M.

8.2.4.2.2.1. B-cell neoplasms

Non-Hodgkin Lymphoma-N.H.L (85%)

Symptoms depend on the type and stage of lymphoma:

- painless progredient lymphadenopathy, splenomegaly, mediastinal syndrome, extranodal involvement (G.I tract-malt lymphomas, urinary tract, C.N.S, thyroid, skin, bone marrow, sinuses); malt-mucosa associated lymphoid tissue

- abdominal pain (especially in the left upper quadrant) due to splenomegaly; epigastric pain, loss of appetite, nausea malt

- systemic symptoms (of type "B": fever, weight loss greater than 10%/6 months, night sweats)-bad prognosis

Physical examination

- localized painless superficial lymphadenopathies - described in the "General physical examination" chapter

- petechia

- splenomegaly (lymphomas/multiple myeloma) sometimes accompanied by

- hepatomegaly

Investigations:

1. C.B.C: normal aspect (early stages), moderate increase in the number of leukocytes (lymphocytosis)/leucopenia; anemia, thrombocytopenia/thrombocytosis (paraneoplastic)

2. lymph node removal - determines type of lymphoma and degree of aggressivity

3. Immunophenotypic analysis: subtypes of lymphoma (diffuse B-cell-N.H.L, follicular N.H.L, “hairy cells”leukemia, lymphoma with “mantle”cells-worst prognosis)

4. Cytogenetic studies-chromosomal translocations

5. malt-lymphomas: digestive endoscopy with biopsies (including for H. pylori), E.U.S, entero-enema, C.T, M.R.I

6. Imaging tests

- Chest X-Ray: mediastinal/hilar lymphadenopathy, pleural effusion, pericarditis

- C.T (neck, thorax, abdomen, pelvis)-staging, follow-up, therapy response assessment: lymphadenopathy, hepatosplenomegaly

- Bone scintigraphy: patients with bone pain/elevated A.F

- Whole-body-F-18.D.G-P.E.T scan: relapse/residual disease assessment

Cardiac U.S: L.V function assessment before chemotherapy

M.R.I (brain, spine): meningitis, lymphoma of C.N.S - Multiple myeloma (M.M)-represents the most frequent tumor of bones/bone marrow.

- Symptoms: localized bone pain (skull, pelvis, spine and extremities); general symptoms (asthenia, fatigue, weight loss); hypercalcemic crisis (polyuria, somnolence, vomiting); nephrotic syndrome; renal failure; 20% asymptomatic

- Physical exam: pallor (skin and mucous membranes) due to anemia due to concomitant or secondary damage to erythropoiesis or hemolysis; splenomegaly; pathological fractures

- Investigations:

- X-ray/M.R.I of wide bones (eg: skull): typical areas of osteolysis

- Bence-Jones proteinuria

- greater than 10% malignant plasma cells (bone marrow)

- monoclonal spectrum of the paraproteins (serum protein electrophoresis-gammaglobulins)

- accelerated B.S.R ( greater than 100 millimeters/h)

8.2.4.2.2.2. T-cell neoplasms

cutaneous lymphoma:

-mycosis fungoides: initial localized erythematous areas with scales, then plaques with skin thickening, pruritus, tumors with erosions and ulcerations, final generalization of all organs

- Sezary-syndrome - triad: generalized erythrodermia+pruritus, lymphadenopathies, leukemic blood count with Sezary-cells

- N.H.L (15%)

• E.A.T.L (enteropathy-associated T-cell) lymphomas

- extranodal lymphoma of G.I-tract

- complication of celiac disease

- abdominal pain (ileocecal area), loss of appetite, nausea

- lower digestive endoscopy with biopsies (ileocecal valve), double-balloon-enteroscopy, E.U.S, entero-enema, C.T, M.R.I

• angioimmunoblastic T-cell lymphoma (X lymphogranulomatosis):

- B-symptoms, rapid enlargement of adenopathies, exanthema

- high inflammatory syndrome, anemia, hypergammaglobulinemia

8.2.4.2.2.3. N.K-cell Neoplasms

• nasal type of extranodal N.K slash T-cell lymphoma-frequent associated with E.B.V (Asia)

8.2.4.2.2.4. Hodgkin Lymphoma (H.L)

Symptoms depend on the type and stage of lymphoma:

- localized painless lymphadenopathy-e.g. cervical+supraclavicular (painful after alcohol consumption) in advanced stages generalized systemic disease also with extranodal involvement, pruritus (more frequent at night and may suggest exacerbations of the disease)

- abdominal pain (especially in the left upper quadrant) due to splenomegaly

- systemic symptoms (of type "B": fever, weight loss greater than 10%/6months, night sweats)-bad prognosis

Physical examination

- superficial lymphadenopathies - described in the "General physical examination" chapter

- intermittent type/Pel-Ebstein-fever

- splenomegaly sometimes accompanied by

- hepatomegaly

Investigations:

1. C.B.C: normal aspect (early stages), moderate increase in the number of leukocytes (lymphocytosis)/leucopenia; anemia, thrombocytopenia/thrombocytosis (paraneoplastic)

2. lymph node biopsy-determines type of lymphoma and degree of aggressivity! Reed-Sternberg giant cells are pathognomonic for H.L

3. poor prognosis: lymphopenia, eosinophilia, serum elevated L.D.H, transaminases, A.F, calcium, beta 2 microglobulin, E.S.R

4. Immunophenotypic analysis: subtypes of lymphoma

5. Cytogenetic studies

6. Imaging tests

Chest X-Ray: mediastinal/hilar lymphadenopathy, pleural effusion, pericarditis

C.T (neck, thorax, abdomen, pelvis)-staging, follow-up, therapy response assessment: lymphadenopathy, hepatosplenomegaly

Bone scintigraphy: patients with bone pain/elevated A.F

• Whole-body-F-18.D.G-P.E.T scan: relapse/residual disease assessment

Cardiac U.S: L.V function assessment before chemotherapy

M.R.I (brain, spine): meningitis, lymphoma of C.N.S

8.2.4.3. Platelets syndromes

This chapter describes the quantitative and qualitative disorders of platelets, and the further 2 categories responsible for hemorrhagic syndrome will be presented in the next chapter.

Hemorrhage (bleeding) appears due to an impaired hemostasis, that involves 3 steps: primary hemostasis (through platelets and vessels), plasmatic coagulation and fibrinolysis. Whenever we are in front of a hemorrhagic syndrome, we have to take into account one or more of the following possibilities:

1. Disorders of platelets (quantitative/qualitative)

2. Coagulopathy

3. Vasculopathy

History taking

Age

Hemorrhagic syndrome manifests immediately after birth, or prolonged bleeding that occurs during the change of milk teeth, vaccinations, blood sampling or after minor traw-muz can mean thrombocytopenic purpura (neonatal).

In childhood, the first manifestations of Werlhof's disease may appear. Gender

The female gender is prone to the appearance of idiopathic thrombocytopenic purpura (I.T.P), disseminated intravascular coagulation (D.I.C) and hypercoagulability states (secondary to the use of oral contraceptives).

Personal history

In liver cirrhosis, hemorrhagic syndrome can be secondary to thrombocytopenia due to hypersplenism.

Prolonged anesthesia, laborious surgical or gynecological operations, incompatible blood transfusions can trigger D.I.C.

Lifestyle and professional factors

Chronic alcohol consumption has been implicated in the occurrence of thrombocytopathies.

8.2.4.3.1. Quantitative disorders

Hemorrhagic syndromes caused by platelets can be determined by thrombocytopenia through:

- Abnormal distribution: splenic sequestration (hypersplenism-e.g. liver cirrhosis)

- Dilution effect: pregnancy

- Decreased production: medullary aplasia (leukemias, lymphomas, irradiation, H.I.V/HCV/E.B.V infections, benzol), deficiency of vitamin B.12 and/or folic acid, chemotherapy, irradiation, myelodysplastic syndromes

- Increased destruction due to:

- immune causes - I.T.P, neonatal alloimmune thrombocytopenia, H.I.V associated, secondary to: lymphomas/autoimmune diseases (S.L.E), medication (Heparin, Fludarabin), blood transfusion

- drugs

- sepsis

- disseminated intravascular coagulation (D.I.C), hellp syndrome

- microangiopathic hemolytic-uremic syndrome (H.U.S)

- thrombotic thrombocytopenic purpura (T.T.P.P)

- pregnancy (disappears 2 months postpartum)

- mechanical prosthetic heart valves

Clinical manifestations in thrombocytopenic patients consist mainly in petechiae. Laboratory data show lower number of thrombocytes less than 150,000 per microliter. Severe bleeding risk appears only if less than 30,000 per microliter.

Cave! False thrombocytopenia might appear due to E.D.T.A-depending agglutinin (blood samples should be taken in citrate medium to clear the situation).

Biopsy of bone marrow shows different amount of megakaryocytes: low (decreased production), high (increased distraction).

Idiopathic Thrombocytopenic Purpura (I.T.P) - Werlhof's Disease

I.T.P is characterized by a decrease in the lifespan of platelets through an autoimmune mechanism - the appearance of antiplatelet antibodies, with their destruction in the spleen and liver. It is more common in children and women, and the role of viral and H. pylori infections in their triggering is controversial.

Clinical manifestations:

- frequent sudden onset, rapidly progressive

- spontaneous non-palpable, painless hemorrhagic purpura with extension over the entire surface of the body, which does not disappear with digital pressure and which in evolution usually disappear without leaving traces

- epistaxis, gingival bleeding and hemorrhagic bubbles in the oral cavity

- menorrhagia

- rare: severe cerebral, G.I hemorrhage

- spontaneous hematomas on minor traw-muz

- fever

Laboratory data:

- platelet count - very low, about 5000 per microliter

- antiplatelet antibodies (may be absent in the beginning)

- very prolonged bleeding time (in the presence of severe thrombocytopenia it can even be dangerous to perform)

- coagulation time - normal

Hemolytic-uremic syndrome (H.U.S)

H.U.S is, together with T.T.P.P, representative for the thrombotic mycroangiopathies.

Clinical manifestations:

- neurological manifestations (confusion, seizures)

- altered general status, fever

Laboratory data:

- acute thrombocytopenia less than 30,000 per microliter

- hemolytic anemia, increased L.D.H

- normal coagulation parameters

- high serum creatinine ( greater than 2,2 milligrams/dl)

Thrombotic Thrombocytopenic Purpura (T.T.P.P)-Moschcowitz Syndrome

T.T.P.P has an acute/subacute onset.

Clinical manifestations:

- neurological (seizures, hemiplegia, visual troubles, hemiplegia)

- rare: severe hemorrhage

- fatigue, fever, petechiae

Laboratory data:

- platelet count - low, anemia

- normal coagulation tests

- peripheral smear: schistocytosis

- elevated L.D.H, D-Dimers, fibrinogen, bilirubin

8.2.4.3.2. Qualitative disorders (thrombopathies)

Thrombopathies consist in intrinsic platelet defect of adhesiveness and/or aggregation of platelets:

- Inherited disorders: Glanzmann's thrombasthenia, Bernard-Soulier syndrome

- Acquired disorders: in M.M, P.V

- Medication (85%): antiplatelet drugs (aspirin, clopidogrel), indomethacin and other N.S.A.I.D's, phenylbutasone

- Chronic renal failure: uremic toxins disrupt the function of thrombocytes

- Cardiopulmonary bypass: due to use of heparin, hypothermia, prolonged exposure on artificial surface and inadequate protamine administration; reduces the amount of platelet membrane glycoproteins on platelets

Clinical manifestations:

- mild bleeding (epistaxis, mucosal hemorrhage at invasive manoevers) Laboratory data:

- functional thrombocyte tests: aggregometry, flow-cytometry

8.2.4.4. Bleeding disorders

Bleeding disorders meet all the signs and symptoms resulting from a decrease in the procoagulant activity of the blood, a decrease that causes the appearance of prolonged and/or recurrent hemorrhages. The common feature of hemostasis diseases is hemorrhagic manifestations at the level of the skin, mucous membranes or viscera.

Causes:

Hemostasis (the complex of physiological phenomena that contribute to the prevention and stopping bleeding) takes place in the 3 stages specified previously. In this chapter, we are going to present the hemorrhagic syndrome due to coagulopathies and vasculopathies; as platelet disorders were exposed in the chapter before. Hemostasis investigation tests can differentiate between the different diseases that make up the hemorrhagic syndrome.

History taking

Age

In the male newborn, prolonged bleeding from the umbilical wound suggests possible hemophilia.

In childhood, the first manifestations of Rendu-Osler, von Willebrand or Schönlein-Henoch purpura may appear.

In adults, hemorrhagic syndromes secondary to other diseases (hepatic, renal failure, bone marrow failure) are more common, and senile purpura (Bateman) is more common in the elderly.

In adults, hemorrhagic syndromes secondary to other diseases (hepatic, renal failure, bone marrow failure) are more common, and senile purpura (Bateman) is more common in the elderly.

Gender

Hemophilia A or B occurs exclusively in males.

Family history

Genetically conditioned diseases include hemophilia, Rendu-Osler disease, or some of the hypercoagulability states (antithrombin three deficiency).

Personal history

Streptococcal infections or the consumption of certain drugs or allergenic foods can be found in the history of patients with Henoch-Schönlein purpura; meningococcal infections (meningitis, septicemia) can cause Waterhouse-Friderichsen syndrome (hemorrhagic exanthema in meningococcal meningitis).

Prolonged immobilizations in bed (postoperative, cerebrovascular accidents) favor venous stasis and blood hypercoagulability states.

Chronic hepatitis and liver cirrhosis can determine low synthesis of coagulation factors, with the appearance of a hemorrhagic syndrome (cutaneous, mucous, visceral).

Lifestyle and professional factors

Vitamin C deficiency in children's diet can cause hemorrhagic gingivitis and petechial purpura (manifestations of infantile scurvy). Prolonged orthostatism can favor the appearance of orthostatic purpura. Smoking can induce states of hypercoagulability. Prolonged use of aspirin or N.S.A.I.D's can cause severe G.I bleeding, and overdose of heparin or oral anticoagulants can cause bleeding in various locations. Certain foods can cause skin purpura through an allergic mechanism; intoxications (chemical substances, venom) can also cause hemorrhagic manifestations.

8.2.4.4.1 Inherited disorders

They usually involve only one factor of coagulation and can cause hemorrhages that appear from the first part of childhood. Thromboembolic events may appear due to deficiencies in coagulation inhibitors (antithrombin three, protein C or S).

a) Coagulopathies

Haemophilia is a hereditary disease with sex-linked recessive autosomal transmission, characterized by the deficiency of factor 8 (hemophilia A) or less often factor 9 (hemophilia B). Boys present the clinical disease and girls are only carriers. The homozygous state is exceptional.

Clinical manifestations:

repetitive hemarthrosis (knee, elbow, glenohumeral or in any other joint); hemophilic arthropathy (with pain, ankylosis, muscle atrophy)

- hematomas - muscular, retroperitoneal, intraperitoneal

- hematuria, G.I tract bleedings

- serious post-traumatic/post-surgery hemorrhages

Laboratory data:

- prolonged bleeding time and coagulation time

- low plasmatic level of factors 8 or 9

- platelet count – normal von Willebrand's disease of type I (quantitative-80%)/two (qualitative)/three: decrease/absence of vWF and factor 8

Clinical manifestations:

- easy bruising, epistaxis, menorrhagia, postoperative bleeding Laboratory tests:

- normal/low platelet count

- typical: decreased activity of f.8, von Willebrand's factor levels, von Willebrand factor antigen; determination the subtype of vW disease

- prolonged bleeding time, A.P.T.T b) Vascular anomalies manifested by hemorrhagic syndrome can appear at the level of arterioles and venules:

Rendu-Osler disease (hereditary hemorrhagic telangiectasia with autosomal dominant transmission); bleeding can be present from birth; flat, red-purple telangiectasias appear, with a diameter of 3 millimeters, located on the face, lips, tongue, ears, plants, which disappear when digital pressure is applied and which sometimes merge to form vascular tumors. Telangiectasias are also present in the viscera (lung, stomach, etcetera); the paleness of the skin and mucous membranes in this disease is due to anemia, caused by repeated, chronic bleeding present right from birth.

Ehlers-Danlos disease, in which there are abnormalities of the connective tissue that supports the vessel wall. These lead to vascular fragility, spontaneous bleeding on minor trauma, and hemorrhages in various locations.

8.2.4.4.2. Acquired disorders

Acquired disorders appear as a result of:

- deficient production of coagulation factors: vitamin K deficiency, liver failure, nephrotic syndrome

- hyperconsumption: disseminated intravascular coagulation

- primary fibrinolysis

- the presence of circulating anticoagulants

a) coagulopathies

Disseminated intravascular coagulation (D.I.C) represents a complex disorder of hemostasis, in which there is initially a generalized activation of coagulation followed by the activation of fibrinolysis. Its acute form related to severe bacterial infections (sepsis), obstetrical complications, hemolysis, extensive tissue destruction, endothelial injuries, and the chronic one to neoplasms.

Clinically, in the same patient, thrombosis and bleeding are simultaneously present, evolving either acute and severely or, more rarely, subacute.

Laboratory data indicate thrombocytopenia (most sensitive parameter), microangiopathic hemolytic anemia, prolonged Q.T and A.P.T.T time, low fibrinogen, the presence of fibrinogen degradation products (high D-Dimers).

b) vascular anomalies manifested by hemorrhagic syndrome can appear at the level of capillaries, arterioles and venules:

Henoch-Schönlein purpura (purpura rheumaticia). It is a generalized leukocytoclastic vasculitis (parietal and perivascular infiltration with deposits of complexes of IgA and C.3 in the capillaries). It occurs in children and young adults and in approximately 50% of cases it is related to infection with β hemolytic streptococcus.

Clinical symptoms (typical triad: 1.purpura, 2.arthritis, 3.abdominal pain):

- joint pain (indispensable)

arthritis (ankles, elbows, knees)

- diffuse abdominal pain, with colicky character, aggravated by meals, vomiting, bloody diarrhea/constipation, upper digestive hemorrhage

- fever

- hematuria, proteinuria, nephrotic syndrome, Berger disease (IgA glomerulonephritis)

- hemorrhages in any territory: meninges, scrotum, peritoneum, etcetera

- hypertension

Physical examination

- palpable, painful, symmetrical purpura, suddenly installed, with size between 1 millimeters and a few centimeters, located especially on the lower limbs (but also on arms, face, trunk), appearing in patches, frequently preceded by hives in the calves, sometimes hemorrhagic nodules, which disappear after a few weeks; they rarely progress to ulceration/necrosis. Severe cases evolve with hemorrhages at the level of the mucous membranes/viscera.

Laboratory data:

- positive inflammation tests: V.S.H, C.R.P, fibrinogen, leukocytosis

- bleeding time, coagulation time and platelet count-normal, capillary fragility (tourniquet test) sometimes positive

- biopsy of skin, kidney

In orthostatic purpura, the hemorrhages are exclusively at the level of the integuments of the lower limbs, the evolution of the purpura being chronic and benign.

Senile purpura is located on the back of the hand, related to exposure to the sun.

Hyperglobulinemic purpura (in M.M patients) appears in the form of episodes of petechial eruption, on the lower limbs, brown pigmentation over time (cutaneous hemosiderosis), characteristic, which allows the recognition of the disease.

Complementary tests of hemostasis abnormalities:

Bleeding time estimates the bleeding time of a puncture wound (3 millimeters wide and 3 millimeters deep) in the earlobe. A bleeding time greater than 5 minutes suggests a hemorrhagic syndrome of vascular or platelet cause.

Coagulation time is assessed by measuring the time it takes for a drop of blood to clot on a glass slide.

The tourniquet test (Rumpel-Leed capillary fragility test) is performed by applying a tourniquet above the elbow or by compressing the arm with the cuff of the tensiometer, creating a distal cyanosis without suppressing the radial pulse. After 10 minutes, unity the tourniquet or the cuff of the tensiometer and examine the integuments of the forearm. Positive test: petechiae appear, which were not present before. This test is positive in vascular/platelet purpura.

Sternal puncture with medulogram allows the evaluation of the number and presence of megakaryocytes.

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