GASTRO-2 Flashcards

Question

Answer 1

Gastrointestinal Stromal Tumor (GIST) ## Footnote A submucosal mass (green overlay) with intact gastric mucosa can be seen within the gastric body. This finding is consistent with gastric lipoma, gastrointestinal stromal tumor (GIST), or fibroma of the stomach. Further diagnostics confirmed a GIST. P = pylorus; C = gastric body

Answer 2

1. Sucralfate → a sucrose sulfate-aluminum complex that reacts with HCl in an acidic environment to create a protective barrier over the gastric/duodenal mucosa * Acts as an acid buffer and promotes HCO₃ production * Should not be taken simultaneously with a PPI or H2 blocker 2. Misoprostol

Answer 3

Free Intraperitoneal Air ## Footnote There are no pathological findings in the lungs, elevated right diaphragm with an air crescent sign under the diaphragm (right \> left, shaded area). The diaphragm is visible on both sides (B). A normal air-filled gastric bladder is visible on the left (A). There is an indication for an emergency laparotomy or laparoscopy.

Answer 4

Free Intraperitoneal Air ## Footnote The left lateral decubitus, or left side down decubitus, radiograph was obtained with the patient's left (L) side dependent on the x-ray table. The image is centered on the nondependent right (R) hemidiaphragm. Free intraperitoneal air (pneumoperitoneum; green overlay) is interposed between the right hemidiaphragm and liver.

Answer 5

Gastrointestinal Perforation ## Footnote Multiple regions of radiolucency (green overlay) are present under the right hemidiaphragm, along the right psoas muscle and along the right abdominal wall. Due to the presence of air inside and outside the bowel, the intestinal wall appears as a thin, radiopaque line (double-wall sign; white arrowheads) in multiple spots. These findings suggest free intraabdominal air in the context of gastrointestinal perforation.

Answer 6

Pneumoperitoneum ## Footnote Air is seen as a radiolucent column (green overlay) underneath the diaphragm (white dashed line), which appears as a thin semicircular radiopacity immediately inferior to the pulmonary shadow. Air underneath the diaphragm is typically seen on x-rays of patients with pneumoperitoneum and indicates the perforation of a hollow viscus.

Answer 7

* Mechanical obstruction of the pyloric channel or duodenum * Etiology * Malignancy (most common) (gastric or duodenal cancer (intrinsic causes) or extrinsic compression by a pancreatic or biliary malignancy or enlarged lymph nodes (e.g., lymphoma)) * PUD * Acute PUD → inflammation and edema * Chronic PUD → scarring and fibrosis * Gastric volvulus * Less common causes of strictures in the pyloric channel → Crohn disease, history of ingestion of a caustic substance, chronic pancreatitis * Clinical features * Postprandial, nonbilious vomiting * Succussion splash → a splashing sound created by the movement of gastric contents * To elicit the succussion splash, place the stethoscope over the epigastrium of a supine patient. Hold the hips of the patient and gently shake the abdomen. * The succession splash is physiologic immediately after a meal. * If present after \> 4 hours of fasting, it suggests a gastric outlet obstruction. * Early satiety * Progressive gastric dilation * Weight loss * Diagnostics * Barium swallow * Abdominal CT scan * EGD (confirmatory test) → identification of the gastric pathology * Laboratory tests → hypokalemic hypochloremic metabolic alkalosis * Saline load test (inject 750 mL of saline into the patient's nasogastric tube on an empty stomach. If the aspirate after 30 minutes is \> 400 mL, gastric outlet obstruction is present) * Management * Symptomatic → nasogastric suction, electrolyte and fluid replacement, and parenteral nutrition * Definitive → surgery or endoscopic dilation

Answer 8

* Symptoms manifest when a genetically predisposed individual develops an immunological response to gliadin, an alcohol-soluble fraction of gluten. * Consumption of food containing gluten → tissue transglutaminase is released → modifies gliadin from gluten proteins → pathogenic T cells react to and are activated by modified gliadin → mediate chronic intestinal inflammation → epithelial damage resulting in villous atrophy, crypt hyperplasia, and loss of brush border → impaired resorption of nutrients in the small intestine (especially in the distal duodenum and proximal jejunum) → malabsorption symptoms

Answer 9

1. Intraepithelial lymphocytic infiltration 2. Crypt hyperplasia 3. Villous atrophy * These findings are not exclusive to celiac disease but are also seen in other conditions, including small bowel bacterial overgrowth, intestinal lymphoma, Helicobacter pylori infection, and Crohn disease.

Answer 10

Advanced Celiac Disease A smooth and atrophic duodenal mucous membrane can be seen.

Answer 11

* Secondary lactase deficiency * Moderately increased risk of malignancies 1. Enteropathy-associated T-cell lymphoma (EATL) * Origin → intraepithelial T cells * Localization → often proximal jejunum * Clinical presentation → initially often asymptomatic, but B symptoms and gastrointestinal symptoms may be present 2. Adenocarcinoma of the small bowel 3. Esophageal cancer * Refractory celiac disease (RCD) → persistence and worsening of celiac symptoms despite strict adherence to gluten-free diet for 12 months

Answer 12

* Primary (lactase nonpersistence) * Most common type of lactose intolerance * Decrease in lactase activity is primarily observed during childhood or adolescence. * Genetic polymorphism of the lactase‑coding gene with subsequent down‑regulation (absence of lactase-persisting allele) * Lactase levels decline with age and are further influenced by genetic factors. * Secondary (acquired) * Due to underlying disorders of the small intestine that result in mucosal damage, e.g.: * Autoimmune disorders (e.g., gluten-sensitive enteropathy) * (Viral) gastroenteritis (e.g., rotavirus) * Developmental → occurs in children born prematurely, as lactase activity develops late during pregnancy * Congenitall → autosomal recessive gene defect (extremely rare)

Answer 13

1. Active and passive smoking of tobacco 2. Familial aggregation 3. Genetic predisposition (e.g., mutation of the NOD2 gene, HLA-B27 association) * Nicotine consumption is the only (known) controllable risk factor for Crohn disease. Therefore, smoking cessation is especially important in patients with CD.

Answer 14

Pyostomatitis Vegetans ## Footnote Oral condition strongly associated with inflammatory bowel disease (especially ulcerative colitis). Manifests with slightly elevated, yellow-white, round mucosal lesions with a characteristic snail-track appearance. Most commonly affects the labial and buccal mucosae, gingivae, and palate.

Answer 15

* Erythema nodosum * Acrodermatitis enteropathica * Pyoderma gangrenosum * Pyostomatitis vegetans * ↑ Inflammatory markers (↑ CRP, ↑ ESR, ↑ thrombocytes, and ↑ leukocytes) * ↑ **Anti-Saccharomyces cerevisiae antibodies (ASCA)** (found in 60–70% of patients with Crohn disease and 10–15% of patients with ulcerative colitis) * pANCA most likely **negative** * Positive ASCA and negative pANCA in symptomatic patients is a strong indicator of Crohn disease. * Stool analysis * **Detection of fecal calprotectin and/or fecal lactoferrin** * Both can be used to differentiate between IBD and other noninfectious causes of gastrointestinal disorders and to monitor the course of the disease.These fecal biomarkers may help avoid the need for otherwise invasive measures to assess intestinal inflammation. * Proteins associated with neutrophils that can be used as a diagnostic tool for inflammatory bowel disease * Direct correlation between detected amount of proteins and severity of intestinal inflammation * Upper GI series with barium swallow and small bowel follow-through (enteroclysis) → used to detect fistulas or stenoses, characteristic findings are: * **String sign** → contrast-filled bowel segment that resembles a string on x-ray (while some sections of the intestines may appear distended; inflammation and fibrosis may narrow the intestinal lumen in other sections, making those sections appear string-like) * **Creeping fat** → pathognomonic hyperplasia of adipose tissue that results in accumulation of mesenteric fat around the circumference of the intestine * May cover more than 50% of the inflamed bowel * Correlates with severity of transmural inflammation * Ileocolonoscopy * Segmental/discontinuous pattern of involvement * **Snail trails → longitudinal ulcerations** * Pinpoint lesions → small, aphthous hemorrhagic mucosal defects * **Cobblestone sign** → inflamed sections followed by deep ulcerations that resemble cobblestones * Erythema and transmural inflammation (all mucosal layers of the intestinal wall are involved) * Fissures, fistulas * Histology * Skip lesions → a pattern of patchy, discontinuous inflammation in the bowel (affected areas interspersed with normal tissue) * Creeping fat * Hypertrophic lymph nodes * Transmural inflammation * Noncaseating granulomas * Giant cells * Distinct lymphoid aggregates of the lamina propria

Answer 16

1. Genetic predisposition (e.g., HLA-B27 association) 2. Ethnicity (white populations, individuals of Ashkenazi Jewish descent) 3. Family history of inflammatory bowel disease 4. Episodes of previous intestinal infection 5. Increased fat intake (esp. saturated fat and animal fat) 6. Oral contraceptive intake 7. NSAIDs may exacerbate UC

Answer 17

1. Appendectomy 2. Smoking has a protective effec

Answer 18

* Skeletal (most common extraintestinal manifestation of ulcerative colitis) → osteoarthritis, ankylosing spondylitis, sacroiliitis * Ocular → uveitis, episcleritis, iritis * Biliary → primary sclerosing cholangitis (PSC) * Rare for patients with UC to develop PSC, but up to 90% of all patients affected by PSC will also be affected by UC. * Cutaneous → erythema nodosum, pyoderma gangrenosum, aphthous stomatitis, pyostomatitis vegetans (multiple aphthae and pustules of the oral mucosa) * General → fatigue, fever * In children/adolescents → growth retardation and delayed puberty

Answer 19

* ↑ ESR, ↑ CRP, leukocytosis * Anemia * **↑ Perinuclear ANCA (pANCA)** * Stool analysis * **Calprotectin and lactoferrin are indicators of mucosal inflammation.** * Endoscopy (e.g., colonoscopy) with histological examination is considered the best test to definitively diagnose UC. * Evaluate the ileum to rule out Crohn disease * Colonoscopy is contraindicated in patients with acute flare because of the high risk of perforation but should be performed once symptoms improve. * Sigmoidoscopy may be considered as an alternative. * Radiography * **Loss of colonic haustra (lead pipe appearance) may be seen in severe cases** * Massive distention in cases of toxic megacolon * Pneumoperitoneum in cases of perforation * Barium enema radiography * Able to detect very early changes * Findings * Granular appearance of the mucosa * Deep ulcerations * **Loss of haustra** * **Pseudopolyps that appear as filling defects** * Gross pathology * Early stages 1. **Inflamed, erythematous, edematous mucosa** 2. **Friable mucosa with bleeding on contact with endoscope** 3. **Fibrin-covered ulcers** 4. **Small mucosal ulcerations** 5. **Loss of superficial vascular pattern** * Chronic disease 1. **Loss of mucosal folds** 2. **Loss of haustra** 3. **Strictures** 4. **Deep ulcerations** 5. **Pseudopolyps** * Raised areas of normal mucosal tissue that result from repeated cycles of ulceration and healing * Ulceration → formation of granulation tissue → deposition of granulation tissue → epithelization * Morphologically resemble polyps but do not undergo neoplastic transformation * Found in advanced disease * In ulcerative colitis, the extent of intestinal inflammation is limited to the mucosa and submucosa. In contrast, Crohn disease shows a transmural pattern of intestinal involvement. * Histological findings * Early stages 1. **Granulocyte (neutrophil) infiltration → limited to mucosa and submucosa** 2. **Crypt abscesses → an infiltration of neutrophils into the lumen of intestinal crypts due to a breakdown of the crypt epithelium** * Chronic disease 1. **Lymphocyte infiltration** 2. **Mucosal atrophy** 3. **Altered crypt architecture** * Branching of crypts * Irregularities in size and shape 4. **Epithelial dysplasia** * Noncaseating granulomas are seen in Crohn disease but are not a feature of ulcerative colitis!

Answer 20

Lead Pipe Sign ## Footnote A loss of haustration (green overlay) of the descending colon can be seen, leading to the characteristic lead-pipe appearance. The lead pipe sign is a classic finding seen in patients with ulcerative colitis.

Answer 21

Acute Ulcerative Colitis ## Footnote Colonoscopy of the sigmoid colon. The mucosa is erythematous and edematous indicating active inflammation. There is a loss of superficial vascular markings, and several linear, semi-confluent ulcerations (green overlay) are present. These findings are characteristic of acute ulcerative colitis.

Answer 22

Pseudopolyps in Ulcerative Colitis ## Footnote Colonoscopy Multiple prominent, raised islands of normal mucosa can be seen as a result of mucosal regeneration and hyperplasia. These findings are characteristic of pseudopolyps seen in ulcerative colitis.

Answer 23

* Idiopathic, inflammatory form of colitis that is characterized by a normal macroscopic appearance of bowel on colonoscopy and collagenous or lymphocytic infiltrates on microscopy * Forms → collagenous colitis and lymphocytic colitis * Etiology → unknown * Clinical features * Chronic, nonbloody, watery diarrhea for \> 4 weeks * Weight loss * Abdominal pain * Gross pathology → normal appearance * Histology * Collagenous colitis → proliferation of collagenous connective tissue that forms a thick, subepithelial collagen band * Lymphocytic colitis → mainly lymphocytic infiltrates with little/no proliferation of connective tissue * Treatment * Cease nonsteroidal anti‑inflammatory drugs (NSAIDs may be a trigger for disease) * Symptomatic therapy (e.g., loperamide for mild diarrhea) * Corticosteroids

Answer 24

* Corticosteroids * Azathioprine * Antibiotics (eg, ciprofloxacin, metronidazole) * Biologics (eg, infliximab, adalimumab)

Answer 25

* 5-aminosalicylic acid preparations (eg, mesalamine) * 6-mercaptopurine * Infliximab * Colectomy

Answer 26

* Rebound tenderness especially in the RLQ (due localized RLQ peritoneal inflammation) * A physical examination finding characterized by an abrupt increase in pain when an examiner suddenly releases compression of the abdominal wall. Caused by irritation of the receptors in parietal peritoneum.

Answer 27

* Deep palpation of the LLQ → ↑ in intraluminal pressure of the descending colon that is transmitted to the cecum and appendix → ↑ RLQ peritoneal irritation and pain * RLQ pain elicited on deep palpation of the LLQ

Answer 28

* Indicates iliopsoas irritation secondary to an inflamed retrocecal appendix * Can be performed in two different ways 1. Can be elicited on flexing the right hip with stretched leg against resistance 2. RLQ pain may be elicited on passive extension of the right hip when the patient is positioned on their left side.

Answer 29

* Indicates obturator internus irritation secondary to an inflamed pelvic appendix * RLQ pain on passive internal rotation of the right hip with the hip and knee flexed

Answer 30

* Pain in the flank when flexing the right hip * Suggests an inflamed retrocecal appendix

Answer 31

Vasa recta perforate muscularis externa

Answer 32

* Caused mainly by lifestyle and environmental factors * Diet (low-fiber, rich in fat and red meat) * Obesity * Low physical activity * Increasing age * Smoking * Other causes → genetic factors * Connective tissue disorders (e.g., Marfan syndrome, Ehler-Danlos syndrome) * Autosomal dominant polycystic kidney disease

Answer 33

Sigmoid colon

Answer 34

Diverticulosis ## Footnote A diverticulum (black dashed outline) filled with inspissated feces (green overlay) is visible in the center of the image. A lymphoid follicle (black arrowhead) is visible in the bottom left corner.

Answer 35

Diverticulosis

Answer 36

Diverticulosis ## Footnote Double-contrast barium enema of the colon Multiple diverticula in the colon can be seen (examples circled in green).

Answer 37

Diverticulitis ## Footnote CT abdomen and pelvis (coronal section; oral and IV contrast) There is **mural thickening (green overlay)** and luminal narrowing (hatched green overlay) of the sigmoid colon with adjacent mesenteric fat stranding, indicating a localized inflammatory process. Multiple well-defined gas shadows (arrows) are visible, either arising from or in close association with the sigmoid colon. These gas shadows are most likely sigmoid diverticula. These features are characteristic of diverticulitis of the sigmoid colon.

Answer 38

* Triangular weak point in the dorsal muscular wall of the hypopharynx, between the **thyropharyngeal and cricopharyngeal parts of the inferior pharyngeal constrictor muscle**

Answer 39

* Herniation of the gastrointestinal wall caused by increased intraluminal pressure (e.g., due to achalasia). * Usually only the mucosal tissue is involved (false diverticulum). * Examples include Zenker diverticula and colonic diverticula in diverticulosis

Answer 40

* Herniation of the gastrointestinal wall (most commonly in the esophagus) caused by scarring and retraction from inflammatory processes (e.g., fungal infections, tuberculosis). * Usually all layers of the wall are involved (true diverticulum).

Answer 41

Vitelline artery; superior mesenteric artery

Answer 42

* Genetic causes 1. RET gene mutations associated with multiple endocrine neoplasia type 2 (MEN2) and familial Hirschsprung disease 2. Endothelin receptor B (EDNRB) gene mutations associated with Waardenburg syndrome * Associated conditions 1. Trisomy 21 2. Multiple endocrine neoplasia type 2 (MEN2) 3. Waardenburg syndrome 4. Neuroblastoma 5. Other conditions → congenital deafness, malrotation, gastric diverticulum, and intestinal atresia

Answer 43

* Abdominal x-ray * Decreased or absent air in rectum * Dilated colon segment immediately proximal to aganglionic region * Distal intestinal obstruction * Rectal biopsy (full-thickness biopsy under general anesthesia; suction rectal biopsy) * Absent calretinin immunostained fibers * Hyperplasia of the parasympathetic nerve fibers * Elevated acetylcholinesterase activity * Absence of ganglion cells in an adequate tissue sample

Answer 44

Intestinal Malrotation

Answer 45

Sigmoid Volvulus ## Footnote X-ray abdomen (AP view) of a child Markedly dilated bowel extends from the upper pelvis into the upper abdomen. The configuration, including the double wall thickness of the two apposed bowel loops, resembles a coffee bean and has been termed the coffee bean sign (or the kidney bean sign or bent inner tube sign).

Answer 46

Target Sign in Intussusception ## Footnote Ultrasound abdomen (transverse view) Two concentric, alternating rings of hyperechoic and hypoechoic bowel are visible in the center-right of the image. The bowel mucosal layers form the hyperechoic bands and the submucosa forms the hypoechoic bands. Together, they produce the target-like appearance.

Answer 47

Infarction of Small Intestine with Ischemia ## Footnote Red overlay → necrotic tissue Green → hemorrhage Black arrows → blood in intestinal lumen

Answer 48

* **Acute arterial embolism** * Most common cause * Most commonly involves superior mesenteric artery (SMA) * Generally resulting from atrial fibrillation, myocardial infarction, valvular heart disease, or endocarditis * Arterial thrombosis → due to preexisting visceral atherosclerosis, arteritis, aortic aneurysm, or dissection

Answer 49

Mesenteric Ischemia

Answer 50

* Common degenerative disorder of GI vessels (mostly venous) that can cause GI bleeding in the stomach, duodenum, jejunum, and colon (in most cases vascular malformations affect veins, but arteriovenous and arterial changes may also occur) * Tortous dilation of vessels → hematocheziaa * **Associated with age \> 60 years, von Willebrand disease, aortic stenosis, and end-stage renal disease** * Manifests with episodic bleeding (hematochezia) that ceases spontaneously in \> 90% of cases * Diagnosis usually requires angiography. * Lesions are usually multiple tortuous dilated vessels, most commonly located in the right-sided colon (∼ 75%) (colonoscopy may be difficult to perform given the episodic nature of the bleeding)

Answer 51

* Usually caused by transient hypoperfusion 1. Thromboembolism 2. Hypotension, hypovolemia (e.g., sepsis, dehydration, hemorrhage) 3. Cardiovascular surgery (especially aortic repairs or cardiac bypass) 4. Vasoconstrictive drugs 5. Thrombophilias (e.g., antiphospholipid syndrome) 6. Colonic obstruction from, e.g., tumors, adhesions

Answer 52

* Edematous thickening of the mucosa causes indentations in the large bowel wall * Appears like thumbprints in CT or plain radiograph * Unspecific sign for colitis (e.g., ischemic colitis [**colonic ischemia**], inflammatory bowel disease, infection).

Answer 53

1. Abdominal surgeries 2. Opiates 3. Hypokalemia 4. Sepsis

Answer 54

* The causes of necrotizing enterocolitis are not fully understood but multiple factors contribute to the development of the condition. 1. Intestinal wall perfusion and motility disorders 2. Defective or underdeveloped immune system 3. Intestinal microbial overgrowth 4. Formula feeding 5. Rapid increase of enteral nutrition (facilitates bacterial growth, as the premature intestinal system is not capable of digesting large amounts of enteral food)

Answer 55

* Neutrophil counts \< 1500/μL are associated with a poor prognosis. * **The degree of thrombocytopenia correlates with the severity of NEC.** * ↑ Inflammatory markers * Metabolic acidosis is associated with advanced NEC. * Imaging * Abdominal radiography * **Pneumatosis intestinalis →** bubbles of gas within the wall of the intestine (string of pearls sign) * Portal venous gas (pneumatosis hepatis) * Increased intestinal wall thickness * Dilated intestinal loops (due to stenosis of the lower intestinal segments) * Air‑fluid levels * Pneumoperitoneum as a result of intestinal perforation

Answer 56

Necrotizing Enterocolitis ## Footnote Distended bowel loops and intramural gas (pneumatosis intestinalis) can be seen.

Answer 57

Free Air in Necrotizing Enterocolitis, Suspected Intestinal Perforation ## Footnote There are visible air crescents (hatched overlay) as well as intramural pockets of gas in the intestinal wall (arrows). A nasogastric tube (green line) can be seen.

Answer 58

* Syndrome marked by gastrointestinal bleeding that is ultimately caused by aortic stenosis. Altered blood flow through a stenotic valve pathologically activates von Willebrand factor, leading to consumption of this procoagulant factor. * In patients with underlying intestinal angiodysplasia (which is common in older adults), the loss of von Willebrand factor impairs the normal clotting/repair mechanisms in intestinal arterioles, leading to clinically apparent gastrointestinal bleeds.

Answer 59

1. Cholinergic agonists (eg, betanechol) 2. AChE inhibitors (eg, neostigmine) 3. Metoclopramide (stimulates 5HT4, inhibits D2) 4. Macrolides

Answer 60

High fiber diets rich in calcium and folic acid

Answer 61

Pedunculated Adenomatous Polyp

Answer 62

* Seen in inflammatory bowel disease, especially ulcerative colitis, secondary to mucosal ulceration and regeneration * Multiple, benign polyps especially in inflamed parts of the colon * Low malignant potential

Answer 63

* Benign (no clinical significance) * Typically small \< 5 mm * Mostly appear like normal mucosa * Low malignant potential

Answer 64

* Benign * Submucosal lesions in the colon may resemble a polyp macroscopically. * Submucosal lipoma is the most common subtype. * May include lipoma, leiomyoma, fibromas, and other lesions * Low malignant potential

Answer 65

* Most common type of nonneoplastic polyp among those with low malignant potential * The risk of malignancy is higher if polyps are large/multiple. * Small (\< 5 mm) * Common in the distal colon (rectosigmoid) * Might transform to serrated polyps * Histology → hyperplasia of normal cellular components with a sawtooth/serrated pattern of crypt epithelium (no dysplasia)

Answer 66

* Hamartomas are tumors composed of cells that are indigenous to the anatomical site they are found in. They are often benign, but hamartomatous colonic polyps have some malignant potential, especially when found in association with syndromes. * May occur throughout the GIT * Composed of normal tissue native to the site of origin (e.g., colon) but with disorganized growth * Associated syndromes * Juvenile polyposis syndrome * Peutz-Jeghers syndrome * Cowden syndrome * Cronkhite-Canada syndrome * Low risk of malignancy for solitary polyps * Increased risk of colonic and extra-colonic malignancies when associated with syndromes (except for Cronkhite-Canada syndrome, which is a non-neoplastic syndrome)

Answer 67

* Neoplastic * **Characterized by CpG island methylator phenotype (CIMP; cytosine base followed by guanine, linked by a phosphodiester bond). Defect may silence MMR gene (DNA mismatch repair) expression. Mutations lead to microsatellite instability and mutations in BRAF.** * “Saw- tooth” pattern of crypts on biopsy. * Up to 20% of cases of sporadic CRC.

Answer 68

* Neoplastic, via **chromosomal instability pathway with mutations in APC and KRAS.** * Tubular histology (branching tubules embeded in lamina propia) has less malignant potential than villous (finger like projections with fibrovascular core and dysplastic epithelium) (“villous histology is villainous”); tubulovillous has intermediate malignant potential. * Usually asymptomatic; may present with occult bleeding.

Answer 69

Hamartomatous Polyp ## Footnote Hyperplastic smooth muscle cells (uninucleated spindle-shaped cells) are visible as broad pink bands arranged in a tree-like pattern. Glandular hyperplasia without distortion of the normal tissue architecture is also visible. These features are consistent with a hamartomatous polyp, which is typically seen in Peutz-Jeghers syndrome.

Answer 70

Tubular Adenoma

Answer 71

Villous Adenoma of the Colon

Answer 72

Colorectal Carcinoma and Adenomatous Polyps Two different pathologic alterations of the mucosa are visible 1. Colorectal carcinoma (purple overlay) 2. Two adenomatous polyps (green overlays; possible preliminary stages of colon carcinomas). The mucosa on the left part of the specimen appears to be intact.

Answer 73

* Autosomal dominant mutations of the APC gene, a tumor suppressor gene on chromosome 5q22 (APC gene encodes a protein called Adenomatous Polyposis Coli which is a negative regulator of the β-catenin/WNT pathway) * 20–25% of cases have a negative family history (these cases are due to new APC gene mutations) * Polyposis typically develops within the second or third decade of life. * Clinical features * Most are initially asymptomatic until progressing to colon cancer. * Altered bowel habits (constipation/diarrhea), blood in stool, and abdominal pain * \> 100 polyps are typically detected in classic FAP (attenuated FAP is characterized by 10–99 colorectal adenomas with a later age of onset) * Histology * Tubular, tubulovillous, and villous adenomas * Desmoid tumors (aggressive fibromatosis) → extremely rare musculoaponeurotic fibromatoses (tumors originate from fiber‑producing connective tissue, are characterized by local and aggressive tumor growth, and do not metastasize. Treatment involves radical surgical resection) * Treatment * Prophylactic proctocolectomy and ileoanal anastomosis at the time of diagnosis * Celecoxib, sulindac, and aspirin can induce regression of polyps. * The lifetime risk of colorectal cancer is 100% by 45 years of age.

Answer 74

Familial Adenomatous Polyposis (FAP)

Answer 75

Familial Adenomatous Polyposis (FAP)

Answer 76

* FAP and extracolonic bony and/or soft tissue tumors (e.g., osteomas of the mandible or skull, desmoid tumors, sebaceous cysts, lipomas, fibromas) * Dental abnormalities (e.g., supernumerary and/or impacted teeth) present in ∼ 30% of cases * Associated with congenital hypertrophy of the retinal pigment epithelium * Round or oval darkly pigmented lesions on fundoscopy * The presence of multiple (\> 4) lesions bilaterally indicates Gardner syndrome. * Solitary lesions have low diagnostic value and are not pathognomonic for a disease. * APC gene mutation with autosomal dominant inheritance * The lifetime risk of developing colorectal cancer is 100%. Turcot syndrome FAP/Lynch syndrome and malignant brain tumors (e.g., gliomas or medulloblastomas) Medulloblastomas are associated with FAP and gliomas with Lynch syndrome. Increased risk of colorectal cancer Attenuated FAP Lesser polyps (10–100), mainly in the right colon More advanced age at presentation Lower risk (∼ 80%) of developing colorectal cancer than with classic FAP

Answer 77

Congenital hypertrophy of the retinal pigment epithelium in Gardner syndrome ## Footnote Montage of several single fundoscopy photos The arrows point to multiple round or oval darkly pigmented lesions. The presence of multiple (\> 4) lesions bilaterally indicates Gardner syndrome, a subtype of familial adenomatous polyposis. After initial diagnosis, this patient, a 20-year-old woman with a family history of FAP, underwent a colonoscopy, during which multiple adenomatous polyps were found.

Answer 78

* FAP/Lynch syndrome and malignant brain tumors (e.g., gliomas or medulloblastomas) * **Medulloblastomas are associated with FAP and gliomas with Lynch syndrome.** * Increased risk of colorectal cancer

Answer 79

* **Autosomal dominant mutation of the STK11 gene on chromosome 19p13.3 → loss of tumor suppressor function → hyperactive serine‑threonine kinase (new mutations in ∼ 20% of cases)** * ∼ 95% of patients have hyperpigmented macules that typically affect the lips (perioral lentigines), buccal mucosa, genitals, palms, and soles * Diagnostics: * Multiple hamartomatous polyps throughout the gastrointestinal tract on endoscopy * The lifetime risk of colorectal cancer is ∼ 40%. * Increased risk of: * **Breast cancer** * **Ovarian cancer** * **Other GI cancers → pancreatic, small bowel, stomach**

Answer 80

* Autosomal dominant with incomplete penetrance * Onset within the first decade of life (most commonly affects children \< 5 years of age) * Gastrointestinal bleeding and anemia (juvenile polyps are very vascular and have a tendency to bleed) * Diagnostics: * \> 10 hamartomatous polyps throughout the gastrointestinal tract (e.g., colon, stomach, small bowel) on endoscopy * Increased lifetime risk of colorectal cancer (∼ 20%) (the lifetime risk of gastric and duodenal cancers is also increased)

Answer 81

* Most commonly due to autosomal dominant mutations of the PTEN gene * Clinical features * Multiple GI polyps with skin manifestations such as papules and hyperkeratosis of the skin (skin manifestations are often the first symptom) * Most patients have thyroid disorders (e.g., multinodular goiter, adenomas) and breast disorders (e.g., fibroadenomas, intraductal papillomas). * Increased risk of breast (∼ 85%), thyroid (∼ 35%), and endometrial cancers (∼ 30%) * Increased risk of colorectal cancer (up to 20% before the age of 50)

Answer 82

* Etiology → probably immune-mediated (rare, nonfamilial disorder) * Clinical features: * GI polyposis with alopecia and cutaneous hyperpigmentation * Treatment: * Immune suppression with glucocorticoids and azathioprine (however, no specific treatment has proven to be effective) * High mortality rate due to GI bleeding, sepsis, and congestive heart failure

Answer 83

* Most common cause of inherited CRC * Accounts for approx. 3–8% of all new cases of CRC * Individuals with Lynch syndrome have a 70–80% lifetime risk of developing CRC * Increased lifetime risk of associated cancers (by age 70) * Endometrial cancer → up to 40% * Gastric cancer → ∼ 10% * Ovarian tumors → ∼ 10% * Urothelial cancer → up to 10% * Skin → ∼ 4% * Small bowel cancer → ∼ 2% * Brain tumor → ∼ 2% * Biliary tract cancer → ∼ 2% * Hereditary disease → autosomal dominant with varying penetrance * **Mutations in various DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) cause microsatellite instability.** * Increased occurrence of adenomas with ∼ 80% risk of progression to carcinomas * Patients are usually asymptomatic until CRC develops * Lynch syndrome-associated CRC usually affects the right (proximal) colon (sporadic CRC is more common in the left colon) * Possibly extracolonic symptoms of associated cancers * Lynch syndrome typically manifests with colorectal cancer of the proximal colon, with only a few adenomatous polyps, in contrast to familial adenomatous polyposis, in which hundreds of adenomatous polyps are present. * Treatment * Surgery * Immunotherapy with an immune checkpoint inhibitor (pembrolizumab or nivolumab) may be used for high MSI or mismatch repair deficient (dMMR) metastatic colorectal cancer. * For women with Lynch syndrome, prophylactic hysterectomy and bilateral salpingo-oophorectomy should be offered when they are no longer of child-bearing age.

Answer 84

* Chromosomal instability pathway in colon cancer: * The adenoma-carcinoma sequence is the progressive accumulation of mutations in oncogenes (e.g., KRAS) and tumor suppressor genes (e.g., APC, TP53) that results in the slow transformation of adenomas into carcinomas. * APC gene mutation (loss of cellular adhesion and increased cellular proliferation) → KRAS gene mutation (unregulated cellular signaling and cellular proliferation) → TP53 and DCC gene mutation * Most cases of sporadic CRC develop via this pathway. * Microsatellite instability pathway in colon cancer → due to methylation or mutations in mismatch repair genes (MMR genes, e.g., MLH1 or MSH2) * Hypermethylation phenotype pathway in colon cancer * CpG island methylator phenotype (CIMP): global hypermethylation of CpG islands → silencing of MMR gene expression * Associated with BRAF mutations * Up to 20% of sporadic CRCs develop from serrated polyps that underwent malignant transformation via this pathway. * COX-2 overexpression * Associated with colorectal cancer * Possible protective effect of long-term use of aspirin and other NSAIDs

Answer 85

* Age → older age (\> 40 years) * Hereditary syndromes * Family history → Approx. 25% of individuals with colorectal cancer (CRC) have a positive family history. * Familial adenomatous polyposis → 100% of individuals will have developed CRC by the age of 40 years, Gardner syndrome, Turcot syndrome, Peutz-Jeghers syndrome, Juvenile polyposis syndrome) * Hereditary nonpolyposis colorectal cancer (HNPCC) → progression to CRC in 80% of cases * Associated conditions * Colorectal adenomas and serrated polyps (the risk of malignant degeneration depends on the histological type (villous \> tubulovillous \> tubular), size (\> 1 cm), and number (≥ 3 polyps)) * Inflammatory bowel disease → chronic inflammation → hyperplasia → non-polypoid dysplasia → neoplasia * Ulcerative colitis (the risk is increased with pancolitis and with ulcerative colitis in association with primary sclerosing cholangitis) * Crohn disease * Endocarditis and bacteremia due to S. gallolyticus * Diabetes mellitus type 2 * Lifestyle * Smoking * Alcohol consumption * Diet * Obesity * Processed meat * High-fat and low-fiber * Other → History of abdominal radiation during childhood

Answer 86

* Long-term use of aspirin and other NSAIDs * Physical activity * Diet rich in fiber and vegetables and lower in meat

Answer 87

* Large bowel malignancies arising from the cecum, ascending colon, or transverse colon * Colorectal cancer can be asymptomatic, particularly during the early stages. * Constitutional symptoms * Weight loss * Fever * Night sweats * Fatigue * Abdominal discomfort (symptoms similar to diverticulitis, especially in carcinoma of the rectosigmoid or descending colon) * Clinical features * Occult bleeding or melena * Manifestations of iron deficiency anemia (due to chronic bleeding) * Diarrhea * Iron deficiency anemia in men \> 50 years of age and postmenopausal women should raise suspicion for colorectal cancer.

Answer 88

* Large bowel malignancies arising from the splenic flexure, descending colon, sigmoid colon, or the rectosigmoid junction * Colorectal cancer can be asymptomatic, particularly during the early stages. * Constitutional symptoms * Weight loss * Fever * Night sweats * Fatigue * Abdominal discomfort (symptoms similar to diverticulitis, especially in carcinoma of the rectosigmoid or descending colon) * Clinical features * Changes in bowel habits (size, consistency, frequency) * Blood-streaked stools (rectal bleeding may be visible or occult) * Colicky abdominal pain (due to obstruction) * Bowel obstruction occurs earlier in left-sided colon carcinomas because the distal colon has a smaller lumen than the proximal colon and contains solid fecal matter.

Answer 89

Liver; portal vein Lower rectal cancers are distinct from other colorectal carcinomas because the lower rectum is drained by the inferior rectal vein into the vena cava. Initial metastases are, therefore, typically to the lungs.

Answer 90

Liver; portal vein Lung; inferior vena cava

Answer 91

MALT Lymphoma of the Small Intestine ## Footnote Endoscopic view of MALT lymphoma of the duodenum with flat-polypoidal lesions and mild contact bleeding. An intact small intestinal mucosa with a villous structure is partially evident (left lower border of the image, at approx. 7 o'clock), which is, however, absent in the mucosa that is infiltrated by the lymphoma.

Answer 92

Colorectal Adenocarcinoma

Answer 93

* Hepatotoxicity 1. Long-standing alcohol use disorder (one of the two most common causes of chronic liver disease in the US) 2. Medications (e.g., acetaminophen, amiodarone, chemotherapy drugs such as methotrexate) 3. Ingestion of aflatoxin (produced by Aspergillus) 4. Industrial chemicals such as tetrachloromethane (formerly used to extinguish fires but no longer in use because of its toxicity) and various pesticides * Inflammation (hepatitis) 1. Chronic viral hepatitis: hepatitis B, hepatitis D, and hepatitis C (most common cause of cirrhosis in the United States) 2. Primary biliary cirrhosis 3. Primary sclerosing cholangitis 4. Autoimmune hepatitis 5. Parasitic infections (e.g., schistosomiasis, leishmaniasis, malaria) 6. IgG4 cholangiopathy * Metabolic disorders 1. Nonalcoholic steatohepatitis (NASH) (risk factors include obesity, diabetes mellitus, and hyperlipidemia) 2. Hemochromatosis 3. Wilson disease 4. α1-antitrypsin deficiency 5. Porphyrias 6. Glycogen storage disease 7. Cystic fibrosis 8. Hereditary fructose intolerance * Hepatic vein congestion or vascular anomalies 1. Budd-Chiari syndrome (partial or complete occlusion of hepatic veins caused by thrombosis) 2. Cardiac cirrhosis (congestive hepatopathy) 3. Osler-Weber-Rendu syndrome (vascular dysplasia leads to an increase of fibrous septa in the liver. Since portal architecture remains unchanged, this type of cirrhosis is considered atypical) * Cryptogenic cirrhosis → cirrhosis of uncertain etiology despite adequate diagnostical efforts * Cryptogenic cirrhosis is a diagnosis of exclusion and should only be considered after a complete patient evaluation has ruled out all other possible causes of cirrhosis. * Hepatitis C, alcoholic liver disease, and NASH are the most common causes of cirrhosis in the US.

Answer 94

* ↑ Prothrombin time (↑ INR) → due to decreased production of coagulation factors (prothrombin time is a measure of the extrinsic pathway. As coagulation factors of the extrinsic system are synthesized in the liver, the prothrombin time is a meaningful parameter for evaluating liver function) * ↓ Total protein (↓ albumin) * ↓ Plasma cholinesterase (CHE) (sensitive parameter that is used to assess the disease course in chronic liver disease) * A circulating enzyme produced by the liver that can hydrolyze several choline-based esters * Involved in the breakdown of muscle relaxants (e.g., succinylcholine) * Decreased serum levels can result from cirrhosis or organophosphate pesticide exposure (occupational or accidental).

Answer 95

Cirrhosis or organophosphate pesticide exposure (occupational or accidental)

Answer 96

Ultrasound of the Liver with Cirrhosis ## Footnote There is a heterogeneous, coarsened parenchyma. Nodular changes (arrows), a grossly dilated biconvex organ shape (green outline), and a blunted liver margin (green color gradient) can be seen. These findings are consistent with liver cirrhosis.

Answer 97

Liver Cirrhosis and Splenomegaly ## Footnote Atrophic changes and nodularity can be seen along the right lateral margin of the liver with retraction of the hepatic contour (indicated by white arrows). There is also a region of hypoattenuation towards the anterior margin of the liver lobe. The spleen is enlarged (green overlay). These findings are consistent with liver cirrhosis and portal hypertension leading to secondary splenomegaly.

Answer 98

* Fibrosis (fibrous septa) * Replacement of normal liver tissue with collagenous regenerative nodules (histological staging is based on the size of the regenerative nodules) * Abnormal cell activation with infiltration of inflammatory cells * Loss of physiological vessel architecture (central vein disappearance)

Answer 99

Histopathology of Liver Cirrhosis ## Footnote A regenerative nodule composed of a cluster of hepatocytes (purple overlay), extensive fibrosis (stained blue), and the portal triad (yellow overlay) can be seen. Regenerative nodules and fibrous septa are characteristic features of liver cirrhosis.

Answer 100

Liver Cirrhosis

Answer 101

Micronodular Cirrhosis

Answer 102

* Decompensated cirrhosis → worsening of liver function in cirrhosis characterized by the presence of jaundice, ascites, variceal hemorrhage, or hepatic encephalopathy * When patients develop major complications (e.g., spontaneous bacterial peritonitis, hepatorenal syndrome), they are considered to have decompensated cirrhosis. * Precipitating factors → infection, alcohol use, medications, bleeding, or dehydration * Major complications * Complications caused by portal hypertension * Ascites and subsequent spontaneous bacterial peritonitis * Esophageal variceal hemorrhage * Hematologic complications → coagulopathy * Prolonged aPTT, INR, and PT * This condition does not respond to vitamin K because the liver cannot utilize it for the synthesis of coagulation factors. Fresh frozen plasma is used as treatment. * Metabolic complications or associated organ impairment * Jaundice * Hepatic encephalopathy * Hepatorenal syndrome * Hepatopulmonary syndrome * Tumors → hepatocellular carcinoma (HCC) * Other complications * Secondary hyperparathyroidism → due to limited enzymatic activation of vitamin D * Cirrhotic cardiomyopathy * Hepatic hydrothorax * Portal vein thrombosis * Diabetes mellitus secondary to liver disease (due to increase insulin resistance) * Cirrhosis associated ascites and edema, as well as the high risk of bleeding, increase the risk for hypovolemic shock.

Answer 103

Barium Swallow of Esophageal Varices ## Footnote There are irregular, serpiginous defects within the esophageal lumen that are not filled with contrast (green overlay). This finding is consistent with esophageal varices.

Answer 104

Cirrhotic Liver with Hepatocellular Carcinoma ## Footnote Cirrhotic liver tissue with multifocal hepatocellular carcinoma (example of tumor nodule indicated by arrow). These nodules can take on a green hue, as seen here, due to tumor-associated bile retention.

Answer 105

Esophageal Varices

Answer 106

* Fluctuations in mental status and cognitive function in the presence of severe liver disease (e.g., cirrhosis) * Cirrhosis → ↓ hepatic metabolism and portosystemic shunt → accumulation of neurotoxic metabolites, especially ammonia (NH3) → excess glutamine and swelling produced by astrocytes → cerebral edema and ↑ intracranial pressure → neurological deterioration (ammonia is the most important laboratory parameter for hepatic encephalopathy. However, serum ammonia levels do not strongly correlate with the severity of clinical symptoms because other neurotoxins accumulate and exert their own neurochemical and inflammatory effects on the CNS) * Hypokalemia → shift of K+ ions out of the cells → shift of H+ ions into the cells to maintain electroneutrality → intracellular acidosis → tubular cells produce more ammonia → neurological deterioration * Metabolic alkalosis → decreased H+ ion availability → decreased conversion of ammonia to ammonium (NH4+) → increased levels of ammonia → diffuses freely through the blood-brain barrier → neurological deterioration * Precipitant factors * Increased absorption or production of ammonia 1. Infections (e.g., spontaneous bacterial peritonitis, SIRS) 2. Gastrointestinal bleeding (blood is a nutritional medium for resident ammonia‑producing bacteria) 3. Constipation 4. Increased dietary protein intake 5. Hypokalemia * Decreased metabolism and clearance of ammonia 1. Renal failure 2. Portal vein thrombosis 3. Portosystemic shunts (e.g., after TIPS placement) 4. Hypovolemia (dehydration, diarrhea, vomit) 5. Metabolic alkalosis 6. Diuretic use (hypokalemia, hyponatremia) * Clinical features * Symptoms are usually reversible. 1. Fatigue, lethargy, apathy 2. Altered levels of consciousness, ranging from mild confusion to stupor or coma 3. Disoriented 4. Irritability 5. Memory loss 6. Impaired sleeping patterns 7. Multiple neurological and psychiatric disturbances 8. Socially aberrant behavior (e.g., urinating/defecating in public, shouting at strangers) 9. Slurred speech 10. Asterixis 11. Muscle rigidity * Diagnostics * Based on the patient's medical history and clinical presentation * Assessment of mental status * **Number connection test** → test in which patients are timed while connecting numbers in order that are randomly distributed over a piece of paper (in hepatic encephalopathy it is completed slower than the age-normalized standard or not completed) * Psychometry‑based diagnostic method (e.g., Mini-Mental State Examination) * Laboratory studies → elevated serum ammonia levels * Treatment * General measures * Avoidance and correction of precipitating factors (e.g., hepatotoxic medication, alcohol, hypovolemia, electrolyte disturbances) * Treatment of further complications that might aggravate the encephalopathy * Pharmacotherapy 1. Lactulose → a synthetic disaccharide laxative * First-line treatment for hepatic encephalopathy * Improves hepatic encephalopathy by decreasing absorption of ammonia in the bowel. Lactulose is converted to lactic acid by intestinal flora → acidification in the gut leads to conversion of ammonia (NH3) to ammonium (NH4+) → ammonium is excreted in the feces → decreased blood ammonia concentration 2. Rifaximin → a broad-spectrum, nonabsorbable oral antibiotic * Reduces the number of ammonia-producing intestinal bacteria * May be added to lactulose to prevent recurrent episodes of hepatic encephalopathy after a second episode

Answer 107

* Deterioration of kidney function in patients with advanced liver disease * The exact pathomechanisms are not completely understood. * **Cirrhosis/portal hypertension → ↑ splanchnic vasodilators (e.g., nitric oxide) → ↓ arterial blood flow → activation of RAAS → renal vasoconstriction → ↓ GFR** * Risk factors * Generally attributed to the loss of volume 1. Drainage of large volume ascites 2. Gastrointestinal bleeding 3. Forced diuresis 4. Excess use of laxatives (lactulose) 5. Post TIPS procedure 6. Spontaneous bacterial peritonitis * Clinical features * Ranging from oliguria up to anuria with progressive kidney failure * Hypotension and wide pulse pressure * Diagnosis * Hepatorenal syndrome is a clinical diagnosis based on reduced glomerular filtration rate in patients with cirrhosis and no other causes for renal failure (e.g., shock) or no detection of renal pathologies on ultrasound. * Diagnostic criteria 1. Cirrhosis 2. Serum creatinine ≥ 0.3 mg/dL within 48 hours or ≥ 50% from baseline 3. Lack of improvement in renal function after volume expansion with albumin and at least 48 hours without diuretics 4. Urinary output ≤ 0.5 ml/kg 5. Decreased urine sodium levels (\< 10 mmol/L) 6. No proteinuria \> 500 mg/dL, no microhematuria, no acute pathological findings in the kidney ultrasound 7. No exposure to nephrotoxic drugs 8. Absence of shock * Treatment * General measures **→** improvement of liver function if possible (e.g., cessation of alcohol use, avoid nephrotoxic drugs) * Pharmacotherapy * Noncritically ill individuals **→** a combination of midodrine, octreotide, and albumin (midodrine causes systemic vasoconstriction. When it is used in combination with octreotide and albumin (plasma expander), systemic and renal hemodynamic status is improved, thereby improving renal function) * Critically ill individuals **→** a combination of norepinephrine and albumin * Surgical/interventional procedures * Renal replacement therapy (dialysis) * Placement of a transjugular intrahepatic portosystemic shunt (TIPS) * A liver transplant is the only curative option.

Answer 108

* Complete or partial closure of the portal vein due to a thrombus * Possibly caused by an imbalance of coagulation factors in patients with impaired hepatic synthetic function * The closure of portal vein flow → ↓ liver blood flow → vasodilation of the hepatic artery and development of collateral hepatic veins in an attempt to maintain liver perfusion * Thrombotic closure of the splenic and superior mesenteric veins may extend to the portal vein → portal hypertension * Etiology * Cirrhosis or chronic liver disease * Local complications of intraabdominal malignancy (e.g., HCC, pancreatic carcinoma) or inflammation (e.g., liver abscess, pancreatitis, cholangitis) * Thrombophilia (e.g., antiphospholipid syndrome, factor V Leiden) or general risk factors of phlebothrombosis * Myeloproliferative disorder * Following TIPS procedure * Chronic mesenteric venous thrombosis * Clinical features * Depend on the extent of thrombosis and the speed of manifestation * Acute portal vein thrombosis * Abdominal pain (RUQ or generalized) * Splenomegaly * Fever * Ascites * Chronic portal vein thrombosis * In cirrhotic patients, chronic PVT is often asymptomatic (incidental finding on ultrasound). * Abdominal pain (RUQ or generalized) * Esophageal variceal hemorrhage * Hepatic encephalopathy (in early disease stages there is sufficient circulation for detoxification. As the disease progresses, circulation decreases, and ammonia builds up) * Splenomegaly and hypersplenism * Jaundice and pruritus due to portal cholangiopathy (enlarged periportal veins compromise portions of the biliary tract) * Diagnostics * Ultrasound findings * Echogenic or isoechoic thrombus in the portal vein * Dilated, coiled periportal veins * Widening of the portal vein * Variable portion of mostly echogenic thrombus material in the portal vein * Color duplex ultrasound * Confirmatory test * Shows decreased flow velocity or complete halt of flow * When PVT is detected in patients with cirrhosis, HCC must be ruled out as the cause. * Treatment * The goal is to prevent precipitant factors, thrombosis extension, and achieve portal vein recanalization. There are no generalized management recommendations for cirrhotic patients with portal vein thrombosis. * Pharmacotherapy → anticoagulants * Surgical/Interventional procedures * Transjugular intrahepatic portosystemic shunt (TIPS) * Percutaneous transhepatic thrombolysis with tissue plasminogen activator (tPA)

Answer 109

* A condition characterized by hypoxemia, intrapulmonary vasodilatation, and portal hypertension in the presence of cirrhosis (pulmonary vasodilation can occur locally or diffusely. Arteriovenous shunts may be present, which causes an additional decrease in oxygenation) * Pathophysiology * Not completely understood * Portal hypertension and liver damage → translocation of bacterial endotoxins → changes in the production of cytokines and pulmonary vasodilators → ↑ nitric oxide in the lung vessels → pulmonary vasodilation → hepatopulmonary syndrome * Clinical features * Dyspnea * Platypnea (shortness of breath that worsens when standing or sitting and improves when lying supine) * Orthodeoxia (decrease in arterial blood oxygen saturation when moving from a lying position to an upright position) * Diagnostics * Medical history → diagnosis of advanced liver disease * Arterial blood gas analysis → alveolar-arterial gradient (AaO2) ≥ 15 mmHg or ≥ 20 mmHg in patients \> 64 years old while in a seating position * Contrast echocardiogram * Gold-standard test * Shows intrapulmonary vasodilation * Lung perfusion scintigraphy (Tc-99m MAA) → helps diagnose and quantify intrapulmonary vasodilation * Treatment * Supportive measures → long‑term treatment with oxygen is recommended. * Surgical procedure → liver transplant

Answer 110

* Form of pulmonary arterial hypertension (PAH) associated with portal hypertension * Pathophysiology * Not completely understood * High cardiac output in advanced liver disease → wall shear stress in pulmonary vasculature → ↑ vasoactive and angiogenic substances (e.g., endothelin-1) → hypertrophy of smooth muscle cells and fibroblasts, fibrosis of intimal sheath, and microaneurysms of pulmonary arterioles * Clinical features * Often asymptomatic * Clinical findings are the same as in pulmonary hypertension * Diagnostics * Medical history → portal hypertension or cirrhosis * Imaging * Transthoracic echocardiography * Right heart catheterization (gold standard test) * Diagnostic criteria * Clinical signs and symptoms of portal hypertension, but not necessarily the presence of cirrhosis * Abnormal hemodynamic measurements from right heart catheterization (mPAP \> 25 mmHg at rest, PCWP \< 15 mmHg, and ↑ PVR) * Treatment * Supportive measures: to alleviate symptoms * Supplemental oxygen * Diuretics → furosemide and spironolactone in cases of right heart failure due to PAH and liver cirrhosis * Pharmacotherapy → Epoprostenol, bosentan, or sildenafil have insufficient data to make generalized recommendations. * Surgical procedure → liver transplantation

Answer 111

1. Portopulmonary hypertension 2. Pneumonia → due to immunosuppression 3. Atelectasis → diaphragm is elevated due to massive ascites 4. Lung emphysema → in α1-antitrypsin deficiency 5. Hepatic hydrothorax → mostly one‑sided pleural effusions (70% right, 18% left) with transudate characteristics * Pathophysiology → caused by increased permeability of the diaphragm on account of microperforations, increased lymphatic leakage, and hypoalbuminemia * Clinical findings → dyspnea (at rest) * Treatment * Pleural tap for symptomatic relief * In cases of recurring fluid accumulation, continuous drainage should be considered.

Answer 112

* Rare type of hepatic encephalopathy that is associated with aspirin use for viral illness in children \< 19 years * Etiology → aspirin use in individuals \< 19 years of age with a febrile illness (particularly associated with upper airway infections due to influenza B virus, varicella infections, and, in rare cases, infections with rubella and influenza A) * Pathophysiology * Viruses alter the metabolism of salicylates → accumulation of salicylate metabolites in the liver → mitochondrial injury and reversible inhibition of enzymes required for fatty acid oxidation → failure of hepatic ATP production → acute hepatic failure → hyperammonemia, metabolic acidosis, and hepatic steatosis → acute encephalopathy * Hyperammonemia → cerebral edema → ↑ ICP * Clinical features * Preceding viral infection (e.g., influenza, varicella or viral gastroenteritis) → the first symptoms of Reye syndrome usually begin 3–5 days after a viral illness. * Acute encephalopathy * Severe vomiting (due to ↑ ICP) * Altered mental status (ranging from lethargy to delirium and coma) * Neurological symptoms (e.g., seizures, fixed pupils) * Liver failure * Fatty degeneration * Hepatomegaly * ↑ AST and ALT (bilirubin levels are usually normal) * Hyperammonemia * Hypoglycemia * Metabolic acidosis * Prolonged INR * Cranial CT/MRI → may show cerebral edema and scattered lesions * Liver biopsy → microvesicular hepatic steatosis * Treatment → supportive * Decrease intracranial pressure (e.g., via osmotic diuresis; elevation of the head) * Correction of hypoglycemia * Cardiopulmonary support if necessary * Prevention * Aspirin should be avoided in individuals \< 19 years of age, especially those with fever. * Exception → children with Kawasaki disease * Prognosis * Outcomes vary from complete recovery to permanent neurological deficits. * Mortality rate → ∼ 20%

Answer 113

* Nonmalignant lesion that most commonly occurs in young women * Thought to result from a hepatic vascular abnormality causing localized hyperperfusion with a secondary hyperplastic response * Lesions appear as small solitary pale nodules composed of cords of normal appearing hepatocytes and a central stellate scar with fibrous septate that surround abnormally large hepatic arterial branches * Most cases do not require treatment and are asymptomatic * Ultrasound * Homogeneous, hypoechoic to isoechoic * Round/oval, sharply defined * **Central, stellate scar (∼ 50% of cases)** * Contrast enhanced sonography → from the central artery, radial arrangement of the peripheral arteries with a typical spoke-like pattern * Contrast enhanced CT scan * Early arterial phase enhancement * Hypointense to isointense and poorly visualized in the portal venous phase * Central scar (“nest of vessels”) * Histology * Light yellow color compared with the surrounding liver tissue * Localized hepatocyte nodules, with large malformed arterial branches and centralized fibrous tissue (central stellate scar) * May resemble macronodular cirrhosis

Answer 114

* Macrovesicular fatty change that may be reversible with alcohol cessation. * Increase glycerol-3-phosphate and availability of fatty acids causes increase TGs synthesis, leading to development of steatohepatitis * AST (aspartate aminotransferase) \> ALT (alanine aminotransferase) (both ↑ ALT and ↑ AST) * ↑ GGT * ↑ Serum ferritin * Macrocytic anemia * **↑ CDT (carbohydrate-deficient transferrin)** * Most specific biomarker of heavy alcohol use regardless of the presence of liver disease * Levels elevated up to 6 weeks after abuse * Histology * Accumulation of lipid droplets in the hepatocytes with gradual single cell necrosis within the lobules * Ultrasound * Mild hepatomegaly * Blood vessels cannot be visualized (the normal echogenicity of the portal and hepatic vein walls is absent) * ↑ Liver echogenicity because of steatosis → may be focal or diffuse (echogenicity of the liver is compared to that of the renal cortex. While the echogenicity of the liver and the renal cortex are normally similar, a fatty liver will appear relatively hyperechoic ("whiter" or “brighter”) in relation to the renal cortex) * CT → ↓ liver attenuation (patients with alcoholic fatty liver, hence steatosis, usually have lower liver attenuation compared to splenic attenuation) * Imaging and laboratory studies in the case of alcoholic fatty liver will show a reversal of changes within a month if the patient abstains from alcohol!

Answer 115

* Requires sustained, long-term consumption. * Swollen and necrotic hepatocytes with neutrophilic infiltration. Mallory bodies (intracytoplasmic eosinophilic inclusions of damaged keratin filaments) * AST/ALT ratio \> 2 * ↑ AST → usually ≤ 500 U/L * ALT → normal or only mildly elevated * ↑ Alkaline phosphatase (ALP) * ↑ GGT * Impaired liver function * ↑ Bilirubin * ↓ Serum albumin * ↑ Prothrombin time (administration of vitamin K does not reverse this coagulopathy) * ↓ Cholinesterase * Macrocytic anemia, thrombocytosis (thrombocytosis indicates an acute inflammatory response. Thrombocytopenia may be present because of myelosuppression), and absolute neutrophilic leukocytosis may be present. * ↑ Glutamate dehydrogenase (GLDH) * ↑ Ammonia * Histology * Fatty liver with hydropic swelling and ballooning degeneration of hepatocytes within the lobules * Damaged hepatocytes typically contain **Mallory bodies (hyaline inclusion bodies that contain keratin filaments and appear eosinophilic on H&E stain)** * Immunoreaction → n**eutrophilic granulocytes infiltrate hepatic tissue.** * Fibrosis → **pronounced excess formation of fibrous collagenous connective tissue with picture of "chicken wire-like network" in perivenous zones** * Mechanical obstruction of the bile ducts → bile duct proliferates in connective tissue * Ultrasound * Resembles alcoholic fatty liver; however, disease is typically diffuse * In addition to those findings → hepatomegaly and periportal edema * CT → ↓ liver attenuation

Answer 116

* Final and usually irreversible form. * Sclerosis around central vein may be seen in early disease. * Regenerative nodules surrounded by fibrous bands in response to chronic liver injuryportal hypertension and end-stage liver disease. * Excessive interstitial TGF-β activity is associated with hepatocyte necrosis and is involved in the development of liver cirrhosis * Histology * Infiltration of lymphocytes * Massive accumulation of fat in hepatocytes * Formation of fibrous septa and regenerative nodules * Perivascular sclerosis of central veins (especially in the early stage)

Answer 117

Fatty Liver ## Footnote Abdominal ultrasound: evidence of a fatty liver by comparing the echogenicity of tissue from the kidney (K) and liver (L)

Answer 118

Fatty Liver ## Footnote Ultrasound of the right lateral liver (perimeter indicated in light gray) and right kidney (perimerter indicated in dark gray) → almost isoechoic normal hepatic and renal parencyhma; vascular rarefaction of the liver (L) with a significantly hyperechoic liver parenchyma compared to the renal parenchyma (K); inhomogeneous appearing parenchymal pattern of the liver. Diagnosis: fatty liver.

Answer 119

Diffuse Hepatic Steatosis ## Footnote Ultrasound of the liver, right subcostal section Diffuse, heterogeneous areas of increased echogenicity of the hepatic parenchyma, indicating diffuse hepatic steatosis (green overlay) surrounded by normal parenchyma. The circular, sharply demarcated, hyperechoic lesion in the center may be due to hepatic steatosis but requires further evaluation (PVB = branch of the portal vein; HV= Hepatic draining into the inferior vena cava (VC); green outline marks the hepatic borders).

Answer 120

Steatohepatitis ## Footnote There are irregularly distributed and ballooned hepatocytes. Displacement of the cytoplasm by globular vacuoles can also be seen (green overlay), as well as diffusely distributed, inflammatory granulomatous infiltrates (red overlay). These consist of lymphocytes, granulocytes, Kupffer cells, histiocytes, and numerous other cells.

Answer 121

Steatohepatitis ## Footnote There are large globular vacuoles of fat (indicated) and ballooned hepatocytes filled with hyaline (striped area), which correlate with the histological image of steatohepatitis. (Arrow = regenerative nodules from lymphocytes, granulocytes, histiocytes, and Kupffer cells)

Answer 122

Steatohepatitis ## Footnote An enlarged hepatocyte (black dashed outline) with reduced cobweb-like cytoplasm and a prominent eosinophilic cytoplasmic inclusion (Mallory body; overlay) is visible. The enlarged hepatocyte is surrounded by an abundance of lipid droplets. Mallory bodies are aggregates of denatured intermediate filaments and, along with intercellular lipid droplets, are histological features of steatohepatitis.

Answer 123

Decompensated Alcohol-Related Cirrhosis ## Footnote Septal, connective tissue reconstruction with lymphocyte infiltration (dashed line) in a regenerative nodule (R); bile duct proliferates (B) at the left margin of the image. (Green overlay = adipose hepatocytes in fatty liver).

Answer 124

Decompensated Alcohol-Related Cirrhosis ## Footnote Septal, connective tissue reconstruction with lymphocyte infiltration (green overlay) in a regenerative nodule (R) with adipose hepatocytes (H). (B = bile duct proliferates)

Answer 125

Histopathology of Liver Cirrhosis ## Footnote A regenerative nodule composed of a cluster of hepatocytes (purple overlay), extensive fibrosis (stained blue), and the portal triad (yellow overlay) can be seen. Regenerative nodules and fibrous septa are characteristic features of liver cirrhosis.

Answer 126

* Non-Alcoholic Fatty Liver Disease (NAFLD) → non-alcohol related accumulation of fat in the liver cells * Non-alcoholic steatohepatitis (NASH) → NAFLD with chronic inflammation and damage of liver cells * Etiology * Obesity and/or type 2 diabetes (metabolic syndrome) (due to excess supply of nutrients in the liver) * Medication (amiodarone, glucocorticoids, estrogen, antiretroviral drugs) * Parenteral nutrition, after resection of the small intestine and other gastrointestinal interventions * Pathology * Hepatocellular lipid accumulation, mostly macrovesicular * Ballooning degeneration and necrosis * Inflammatory infiltrates, with scattered lymphocytes, neutrophils, and Kupffer cells * Pathophysiology * ↑ Insulin resistance * ↑ Peripheral lipolysis * ↑ Triglyceride synthesis * ↑ Hepatic uptake of fatty acids * Clinical presentation * Often asymptomatic * Hepatomegaly * May progress to cirrhosis (it may be responsible for \> 50% of cryptogenic cirrhosis cases) * Diagnostics * ↑ Transaminases (AST/ALT ratio \< 1) * The reversal of the AST/ALT ratio to values \> 1 may indicate progression to cirrhosis. * Rule out other causes of chronic hepatitis (e.g., heavy alcohol use, hepatitis B, hepatitis C, Wilson disease, autoimmune hepatitis, hemochromatosis, α1-antitrypsin deficiency) * Therapy * Weight loss, optimization of diabetic treatment * Discontinue responsible medication * Studies suggest that ursodeoxycholic acid may have anti-inflammatory and anti-apoptotic effects in the liver and that vitamin E may decrease oxidative stress and improve aminotransferase levels in NASH patients. * Complications → cirrhosis, hepatocellular carcinoma

Answer 127

Ursodeoxycholic acid; vitamin E

Answer 128

* Acute hemolytic anemia (particularly due to portal hypertension, which may lead to hypersplenism and, in turn, induce cytopenia) after excessive alcohol use over the course of several years, characterized by the following triad: 1. Alcoholic hepatitis 2. Jaundice 3. Hyperlipidemia

Answer 129

* Liver cirrhosis → 80% of cases * Risk factors independent of cirrhosis * Chronic hepatitis B or C virus infection (even without progression to cirrhosis, chronic hepatitis B infection predisposes patients to HCC. An increased viral load correlates with increased risk. Accordingly, hepatitis B vaccination and appropriate treatment of hepatitis B infection help prevent the development of HCC) * Alcoholic liver disease * Nonalcoholic steatohepatitis (NASH) * Hemochromatosis * Wilson's disease * Alpha-1 antitrypsin deficiency * Hepatic autoimmune diseases (e.g., autoimmune hepatitis) * Schistosomiasis * Glycogen storage disease * Chronic ingestion of food contaminated with aflatoxin (carcinogen produced by Aspergillus flavus) (can grow on improperly stored food such as nuts, pistachios, rice, and corn) * Results in G:C → T:A transversion in codon 249 of TP53 gene leading to an inactivating mutation

Answer 130

* ↑ Serum alpha-fetoprotein (AFP) * Laboratory studies consistent with hepatitis and cirrhosis (e.g., ↑ transaminases, positive hepatitis serologies, ↓ coagulation factors) * Paraneoplastic syndromes → erythrocytosis (due to tumor EPO production), hypoglycemia, hypercalcemia (due to PTHrP) * In patients with cirrhosis of the liver or chronic hepatitis B/C infection, AFP is used as a screening test for HCC! * Ultrasound → best initial test * Irregular mass borders * Vascular invasion of the tumor may be visible (e.g., portal vein thrombosis) * Underlying cirrhosis may be seen * Abdominal CT or MRI (with contrast) → confirmatory test * Hypodense lesions (single or multifocal) * Irregular mass borders * Possible local invasion * Chest CT → detection of pulmonary metastases (rare) * Bone scintigraph → detection of bone metastases (rare) * Liver biopsy * **Can provide a definitive diagnosis but carries the risk of bleeding and tumor spread** * Recommended when both lab and imaging studies are inconclusive

Answer 131

Hepatocellular Carcinoma ## Footnote A hypodense hepatic mass (green overlay) with no clear demarcation to the healthy hepatic tissue can be seen. These findings are characteristic of hepatocellular carcinoma. A biopsy should be performed to confirm the diagnosis.

Answer 132

Hepatocellular Carcinoma

Answer 133

Hepatocellular Carcinoma

Answer 134

* Hematogenous * Most common locations for metastatic spread are: 1. Lungs 2. Abdomen 3. Bones

Answer 135

* Most common malignant lesion of the liver * Typical primary tumor site → gastrointestinal tract (colon, stomach, pancreas), lungs, and breasts * Diagnostics * Abnormal liver function tests * CT scan → typically multiple hypodense lesions (solitary metastases are very rare)

Answer 136

* Third most common primary hepatic malignancy * Etiology → associated with exposure to vinyl chloride, arsenic, and thorium dioxide * Histology (biopsy) → **endothelial cells positive for PECAM-1 (CD31)** * Treatment: * Surgical resection +/- adjuvant therapy * The tumor is resistant to radiotherapy and often unresponsive to chemotherapy. * Prognosis: * High rate of recurrence, poor overall prognosis

Answer 137

Liver Metastases ## Footnote Cross-section of a liver obtained from an autopsy of a patient with stage IV colon cancer Multiple pale spherical nodules and masses of varying sizes are visible throughout the hepatic parenchyma, some of which have caused the overlying Glisson capsule to become raised. This is the characteristic gross appearance of liver metastases

Answer 138

Liver Metastases CT scan of the upper abdomen of an adult patient (axial view; IV contrast) There are multiple hypoattenuating lesions (blue overlay) of varying sizes throughout the hepatic parenchyma. Each lesion has a hyperattenuating rim of contrast (white arrowheads). Ascites is visible as the free intraperitoneal fluid in the perisplenic and perihepatic regions (red overlay). These intraparenchymal hepatic lesions are characteristic of hepatic metastases. This patient's ascites could be secondary to hepatic dysfunction or could be a malignant ascites.

Answer 139

* Etiology * Possible hormonal component; estrogen therapy associated with increased growth * Ultrasonography * Usually well-demarcated, homogeneous, hyperechoic (pale) * Biopsy is contraindicated as it may cause bleeding * Contrast enhanced sonography * Early arterial phase peripheral nodular enhancement with complete centripetal filling in the portal venous and late phases * Iris diaphragm phenomenon * Contrast enhanced CT scan * Well-demarcated * Early arterial phase discontinuous, nodular, or peripheral enhancement * Subsequent gradual centripetal enhancement (iris diaphragm phenomenon) * Delayed-phase hyperintensity due to retention of contrast * Histology * Possibly pedunculated, cystic lesions with a dark color * Cavernous vascular spaces of variable size, lined by flat endothelial cells

Answer 140

* Etiology * Oral contraceptives * Anabolic steroids * Ultrasonography * Mainly isoechoic * No characteristic vascularization * Inhomogenous due to bleeding * More frequent in the right lobe of the liver * Contrast enhanced sonography * Fast centripetal or mixed filling in the arterial phase * Hypervascularity compared to the adjacent liver parenchyma * Sustained enhancement or weak washout in the delayed phase * Contrast enhanced CT scan * Well-demarcated * Heterogenous density due to the presence of fat, glycogen, and hemorrhagic products * Early arterial phase peripheral enhancement due to feeding arteries * Subsequent centripetal pattern of enhancement * No retention of contrast due to arteriovenous shunting on delayed-phase * Histology * Normal hepatic lobular architecture is absent. * Enlarged hepatocytes, with small and regular nuclei, cytoplasmic glycogen and lipid deposits * Arranged in sheets or 2-cell thick cords * Treatment * Discontinue oral contraceptives

Answer 141

Focal Nodular Hyperplasia ## Footnote Contrast-enhanced ultrasound of the liver in the portal venous phase (1:04 min after contrast medium administration). There is a round isoechoic lesion (green circled area) in both the contrast-enhanced image (left) and the mixed image (right). Vascular perfusion with the contrast agent shows a radial arrangement of the vascular supply (shaded green area). This spoke-like pattern is characteristic of focal nodular hyperplasia.

Answer 142

Focal Nodular Hyperplasia ## Footnote Contrast-enhanced axial CT scan of the abdomen, late arterial/portal venous phase: contrast enhancement in the liver with a hypodense central scar.

Answer 143

Cavernous Hemangioma of the Liver ## Footnote ``` Numerous cystic spaces lined by a single layer of endothelial cells are visible throughout this microscopic field (example in green overlay). The cyst walls are thin and composed of smooth muscle, elastic tissue, and fibrous tissue. Multiple thrombi (black arrowhead) are visible within the cysts. ```

Answer 144

Focal Nodular Hyperplasia ## Footnote Circumscribed, central local scar, which appears as a central region of connective tissue (S). The surrounding liver parenchyma shows nodular changes (L) and resembles cirrhotic tissue.

Answer 145

Hepatocellular Adenoma ## Footnote Sheets of hepatocytes arranged in two-cell thick cords are visible. The cytoplasm of most hepatocytes is pale or clear, indicating intracytoplasmic glycogen accumulation. There is no nuclear atypia. The normal hepatic architecture of hexagonal lobules with a central vein and surrounding portal triads is absent. This disorganized mass of benign hepatocytes is the characteristic histological appearance of a hepatocellular adenoma.

Answer 146

Focal Nodular Hyperplasia ## Footnote Cross-section of a liver pathology specimen A well-demarcated oval tumor (yellow overlay), which is lighter and more yellow in color than the surrounding liver tissue, can be seen. This finding is consistent with focal nodular hyperplasia.

Answer 147

Hepatic Hemangioma ## Footnote Ventral to the portal vein (PV), there is a sharply bordered, circular, hyperechoic lesion (green area) with acoustic shadowing (white area). This finding is characteristic of a hemangioma.

Answer 148

* Secondary to conditions associated with hypercoagulability (most common) * **Polycythemia vera (most important cause)** (an increased blood cell mass can also be caused by other conditions associated with polycythemia, such as increased EPO production by renal cell carcinomas) * Paraneoplastic thrombocytosis * Pregnancy and postpartum period * Clotting disorders (e.g., factor V Leiden thrombophilia, antiphospholipid syndrome) * Chronic inflammatory diseases (e.g., Behcet's disease) * Side effect of medication (e.g., hormonal contraception) * Secondary to invasion or compression of the hepatic veins (less common) * Hepatocellular carcinoma, renal carcinoma * Chronic infections and hepatic lesions (e.g., amebiasis, aspergillosis, syphilis, tuberculosis)

Answer 149

* Obstruction (e.g., due to thrombosis or compression) of hepatic veins → ↓ blood outflow → hepatic venous congestion → increased sinusoidal pressure, cellular hypoxia, centrilobular necrosis → congestive hepatopathy * May develop into “nutmeg liver” because of ischemia and fatty degeneration, the tissue appears speckled with dark spots. * Clinical symptoms depend on the extent of hepatic injury and portal hypertension.

Answer 150

Hepatic Congestion (Nutmeg Liver) ## Footnote Yellow streaks of fat and speckles of dark spots can be seen throughout the hepatic tissue. These findings are consistent with hepatic congestion. The dilated liver sinusoids appear as dark spots. The lack of nutrient supply to the hepatocytes surrounding the central vein leads to additional atrophy and fatty degeneration, causing the liver to resemble a nutmeg seed – hence the name “nutmeg liver.”

Answer 151

* Abdominal pain * Tender hepatomegaly * Ascites and abdominal distention * Jaundice * Signs of increased perfusion of portocaval anastomoses (e.g., esophageal varices, or caput medusae) * In severe cases → ankle edema, splenomegaly, and renal impairment * **In contrast to congestive heart failure, which can also cause hepatic congestion, Budd-Chiari syndrome does not lead to jugular venous distension.**

Answer 152

HELLP syndrome

Answer 153

* **Increased hemoglobin breakdown** * Hemolysis * Physiologic in newborns → neonatal jaundice (due to hemolysis of fetal hemoglobin and immature hepatic conjugation of bilirubin) * Pathologic in conditions such as: 1. G6PD deficiency 2. Sickle cell anemia 3. Spherocytosis 4. Hemolytic disease of the fetus and newborn 5. Blood transfusions (especially in trauma patients who require multiple transfusions) * Dyserythropoiesis (accelerated decomposition of erythrocytes increases unconjugated bilirubin levels) 1. Thalassemia 2. Pernicious anemia 3. Sideroblastic anemia * Resolving hematoma or internal hemorrhage (e.g., in trauma patients or postoperatively) * **Impaired hepatic uptake of bilirubin** * Drugs (e.g., rifampin, probenecid, sulfonamides) * Portosystemic shunt * **Defective conjugation of bilirubin** * Inherited hyperbilirubinemia 1. Gilbert syndrome 2. Crigler-Najjar syndrome * Liver disease 1. Hepatitis (e.g., viral, autoimmune, toxic/alcoholic) 2. Cirrhosis 3. Wilson disease * Thyroid disease 1. Hypothyroidism 2. Hyperthyroidism

Answer 154

* **Decreased excretion/impaired reuptake of bilirubin** * Inherited disorders 1. Dubin-Johnson syndrome 2. Rotor syndrome 3. Progressive familial intrahepatic cholestasis * Biliary atresia * **Intrahepatic cholestasis** * Liver disease 1. Hepatitis 2. Cirrhosis 3. Congestive hepatopathy * Biliary tract disorders 1. Primary biliary cholangitis 2. Postoperative cholestasis * Infiltrative disorders 1. Tuberculosis 2. Sarcoidosis 3. Amyloidosis 4. Lymphoma * Other causes 1. Drugs (e.g., estrogens, macrolides, arsenic) 2. Pregnancy 3. Parenteral nutrition 4. Sepsis * **Extrahepatic cholestasis (biliary obstruction)** * Biliary tract disorders 1. Choledocholithiasis 2. Cholangitis 3. Postoperative bile leaks or biliary duct strictures 4. Malformations of the bile ducts (e.g., postoperative/inflammatory strictures, and biliary cysts) 5. Mirizzi syndrome * Tumors * Pancreatic cancer * Cholangiocellular carcinoma * Hepatic tumors * Intrahepatic metastases * Gallbladder cancer * Inflammatory processes * Primary sclerosing cholangitis * Primary biliary cholangitis * Acute and chronic pancreatitis * Infectious diseases * Liver flukes * Weil disease * Yellow fever

Answer 155

Hepatitis and cirrhosis

Answer 156

* ↑ LDH * ↑ Indirect bilirubin * ↓ Haptoglobin

Answer 157

Both the common bile duct and the pancreatic duct

Answer 158

Obstructive Extrahepatic Cholestasis ## Footnote Ultrasound of the liver (white dotted line; intercostal view) In the center, there is a dilated bile duct (green overlay) approx. 12.8 mm in size and with a diameter larger than that of the portal vein (red overlay). The finding of a dilated bile duct is consistent with obstruction of the bile duct in extrahepatic cholestasis.

Answer 159

* Deposition of carotene in the skin (carotenoderma) can also cause yellow discoloration of the skin. * Usually occurs after excessive consumption of multivitamin supplements or fruits and vegetables rich in carotenes, such as carrots, sweet potatoes, kale, and oranges * In contrast to jaundice, it does not lead to scleral icterus.

Answer 160

* Unconjugated hyperbilirubinemia caused by * Short lifespan of erythrocytes in the newborn (during the first three months, fetal hemoglobin (HbF) is replaced by adult hemoglobin (HbA); as a result, bilirubin levels rise and hemoglobin levels drop to 10–13 g/dL) * Insufficient hepatic bilirubin metabolism → due to immature UDP-glucuronosyltransferase * ↑ Enterohepatic circulation of bilirubin (low concentration of bacteria in neonatal digestive tracts → less bilirubin is reduced to urobilin and excreted → unconjugated bilirubin is reabsorbed and recycled into the circulation) * Always unconjugated hyperbilirubinemia * Clinical Features * Asymptomatic, except for transient icterus * Jaundice manifests after 1st day of life and usually **resolves without treatment in 1 week (in term infants) or 2 weeks (in preterm infants)** * Usually most severe on the 5th day * **\> 24 hours after birth** * Peak total serum bilirubin * \< 15 mg/dL (in the case of a full-term, breastfed infant) (direct bilirubin in physiological jaundice is \< 10% of total) * Daily rise in bilirubin levels * \< 5 mg/dL/day * Treatment * Phototherapy is the primary treatment in neonates with unconjugated hyperbilirubinemia. * Exposure to blue light (non-UV, wavelength: 420–480 nm) → photoisomerization (major mechanism) and photooxidation (minor mechanism) of unconjugated (hydrophobic) bilirubin in skin to water-soluble forms → excretion of water-soluble form in urine and/or bile * Adequate fluid supplementation to prevent dehydration * Eye protection to prevent retinal damage * Contraindications → family history of porphyria * Side effects 1. Diarrhea, dehydration 2. Changes in skin hue (bronzing) and skin rashes 3. ↑ Risk of AML 4. Bronze baby syndrome (rare)

Answer 161

* Obliteration or discontinuity of the extrahepatic biliary system, most commonly of the common bile duct * Exact etiology unknown, most likely an embryonal malformation or acquired lesion (pathogens (e.g., reovirus type 3, CMV, rotavirus) may cause inflammation and destruction of the extrahepatic bile system) * Approx. 10–35% of cases involve additional anatomical malformations (e.g., situs inversus, asplenia, polysplenia, cardiac anomalies) * Discontinuity of the biliary system due to obliteration or fibrosis → obstruction of bile flow (cholestasis) → secondary biliary cirrhosis and portal hypertension * Clinical features * **Prolonged neonatal jaundice (\> 2 weeks of life)** * Acholic stools, dark urine * Hepatomegaly * Laboratory analysis * Conjugated hyperbilirubinemia * ↑ Aminotransferases and alkaline phosphatase * ↑ GGT * Ultrasonography * Absence of the gallbladder * No dilatation of the biliary tree * Liver biopsy * Active inflammation with bile duct degeneration and fibrosis * **Bile duct proliferation** * **Portal stromal edema** * Treatment * Kasai procedure (hepatoportoenterostomy) → a connection is created between the liver and the small intestine to allow for bile drainage. * In cases of liver cirrhosis → liver transplantation (primary reason for liver transplantation in children) * Complications * If undetected * Early biliary liver cirrhosis (at approx. 9 weeks of age) * Children may die within the first 2 years of life * Postoperative * Cholangitis in 50% of cases * Portal hypertension in \> 60% of cases

Answer 162

* Genetic condition that is characterized by intrahepatic biliary duct aplasia or hypoplasia * Etiology * Autosomal-dominant inheritance * Mutation in the JAG1 gene on chromosome 20 in 90% of patients * Clinical features * Hepatic manifestations * Cholestasis * Jaundice * Pruritus * Cirrhosis * Facial dysmorphism * Triangular face * Deep set eyes * Broad nasal bridge * Congenital heart defects (e.g., peripheral pulmonary stenosis) * Butterfly vertebrae * Posterior embryotoxon * Renal dysplasia * Laboratory findings * Conjugated hyperbilirubinemia * ↑ Serum aminotransferases * ↑ γ-GT * Liver biopsy → decreased number of interlobular bile ducts * Treatment * Depends on the affected organ systems * Conservative management of cholestasis and pruritus (e.g., ursodeoxycholic acid, cholestyramine)

Answer 163

* Etiology * Idiopathic * AIH is commonly associated with other autoimmune conditions (e.g., type 1 diabetes mellitus, Hashimoto thyroiditis, celiac disease) * Insidious onset in most patients and its presentation varies widely, ranging from asymptomatic disease to severe symptoms or even acute liver failure. * Nonspecific symptoms * Fatigue * Abdominal pain * Weight loss * Signs of acute liver failure (∼ ⅓ of patients) * Jaundice * RUQ pain * Fever * Laboratory tests * ↑ ALT and ↑ AST (aminotransferases are generally greater elevated than bilirubin and alkaline phosphatase) * Normochromic anemia, thrombocytopenia, mild leukopenia, ↑ erythrocyte sedimentation rate (ESR) * Autoantibodies → antinuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA). Other antibodies (e.g., anti-liver-kidney microsome-1 antibody or anti-soluble liver antigen antibody) are much less common. * Hypergammaglobulinemia (↑ IgG) * Liver biopsy → Biopsy should be performed following the detection of AIH antibodies to confirm the diagnosis. * **Histological findings reveal an ongoing inflammatory process with lymphocytic infiltration and necrosis.**

Answer 164

* Age of onset → adolescence (hormonal changes during puberty lead to increased plasma bilirubin concentration, which may cause intermittent jaundice as the first clinical manifestation of the disease) * Etiology * Mutation in the promoter region of UGT1A1 gene → mild reduction of UDP-glucuronosyltransferase activity → ↓ conjugation of bilirubin → ↑ indirect bilirubin (in this case, Gilbert syndrome is inherited in an autosomal recessive pattern) * Alternative: missense mutation in UGT1A1 gene (in this case, Gilbert syndrome is inherited in an autosomal dominant pattern) * Impaired hepatic bilirubin uptake * Inheritance → autosomal recessive or autosomal dominant * Clinical features * Asymptomatic or unspecific symptoms such as fatigue and loss of appetite * Transient, usually mild jaundice (varying from mild scleral jaundice to general jaundice) (patients with Gilbert syndrome are at increased risk of developing cholelithiasis) * Triggering factors of transient jaundice * Stress (e.g., trauma, illness, exhaustion) * Fasting periods * Alcohol consumption * Diagnosis * Slightly ↑ indirect bilirubin but \< 3 mg/dL (higher levels are possible during episodes of increased bilirubin breakdown) (Because UDP-glucuronosyltransferase still has some residual activity, there is only a minor increase in bilirubin. Therefore, there is no risk of bilirubin encephalopathy (kernicterus) in the case of Gilbert syndrome, in contrast to Crigler-Najjar syndrome type I) * Normal liver function * No evidence of hemolysis * Treatment → not required (benign condition)

Answer 165

* UDP-glucuronosyltransferase is (almost completely) absent. * Inheritance → autosomal recessive * Clinical features * Excessive, persistent neonatal jaundice * Kernicterus → neurological symptoms (onset during infancy or later in childhood) * Diagnosis * ↑ Indirect bilirubin (20–50 mg/dL) * Normal liver function tests * No evidence of hemolysis * Treatment * Phototherapy → conversion of unconjugated bilirubin (hydrophobic bilirubin) to more polar, water-soluble form → ↑ excretion via urine and/or bile * Plasmapheresis during acute rises in serum bilirubin levels (unconjugated bilirubin is bound to albumin, which is removed during plasmapheresis, reducing high levels of serum bilirubin.) * Tin protoporphyrin (alters heme breakdown to reduce formation of bilirubin) * Calcium carbonate (forces excretion of unconjugated bilirubin in the bile) * **Liver transplantation is the only curative treatment.** * Without treatment, Crigler-Najjar syndrome type I is incompatible with life because it causes kernicterus. * If treated, patients may survive past puberty, but most will eventually develop kernicterus.

Answer 166

* **Reduced** levels of UDP-glucuronosyltransferase * Inheritance → autosomal recessive or autosomal dominant * Clinical features * Often asymptomatic * No neonatal jaundice, although jaundice may occur during the patient's first year of life (later age of onset) * No neurological symptoms * Diagnosis * ↑ Indirect bilirubin (\< 20 mg/dL) * Normal liver function tests * No evidence of hemolysis * Responds to phenobarbital → ↓ serum bilirubin levels * Examining the effect of phenobarbital on serum bilirubin levels can help differentiate between type I and type II. Phenobarbital does not lower serum bilirubin levels in Crigler‑Najjar syndrome type I. * Treatment: * Patients are less likely to develop kernicterus. Specific treatment may therefore not be required. The following treatment options are, however, available if patients become icteric. * Phenobarbital → leads to induction of UDP-glucuronosyltransferase (usually sufficient to prevent or limit clinical manifestation) * **Avoid hormonal contraception and hepatic enzyme inhibitors**

Answer 167

* Defective multidrug resistance-associated protein 2 (MRP2) → impaired excretion of conjugated bilirubin from the hepatocytes into the bile canaliculi * Inheritance → autosomal recessive * Clinical features * Mild to moderate jaundice * Onset often occurs during adolescence * May worsen because of medication (particularly contraceptives) or pregnancy * Splenomegaly may occur in rare cases. * Diagnosis * Direct hyperbilirubinemia (direct bilirubin/total bilirubin up to 50%) * Liver biopsy → **dark, granular pigmentation (due to accumulation of epinephrine metabolites)** * Treatment → not required (benign condition) * Special considerations * Be careful when administering a drug that is toxic to the liver, as it may worsen jaundice. * **Contraindication for oral contraception (this may worsen jaundice, as MRP2 is also involved in estrogen and progesterone metabolism)**

Answer 168

* Defective organic anion transport proteins (OATP) 1B1 and 1B3 in hepatocytes → impaired transport and reduced storage capacity of conjugated bilirubin (direct bilirubin) * Inheritance → autosomal recessive * Clinical features * Usually asymptomatic but mild jaundice may occur (milder presentation compared to Dubin-Johnson syndrome) * Diagnosis * Moderate, direct hyperbilirubinemia and mild, indirect hyperbilirubinemia * Normal liver function test * **↑ Urinary coproporphyrins I and III (fraction of isomer I \< 70% of total)** * Liver biopsy → normal, no pigmentation * Treatment → not required * Special considerations * **Be careful when administering a drug that is toxic to the liver, as it may worsen jaundice.** * **Contraindication for oral contraception (this may worsen jaundice, because OATP is also involved in estrogen and progesterone metabolism)**

Answer 169

* Autosomal recessive mutations in the ATP7B gene (Wilson gene) on chromosome 13, which encodes for a membrane-bound, copper-transporting ATPase → defective ATP7B protein * Reduced incorporation of copper into apoceruloplasmin (once apoceruloplasmin binds to copper, it is converted to ceruloplasmin, which is known as the copper transport protein, as it binds approx. 90% of circulating copper) → ↓ serum ceruloplasmin * Reduced biliary copper excretion (caused by impaired copper transport from hepatocytes into bile) * Results in ↑ free serum copper → accumulation in the liver, cornea, CNS (basal ganglia, brain stem, cerebellum), kidneys, and enterocytes

Answer 170

* Liver → different degrees of liver disease possible, including acute liver failure, acute or chronic hepatitis, and cirrhosis * Hepatosplenomegaly * Portal hypertension * Abdominal pain * Jaundice * Ascites * Hepatic encephalopathy * **Kayser-Fleischer rings** * **Copper accumulation in Descemet membrane of the cornea** that results in 1–2 mm wide, green-brown rings in the periphery of the iris * While the rings are characteristic for Wilson disease and occur in ∼ 98% of patients who also have neurological symptoms, their absence does not rule out the condition. * Neurological symptoms → extrapyramidal motor disturbances, **but no sensory changes** * Dysarthria * Dystonia * **Parkinsonism** * Drooling * Tremor (usually asymmetric, affecting the hands), which may be any combination of: * Resting tremor * Intention tremor * Wing-beating tremor → a low frequency, high amplitude tremor that is most prominent with the arms outstretched anteriorly or laterally * Behavioral changes (e.g., depression, irritability, psychosis) * Cognitive impairment * **Renal → Fanconi syndrome**

Answer 171

* Copper accumulation in Descemet membrane of the cornea that results in 1–2 mm wide, green-brown rings in the periphery of the iris * While the rings are characteristic for Wilson disease and occur in ∼ 98% of patients who also have neurological symptoms, their absence does not rule out the condition * Seen in Wilson disease

Answer 172

Kayser-Fleischer Ring ## Footnote A brown ring approx. 1–2 mm in diameter is visible in the periphery of the iris (Kayser-Fleischer ring; green overlay). Kayser-Fleischer rings are typically seen in patients with Wilson disease.

Answer 173

Kayser-Fleischer Ring ## Footnote A brown ring (green overlay) is visible in the periphery of the cornea. Kayser-Fleischer rings are characteristic of Wilson disease.

Answer 174

* **Slit lamp examination → Kayser-Fleischer rings (best initial test)** * Blood tests * ↑ Transaminases * Coombs-negative hemolytic anemia * Thrombocytopenia (indicative of hypersplenism caused by portal hypertension) * ↓ Serum ceruloplasmin (normal value \> 20 mg/dL) * **↑ Free serum copper, but ↓ total serum copper (in healthy individuals, total body copper consists of ∼ 10% free copper and ∼ 90% ceruloplasmin-bound copper. As tests detect copper bound to ceruloplasmin, total serum copper concentrations decrease proportionately to serum ceruloplasmin levels)** * Urine tests → ↑ Urine copper excretion (over 24 hours) (especially important for monitoring the results of copper-chelating therapy) * Liver biopsy → if other tests are inconclusive * Hepatic copper concentration (\> 250 μg/g dry weight) [8] * Histology → copper staining (histological findings of Wilson disease are often similar to that of other hepatic diseases. Positive copper staining is highly indicative of the condition but its absence does not rule out the possibility of Wilson disease) * Cranial MRI * **Hyperintensities in the putamen (lenticular nucleus), thalamus, and brain stem due to copper accumulation** * **In some cases, a specific pattern of midbrain copper accumulation occurs, known as the “face of the giant panda” sign**

Answer 175

* General management * Low-copper diet → avoid foods such as organ meats, shellfish, nuts, and chocolate * Regular check-ups → liver biochemical tests every 6 months if disease is stable * Liver transplantation in cases of fulminant liver failure * Medical therapy * Initial therapy → chelating agents (facilitate renal excretion of copper by forming water-soluble compounds) * **Penicillamine → side effects in ∼ 30% of cases (e.g., sensitivity reactions)** * **Alternatives → trientine or zinc salts** * Maintenance therapy → zinc salts or low dose chelating agents (zinc ions induce metal-binding proteins in intestinal enterocytes, thereby reducing the amount of circulating copper. The bound copper is then excreted fecally during normal enterocyte turnover)

Answer 176

* Homozygous or heterozygous for the HFE gene defect * **Located on chromosome 6** * **Most commonly affects C282Y and H63D** * **Associated with HLA-A3 genotype** * Inheritance → autosomal recessive with incomplete penetrance * **Alcohol increases the absorption of iron** * **HFE gene defect (homozygous) → defective binding of transferrin to its receptor → ↓ hepcidin synthesis by the liver → unregulated ferroportin activity in enterocytes → ↑ intestinal iron absorption → iron accumulation throughout the body → damage to the affected organs** * In hereditary hemochromatosis, decreased hepcidin leads to iron overload. In secondary hemochromatosis, iron overload leads to increased hepcidin immediately after a blood transfusion (unless liver fibrosis or cirrhosis, which leads to decreased hepcidin synthesis, is present).

Answer 177

* Asymptomatic → 75% of cases * General symptoms * Fatigue, lethargy (often the first symptom, along with arthralgia and impotence) * **Increased susceptibility to infections** (especially infections by pathogens that are able to exploit host iron overload. This includes bacteria (e.g., gram-negative bacteria, such as Listeria, Pseudomonas), fungi (e.g., Candida, Histoplasma), and viruses (e.g., HBV, cytomegalovirus)) * Organ-specific symptoms * Liver * Abdominal pain * Hepatomegaly * Cirrhosis * Increased risk of hepatocellular carcinoma (common cause of death) (increased even without the presence of cirrhosis) * Pancreas → signs of diabetes mellitus (polydipsia, polyuria) * Skin → hyperpigmentation, bronze skin (in addition to iron deposits in the skin, **increased melanin production via the pro-inflammatory activity of iron is thought to contribute to hyperpigmentation)** * **Pituitary gland → hypogonadism, erectile dysfunction, testicular atrophy, loss of libido, amenorrhea** (symptoms may also be caused by iron accumulation in the gonads) * Joints → arthralgia **(typically symmetrical arthropathy of the MCP joints II and III), chondrocalcinosis (accumulation of calcium pyrophosphate)** * Heart 1. **Cardiomyopathy** * **Restrictive cardiomyopathy** * **Dilated cardiomyopathy (reversible)** 2. **Cardiac arrhythmias** → paroxysmal atrial fibrillation (most common), sinus node dysfunction, complete AV block, atrial and ventricular tachyarrythmias, and sudden cardiac death 3. Congestive heart failure

Answer 178

* Laboratory tests * ↑ Serum iron * ↑ Ferritin in serum (\> 200 μg/L) * **↓ Total iron-binding capacity (TIBC)** * **↑ Transferrin saturation (\> 45%)** * ↑ Liver enzymes (AST, ALT) * MRI → noninvasive way to estimate the iron concentration in the liver * Liver biopsy * Color stain → Prussian blue * Pronounced siderosis in iron staining with iron deposits primarily observed in hepatocytes * **Macrophages containing hemosiderin → cytoplasmic granules that stain golden-yellow (caused by chronic hemolysis)**

Answer 179

* Dietary changes * Diet low in iron * **Restriction of alcohol and vitamin C supplements** * Consumption of tea (tannates bind iron and reduce absorption) * **Therapeutic phlebotomy (first-line treatment)** * Drug-induced iron chelation * Agents → deferoxamine, deferasirox, or deferiprone * Indication → particularly when phlebotomy is contraindicated, e.g., in cases of anemia, severe heart disease, or difficult venipuncture

Answer 180

* The exact cause is still unclear; however, it is considered as an autoimmune disease. * Associated with other autoimmune conditions * Positive family history is a predisposing factor. * **Inflammation and progressive destruction (likely due to an autoimmune reaction) of the small and medium-sized intrahepatic bile ducts (progressive ductopenia)** → defective bile duct regeneration → chronic cholestasis → secondary hepatocyte damage due to increased concentration of toxins that typically get excreted via bile → gradual portal and periportal fibrotic changes → liver failure → liver cirrhosis and portal hypertension (in advanced stage) * Patients are initially often asymptomatic. Signs and symptoms are mainly due to the resulting cholestasis, liver cirrhosis, and portal hypertension. * Fatigue (usually the first symptom) * Marked generalized pruritus * Hyperpigmentation * Hepatomegaly, dull lower margin, RUQ discomfort * Splenomegaly * Jaundice * Pale stool, dark urine * Maldigestion (may involve manifestations of deficiency of fat-soluble vitamins; e.g., osteoporosis) * **Xanthomas and xanthelasma** * Frequently associated with other autoimmune conditions * Rheumatoid arthritis * Autoimmune thyroid disease, especially Hashimoto thyroiditis * Celiac disease * CREST syndrome * Sicca syndrome * Laboratory tests * ↑ Cholestasis parameters (ALP, γ-GT, conjugated bilirubin) * Transaminases (AST/ALT) are within normal limits or slightly elevated * **↑ Antimitochondrial antibodies (AMA) (\> 95%)** * **↑ ANA (up to 70%)** * **↑ IgM** * Histology * **Lymphocytic infiltration of portal areas and periductal granulomas** * **Bile duct ductopenia, progressive fibrosis** * Liver cirrhosis * Treatment * There is no cure for PBC. Treatment consists of slowing disease progression and alleviating symptoms. * **Liver transplantation is the only definitive treatment.** * **First-line medical therapy → ursodeoxycholic acid (also known as ursodiol, or UDCA)** * Slows progression of the disease and improves clinical symptoms * Delays the need for transplantation * Active ingredient is a hydrophilic bile acid * Hepatoprotective; antiapoptotic (suppresses hydrophobic and membrane-toxic bile acids and helps stabilize the membrane) * Immunomodulatory **→** UDCA suppresses immune reactions that promote disease progression (due to a slight cytokine secretion) * Also used in primary sclerosing cholangitis, cholestasis of pregnancy, and small cholesterol stones * Complications * Malabsorption * Liver cirrhosis and portal hypertension * Osteoporosis (the exact pathomechanism is not fully understood)

Answer 181

* The exact cause is unknown. * Associations * **Chronic inflammatory bowel diseases (IBD)** * **∼ 90% of PSC patients have IBD (from these patients, ∼ 87% have ulcerative colitis (UC) and 13% have Crohn's disease.** * However, only ∼ 5% of patients with UC and \< 5% of patients with Crohn's disease develop PSC. * **Presence of HLA-B8 and HLA-DR3** * Other autoimmune conditions (e.g., hypergammaglobulinemia IgM) * Clinical Features * Often initially asymptomatic * Signs of cholestasis * Jaundice/scleral icterus * Pruritus * Pale stool, dark urine * Fatigue * Can lead to acute cholangitis (fever, chills, right upper quadrant pain) * Later stages → signs of cirrhosis * Hepatosplenomegaly * Portal hypertension * Liver failure * Symptoms of chronic inflammatory bowel disease, which is frequently associated with PSC, or other associated comorbidities * Laboratory findings * **Perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are present in up to 80% of cases** * ↑ Cholestasis parameters (ALP, GGT, conjugated bilirubin) * Transaminases (AST/ALT) are within normal limits or slightly elevated (\< 300 U/L). * **↑ Cholesterol** * **↑ IgM** * Magnetic resonance cholangiopancreatography (MRCP) → **multifocal strictures alternating with dilation and beading of bile ducts** * Ultrasound * Irregular diameter of the bile duct * Diffuse thickening of the wall of the common hepatic and bile ducts * Liver biopsy * **Concentric "onion skin" scarring and fibrosis of bile ducts** * Treatment * Symptomatic * Ursodeoxycholic acid and immunosuppressives (e.g., tacrolimus) → may decrease transaminases, ALP, and serum bilirubin, but do not prevent disease progression * **Liver transplantation is the only curative option and is performed in the case of advanced liver cirrhosis** * Complications * Steatorrhea and deficiency of fat-soluble vitamins (possibly due to defective bile secretion into the small intestine or diseases associated with PSC) * Liver cirrhosis * Malignancy 1. Cholangiocarcinoma (∼ 10–15% of cases) [10] 2. Gallbladder carcinoma 3. Colorectal carcinoma (patients with IBD and concomitant PSC are at increased risk for developing colorectal cancer (CRC) when compared with patients with IBD alone, although the cause of this increased risk is not known) 4. Hepatocellular carcinoma (HCC) 5. Pancreatic carcinoma

Answer 182

* Develops secondary to an underlying condition, including: * Chronic biliary obstruction (e.g., stones, tumors, strictures) * Trauma or surgery of the biliary tract * Chronic pancreatitis * Ischemic injury to the biliary tract (e.g., post-transplantation, critically ill patients) * **Extrahepatic biliary obstruction → increase pressure in intrahepatic ducts → injury/fibrosis and bile stasis** * Cholestasis and elevated pressure in intrahepatic bile ducts lead to progressive fibrosis and eventually cirrhosis * Presentation similar to primary sclerosing cholangitis * Pruritus * Fatigue * Jaundice * Hepatomegaly * Additional symptoms corresponding to the underlying condition * Poor prognosis * ↑ ALP, GGT, and conjugated bilirubin * Additional changes corresponding to the underlying condition * May lead to ascending cholangitis

Answer 183

* RUQ ultrasound * Best initial test in suspected symptomatic cholelithiasis * Characteristic findings 1. Cholelithiasis * Intraluminal highly echogenic foci * **Strong posterior acoustic shadowing** 2. Biliary sludge * Low-level echogenic material in the dependent portion of the GB * **No posterior acoustic shadowing** * Slow movement with the changing of patient posture

Answer 184

* May manifest with biliary colic and is a risk factor for cholangitis and biliary pancreatitis. * Should be considered in patients with classic symptoms of biliary colic if cholelithiasis cannot be visualized on ultrasound. * RUQ ultrasound * Low-level echogenic material in the dependent portion of the GB * No posterior acoustic shadowing * Slow movement with the changing of patient posture

Answer 185

* Benign tumor of the gallbladder wall with low metastatic potential * 5% of polyps are adenomas, which are premalignant * Up to 50% of polyps \> 1 cm are carcinomas * Diagnosis → ultrasound (transabdominal or endoscopic) * P**arietal echogenic tumor, easily mistaken for a gallstone** * **No change in position of pathology during movement or acoustic shadow (in contrast to a gallstone)**

Answer 186

Gallbladder Mucocele ## Footnote The gallbladder (G; green outline) is grossly distended and filled with a heteroechoic fluid (yellow overlay) as evidenced by the fluid meniscus. These findings in a patient with an asymptomatic right upper quadrant mass are characteristic of a gallbladder mucocele. L = liver (which appears cirrhotic); A = ascites

Answer 187

Choledocholithiasis ## Footnote A solitary stone is visible as a well-defined round hyperdense lesion (white arrow) in the distal end of the common bile duct (dashed outline), which appears dilated. These features are characteristic of choledocholithiasis.

Answer 188

Porcelain Gallbladder ## Footnote A well-defined oval lesion is visible in the right upper quadrant of the abdomen, encapsulated in a thin rim of radiodense material, indicating intramural calcification of the gallbladder. This is the typical appearance of porcelain gallbladder, which is a consequence of chronic gallbladder inflammation that is usually secondary to cholelithiasis.

Answer 189

Cholesterol Polyps in the Gallbladder ## Footnote The two sharply demarcated, hyperechoic structures (green overlay) are cholesterol polyps (cholesterolosis). Cholesterol polyps do not show posterior acoustic shadowing and are attached to the gallbladder wall.

Answer 190

Cholelithiasis ## Footnote Several well-defined, hyperechoic structures varying in size and shape (green overlay) are visible in the dependent position of the gallbladder lumen (G). These structures are obstructing the passage of the ultrasound beam (dotted white line), resulting in posterior acoustic shadowing (hypoechoic area; hatched green overlay). Hyperechoic intraluminal structures casting a posterior acoustic shadow are characteristic features of cholelithiasis. L = liver

Answer 191

Gallbladder Calculi and Wall Thickening ## Footnote Acoustic enhancement (green overlay) is seen deep to much of the gallbladder. However, multiple small dependent hyperechoic calculi (yellow overlay) reflect the ultrasound beam and cast an acoustic shadow (green hatched overlay). Biliary sludge (yellow hatched overlay) is slightly hyperechoic compared to anechoic bile. The gallbladder wall is thickened (normal = 1-2 mm) and has a layered appearance (red overlay), with central hypoechoic edema. The findings are not pathognomonic for acute calculous cholecystitis but are consistent with the diagnosis in the proper clinical setting. Additional findings that, if present, would support a diagnosis of cholecystitis include an obstructing calculus, positive Murphy sign, pericholecystic fluid, gallbladder dilatation, and hyperemia of the gallbladder wall on color Doppler. G = gallbladder; L = liver

Answer 192

Kernicterus

Answer 193

* Increase cholesterol and/or bilirubin, decrease bile salts, decrease phosphatidylcholine, and gallbladder stasis all cause stones. * 2 types of stones: * Cholesterol stones (radiolucent with 10- 20% opaque due to calcifications) 80% of stones. Associated with obesity, Crohn disease, advanced age, estrogen therapy, multiparity, rapid weight loss, Native American origin. * Pigment stones (black= radiopaque [Ca+2 bilirubinate], increase enterohepatic cycling of bilirubin (eg, ileal disease) or hemolysis (eg, sickle cell anemia, spherocytosis); brown = radiolucent, infection (eg, E coli, liver fluke) due to release of β-glucoronidase). Increase uncojugated bilirubin leads to increase Ca2+ bilirubinate. Associated with Crohn disease, chronic hemolysis, alcoholic cirrhosis, advanced age, biliary infections, total parenteral nutrition (TPN). * Risk factors (4 F's): * Female * Fat * Fertile (multiparity) * Forty * Most common complication is cholecystitis; can also cause acute pancreatitis, ascending cholangitis. * Diagnose with ultrasound. * Treat with elective cholecystectomy if symptomatic. * Usodeoxycholic acid is the first line nonsurgical treatment. It dissolves gallstones by solubilizing cholesterol. * Administration of hydrophilic bile acids, decrease cholesterol secretion and increase biliary acid concentration, thus improvs cholesterol solubility and promotes gallstones disolution. *

Answer 194

* Sudden pausing during inspiration upon deep palpation of the RUQ due to pain * During inspiration, the pressure-sensitive gallbladder is pushed caudally (towards the hand), inducing pain. This examination may be performed with the patient in the supine or sitting position. * Murphy sign may be falsely negative in patients \> 60 years.

Answer 195

* Rare but life-threatening form of acute cholecystitis characterized by air within the gallbladder wall that is caused by gas-forming bacteria (e.g., Clostridium spp., E.coli) * Rare; most commonly seen in elderly diabetic men (esp. 50–70 years of age) * Clinical features * Similar to acute calculous cholecystitis: fever, RUQ pain, referred pain * Symptoms progress rapidly. * Associated with early gangrene and gallbladder perforation * Diagnostics * Laboratory studies and findings → similar to those of acute calculus cholecystitis * The characteristic feature of EC on imaging is air within the gallbladder wall or lumen. * Treatment * Initial supportive management → NPO, IV fluids, analgesics * Broad-spectrum IV antibiotics with anaerobic coverage

Answer 196

* RUQ transabdominal ultrasound * Preferred initial imaging modality in suspected acute cholecystitis * Characteristic findings * **Gallbladder wall thickening \> 3–5 mm** * **Gallbladder distension (8–10 x 4 cm)** * **Gallbladder wall edema (double-wall sign)** → the innermost and outermost layers appear hyperechoic; edematous tissue appears as a hypoechoic layer in between. * **Sonographic Murphy sign** * **Pericholecystic free fluid** * Presence of gallstones and/or biliary sludge * In emphysematous cholecystitis, mural air appears as hyperechoic shadows within the gallbladder wall.

Answer 197

* 25–70% of patients present with all three features 1. Abdominal pain (most commonly RUQ) 2. High fever 3. Jaundice (least common feature)

Answer 198

* Charcot cholangitis triad PLUS hypotension and mental status changes * Charcot cholangitis triad: * Abdominal pain (most commonly RUQ) * High fever * Jaundice (least common feature)

Answer 199

* Most common causes 1. Biliary pancreatitis (e.g., gallstones, constriction of the ampulla of Vater) ∼ 40% of cases 2. Alcohol-induced (∼ 30% of cases) 3. Idiopathic (∼ 15%–25% of cases) * Other causes 1. Severe hypertriglyceridemia (\> 1,000 mg/dl), hypercalcemia 2. Post-ERCP 3. Certain drugs * Steroids * Azathioprine * Sulfonamides * Loop and thiazide diuretics * Estrogen * Protease inhibitors * NRTIs * Anticonvulsants 4. Scorpion stings 5. Viral infections (e.g., coxsackievirus B, mumps) 6. Trauma (especially in children) 7. Autoimmune and rheumatological disorders (e.g., Sjögren syndrome) 8. Pancreas divisum 9. Hereditary (e.g., mutation of the trypsinogen gene, cystic fibrosis)

Answer 200

* Constant, severe epigastric pain * Classically radiating towards the back * Worse after meals and when supine * Improves on leaning forwards * Nausea, vomiting * General physical examination * Signs of shock → tachycardia, hypotension, oliguria/anuria (due to distributive shock from cytokine release, and third-spacing of intravascular fluid) * Possibly jaundice in patients with biliary pancreatitis * Abdominal examination * Abdominal tenderness, distention, guarding * Ileus with reduced bowel sounds and tympany on percussion * Ascites * Skin changes (rare) (circulating pancreatic enzymes cause swelling of the subcutaneous tissue and localized hemorrhages. These signs, though nonspecific, suggest retroperitoneal bleeding and are associated with a poor prognosis) * **Cullen's sign → periumbilical ecchymosis and discoloration (bluish-red)** * **Grey Turner's sign → flank ecchymosis with discoloration** * **Fox's sign → ecchymosis over the inguinal ligament**

Answer 201

Cullen Sign ## Footnote Periumbilical ecchymosis as a result of retroperitoneal hemorrhage, commonly seen in acute pancreatitis.

Answer 202

Grey Turner Sign ## Footnote Right-sided flank ecchymosis suggestive of retroperitoneal hemorrhage, commonly seen in acute pancreatitis.

Answer 203

Necrotizing Pancreatitis ## Footnote An enlarged pancreas with interspersed regions of parenchymal hyperdensity and hypodense necrosis (green overlay) can be seen. These findings are consistent with necrotizing pancreatitis.

Answer 204

Acute Pancreatitis ## Footnote Fatty and fascial stranding (yellow overlay) anterior to the pancreas (P) indicates peripancreatic inflammation. The gallbladder (yellow outline) contains calculi (examples indicated by red overlay) and sludge, and the common bile duct (green overlay) is slightly dilated. The passage of a gallbladder calculus through the common bile duct can result in acute pancreatitis. A → aorta; Vc → ascending vena cava; L → liver; Sp → spleen Red arrow → hepatic artery; Green outline → stomach

Answer 205

Pancreatic Pseudocyst

Answer 206

Pancreatic Abscess ## Footnote A well-defined, complicated collection (solid outline) containing gas (examples indicated by arrows) is seen in the region of the pancreatic body and tail. Abdominal ascites (hatched overlay) and inflammatory fatty and fascial stranding are present in the right upper quadrant. L → liver; G → gallbladder; CBD → common bile duct; A → abdominal aorta; K → kidney; V → vertebra

Answer 207

* Chronic heavy alcohol use (60–70% of cases, esp. men) * Pancreatic ductal obstruction (\< 10%) → strictures (e.g., due to trauma, stones) * Tobacco use * Idiopathic pancreatitis (20–30%) * Hereditary pancreatitis (∼ 1%) * **PRSS1 gene mutation (autosomal dominant inheritance), SPINK1 gene mutation** * Age of onset \< 20 years * Characterized by a positive family history and the absence of other risk factors * Autoimmune pancreatitis * Systemic disease * Cystic fibrosis → ∼ 2% of cystic fibrosis patients develop chronic pancreatitis. * Severe hypertriglyceridemia (levels \> 1,000 mg/dL) (pancreatic lipase breaks triglycerides into free fatty acids, which damage the pancreatic parenchyma) * Primary hyperparathyroidism (hypercalcemia) (hypercalcemia causes pancreatic enzyme secretion and premature activation of trypsinogen to trypsin, with subsequent pancreatic autodigestion) * Tropical pancreatitis * Most common cause in the tropics (esp. southern India) * Young age at onset (high consumption of cassava has been implicated in its pathogenesis)

Answer 208

* Abdominal CT (plain and contrast-enhanced CT) → best initial imaging modality to screen for chronic pancreatitis * Pancreatic ductal dilations and calcifications on plain CT (more sensitive than x-ray) * “Chain of lakes” appearance of the main pancreatic duct (caused by the alternating dilation and stricture of the duct) * Pancreatic atrophy * ERCP → detection of early pathologies and simultaneous treatment possible (e.g., duct dilation, stent insertion) * Ductal stones, which are visible as filling defects * “Chain of lakes” or “string of pearls” appearance (characteristic feature) * Irregularity and/or dilation of the main pancreatic duct * Abdominal ultrasound * Indistinct margins and enlargement * Pancreatic calcifications * Ductal strictures, dilation, or stones * Abdominal x-ray → visible pancreatic calcifications (highly specific, but only seen in ∼ 30% of cases)

Answer 209

Pancreatic Calcifications ## Footnote CT abdomen (IV contrast; arterial phase; axial view) Multiple microcalcifications (red) are visible in the pancreatic parenchyma. The pancreatic head contains a hypodense lesion (green). There is also evidence of cholecystectomy (white clipping material in the liver; circled). These findings are consistent with chronic pancreatitis.

Answer 210

Acute Episode of Chronic Pancreatitis ## Footnote The pancreatic head shows an inflammatory mass with calcifications (green overlay). The colon contains gas and contrast agents (hatched overlay). These findings are characteristic of chronic pancreatitis. Incidental findings include a small cyst in the dorsal parenchyma of the left kidney and calcifications of the abdominal aorta.

Answer 211

* Indications → family history of chronic pancreatitis, young patients with idiopathic pancreatitis 1. PRSS1 gene mutations (serine protease 1 gene) * Gene that encodes cationic trypsinogen * Mutations in this gene cause hereditary pancreatitis and may play a role in the development of idiopathic pancreatitis. * Diagnostic of hereditary pancreatitis * If the mutation is present, these individuals should undergo regular surveillance for early detection and management of pancreatic adenocarcinoma. 2. CFTR gene mutations → seen in ∼ 30% of patients with idiopathic chronic pancreatitis 3. SPINK1 gene mutations (serine protease inhibitor, Kazal type 1 gene, PSTI gene, pancreatic secretory trypsin inhibitor gene) * Gene that encodes a pancreatic trypsin inhibitor. * Mutations of this gene are associated with hereditary pancreatitis. * Seen in ∼ 20% of patients with chronic pancreatitis

Answer 212

1. Pancreatic insufficiency * Tissue atrophy and fibrosis cause: * Exocrine insufficiency → deficiency of lipase, amylase, and protease → maldigestion, steatorrhea, malabsorption * Destruction of beta cells → endocrine insufficiency with pancreatic diabetes 2. Pancreatic pseudocysts 3. Splenic vein thrombosis 4. Pancreatic ascites 5. Pancreatic abscess 6. Portal vein thrombosis 7. Pancreatic diabetes 8. Pancreatic cancer (especially in patients with hereditary pancreatitis)

Answer 213

* Encapsulated collection of pancreatic fluid that develops 4 weeks after an acute attack of pancreatitis (can occur in both acute and chronic pancreatitis ) * Pancreatic secretions leak from damaged ducts → inflammatory reaction of surrounding tissue → **encapsulation of secretions by granulation tissue** * Clinical features * Often asymptomatic * Painless abdominal mass * Pressure effects * Gastric outlet obstruction (early satiety, nonbilious vomiting, abdominal pain) * Obstruction of the distal duodenum (bilious vomiting) → may result in steatorrhea * Bile duct obstruction with jaundice * Diagnostics → abdominal ultrasound/CT/MRI * Extrapancreatic fluid collection within well-defined wall/capsule * No solid cyst components detectable * Treatment * Cystogastrostomy/cystoduodenostomy/cystojejunostomy * Ultrasound/CT-guided percutaneous drainage * Complications * Infection → fever, abdominal pain, sepsis * Pseudocyst rupture → pancreatic ascites/pancreaticopleural fistula * Erosion into an abdominal vessel → hemorrhage into the cyst → sudden abdominal pain, signs of hemorrhagic shock

Answer 214

* Occurs in 10% of patients with chronic pancreatitis * Inflammation of the splenic vein (which lies adjacent to the pancreas) → thrombus formation → left-sided portal hypertension → **gastric varices (without esophageal varices)** * Can present with upper GI bleeding, ascites, and splenomegaly * Treatment * Acute → anticoagulation and/or thrombectomy * Chronic and symptomatic → splenectomy

Answer 215

* Ductal disruption (due to an acute attack of pancreatitis, pancreatic surgery and/or trauma) or a pseudocyst leak/rupture → pancreatic ascites * Develops when the pancreatic leak is not walled off by fibrous/granulation tissue. It is a rare complication (∼ 1%) that is mostly seen in patients with chronic pancreatitis secondary to heavy alcohol use. * Clinical features * Abdominal distention; variable abdominal pain * Dyspnea * Peripheral edema (due to hypoalbuminemia secondary to the loss of protein into the abdominal cavity) * Free fluid in the peritoneal cavity * Diagnostics * Ascitic fluid analysis → exudate with high amylase levels (\> 1,000 IU/L) * Imaging → ERCP, CECT, MRCP * Identify ascites and the site(s) of the leak * ERCP is preferred, as it allows treatment to be performed in the same sitting. * Treatment * Conservative management → indicated in all patients; ∼ 30% require no further treatment * Nothing by mouth, IV fluids, parenteral nutrition * Somatostatin analogs (octreotide) (inhibits pancreatic secretion → decreased leakage of pancreatic secretions into the abdominal cavity) * Repeated ascitic taps

Answer 216

* **Exogenous risk factors** 1. Smoking (considered to be one of the leading causes of pancreatic cancer and associated with an up to 6-fold increase in the risk of developing malignancy) 2. Chronic pancreatitis (especially when present for more than 20 years) 3. High alcohol consumption (alcohol use is associated with an increased risk of developing conditions that predispose to pancreatic cancer, including chronic pancreatitis and liver cirrhosis. However, a direct connection between alcohol toxicity and tumor development has not been established yet) 4. Type 2 diabetes mellitus 5. Obesity 6. **Occupational exposure to chemicals used in the dry cleaning and metalworking industrie**s 7. Possibly infections with: * H. pylori (and excess stomach acid) * Hepatitis B * **Endogenous risk factors** * Age \> 50 years * Inherited genetic syndromes (10% of pancreatic cancers) 1. Familial atypical multiple mole melanoma (FAMMM) syndrome 2. Hereditary breast and ovarian cancer syndrome (BRCA1 and BRCA2 mutations) 3. HNPCC 4. Von-Hippel-Lindau syndrome 5. Neurofibromatosis type 1 6. Multiple endocrine neoplasia type 1 7. Familial pancreatic carcinoma 8. Hereditary pancreatitis (mutations in the PRSS1 gene) 9. Peutz-Jeghers syndrome

Answer 217

* In most cases, there are no early symptoms suggestive of pancreatic cancer * Constitutional symptoms * Poor appetite * Weight loss * Weakness * Gastrointestinal symptoms * Belt-shaped epigastric pain which may radiate to the back (abdominal pain in advanced pancreatic cancer is significantly intensified by tumor infiltration of the visceral nerve plexus) * Nausea * Malabsorption, diarrhea (possibly steatorrhea secondary to exocrine pancreatic insufficiency) * Jaundice caused by obstruction of extrahepatic bile ducts (especially in tumors of the pancreatic head) * Courvoisier sign → enlarged, nontender gallbladder and painless jaundice. Courvoisier sign is the most common initial symptom of pancreatic cancer but usually does not occur when the primary tumor is located in the tail or body of the pancreas. Painless jaundice may also occur in cholangiocarcinoma. Gallstones, instead, cause obstructive jaundice with a painful gallbladder. * Pale stools, dark urine, and pruritus * Impaired glucose tolerance (rarely) * Hypercoagulability * **Trousseau syndrome** → superficial thrombophlebitis (in 10% of cases) * Recurring thrombophlebitis in changing locations (migratory) * Red, tender extremities * Classically associated with pancreatic cancer * Thrombosis (e.g., phlebothrombosis, splenic vein thrombosis) * A thrombosis of unknown origin may be caused by an undiagnosed malignancy (especially pancreatic cancer, but also pulmonary, and prostatic carcinoma, the "3P's").

Answer 218

* No screening tests available * Tumor markers → used to monitor the progression of cancer and treatment efficacy * CA 19-9 * CEA (less specific) * Possibly ↑ lipase * Abdominal ultrasound/contrast-enhanced CT * Poorly defined, hypodense/hypoechoic and hypovascular mass * Double-duct sign → with increasing size, tumors of the pancreatic head may block bile drainage in both the common bile duct and the pancreatic duct, leading to dilatation of both structures. * Location * **Pancreatic head → 65% of cases** * Pancreatic body and tail → 15% of cases * Diffuse → 20% of cases

Answer 219

Head; epithelial cells within the tubules

Answer 220

Pancreatic Ductal Adenocarcinoma ## Footnote Adenocarcinoma of the pancreatic head is visible originating from the ductal cells, which have an atypical, uneven, multilayered epithelium (green overlay). F = fibrous septa

Answer 221

Pancreatic Ductal Adenocarcinoma