Pocket Medicine (Pocket Notebook Series)

ESOPHAGEAL AND GASTRIC DISORDERS

Dysphagia

• Oropharyngeal: inability to propel food from mouth through UES into esophagus

• Esophageal: difficulty swallowing & passing food from esophagus into stomach

Structural dysphagia (solids >liquids; JAMA 2015;313:18; Gastro 2018;155:1022)

• Oropharyngeal

Zenker’s divertic. (pharyngeal pouch): in elderly, a/w aspir., dx w/ video fluoro, Rx endo/surg

Malignancy; proximal strictures/rings/webs; infection; radiation injury; goiter; osteophytes

• Esophageal

Rings (intermittent dysphagia, concentric obstructing tissue, Schatzki ring): near GE jxn, a/w food impaction, linked to GERD; Rx w/ PPI, dilation

Webs: thin, partially occlusive structure, proximal, a/w Fe defic. (Plummer-Vinson synd.)

Peptic or XRT strictures, foreign body, tumor, vascular rings (dysphagia lusoria), compression from dilated left atrium compression

Infxn esophagitis: odynophagia >dysphagia; often immunosupp w/ Candida, HSV, CMV

Pill esophagitis: odynophagia >dysphagia; NSAID, KCl, bisphosp., doxy & tetracycline

Eosinophilic esophagitis (JAMA 2021;326:1310): often young/middle-aged ♂. Dx: >15 eos/hpf on bx, esoph dysfxn (ie, dysphagia, food impaction). Rx: 1^st line is PPI (½ respond); alternative (or if fail PPI) is 3Ds: 1^st elimination Diet (Ø milk, soy, eggs, wheat, nuts, fish); if no Δ, Drugs (swallow inh steroids); if ongoing sx & stricturing, Dilation (Gastro 2020;158:1776).

Neuromuscular dysphagia (solids & liquids; Neurogastero Motil 2021;33:e14058)

• Caused by aberrant motility or innervation of oropharynx/esophagus

• Oropharyngeal: consider CNS disorders (eg, stroke, ALS, myopathies, CNS tumors)

• Esophageal: motility disorder w/ dysphagia, chest pain, GERD; dx: conventional or high-res manometry w/ esophageal pressure topography. Chicago classification v4.0:

1. Disorders of EGJ Outflow: Isolated EGJ outflow obstruction or achalasia. Achalasia: simult. ↓ amp contractions & ↓ LES relaxation; barium swallow w/ dilated esophagus & distal “bird’s beak” narrowing; mostly idiopathic, although can be a/w Chagas; Rx: pneumatic dilation as effective as Heller myotomy (local expertise dependent) (Gut 2016;65:732); peroral endoscopic myotomy; CCB/nitrates/PDEi; botox if Ø surg cand.

2. Disorders of Peristalsis: Absent contractility (failed peristalsis); distal esophageal spasm (uncord. peristalsis w/ simult. contractions); hypercontractile esoph (high amp contract.; Rx w/PPI, nitrates/CCB/PDEi, TCA); ineffective esophageal motility (↓ amp of distal esoph contractions; seen in scleroderma, DM, hypothyroid.; Rx w/ underlying disorder & w/ PPI)

GASTROESOPHAGEAL REFLUX DISEASE (GERD)

Pathophysiology (JAMA 2020;324:2536)

• ↑ acid exposure in esophagus, caused by ↑ transient LES relaxations. Worsened by ↑ intraabd pressure (eg, obesity, pregnancy), ↓ esophagogastric motility, hiatal hernia. Rarely caused by ↑ secretory states (eg, Zollinger-Ellison).

• Precipitants: supine, fatty foods, caffeine, alcohol, cigarettes, CCB, pregnancy, obesity

Clinical manifestations

• Esophageal: heartburn, atypical chest pain, regurgitation, sour taste, dysphagia

• Extraesophageal: dry cough, asthma (often poorly controlled), laryngitis, dental erosions

Diagnosis (Annals 2015;163:ITC1; Nat Rev Gastro Hepatol 2016;13:501)

• Clinical diagnosis based on sx and response to empiric trial of PPI (“PPI test”)

• EGD if: Ø response to PPI or alarm features: dysphagia, vomiting, ↓ wt, anemia, age >60

• If dx uncertain & EGD nl → esoph manometry w/ 24-h pH monitoring ± impedance to dx:

“Nonerosive reflux disease”: no erosion, ulceration or Barrett’s; ½ abnl pH. Unpredictable response to PPI. Most will not progress to erosive esophagitis or Barrett’s.

“Reflux hypersensitivity”: nl acid exposure on pH/impedance w/ symptom–reflux assoc.

“Functional heartburn”: nl acid exposure on pH/impedance w/o symptom–reflux assoc.

Treatment (World J Gastrointest Endosc 2018;10:175; Am J Gastro 2022;117:27)

• Lifestyle: avoid precipitants, lose weight, no eating 2 hrs before bed, exercise, Ø tobacco

• Medical: start low-dose PPI, uptitrate up to 40 mg bid; H2 blockers for intermittent sx

• Refractory (max dose ≥8 wks): confirm w/ pH testing on or off PPI, consider hernia repair

If acidic or sx correlate w/ reflux episodes: surgical fundoplication (emerging Rx: LES sphincter augmentation w/ radiofrequency, implantable magnetic or electrical devices)

If nl pH or no sx correlation = “fxnal dyspepsia” (Gastro 2020;158:2286); Rx w/ TCA, SSRI

Complications (Gastro 2020;158:760)

• Reflux esophagitis (erosions/ulcers above GE jxn), strictures (caused by chronic inflamm)

• Barrett’s esoph. (BE): metaplastic columnar mucosa above GE jxn replaces squam epithel.

Screen if chronic (>5 y) and/or frequent GERD (≥1/wk) in ♂ w/ ≥2 risk factor for Barrett’s/esophageal adeno: >50 y, white, hiatal hernia, central adiposity, smoking, FHx of Barrett’s/esophageal adeno. In ♀, consider only if multiple RFs. 0.1–0.3%/y risk of esoph adenocarcinoma, ↑ if ↑ dysplasia (Am J Gastro 2016;111:30).

Mgmt: PPI. W/o dysplasia: surveillance EGD q3–5y. Low-grade dysplasia: EGD q12mo; possible endoscopic eradication. High-grade dysplasia: endoscopic eradication; consider chemoprophylaxis w/ high-dose PPI & ASA (Lancet 2018;392:400).

PEPTIC ULCER DISEASE (PUD)

Definition & etiologies (BMJ 2019;367:5495)

• Ulcers (break in mucosal lining >5 mm) & erosions (<5 mm) in stomach and duodenum

• Principal risk factors: H. pylori infection >ASA/NSAID use

• H. pylori infection: causes ~80% of duodenal ulcers (DU) & ~30–40% of gastric ulcers (GU). ~50% of world colonized w/ H. pylori, but only 5–10% will develop PUD.

• ASA/NSAIDs: damage to mucosa caused by ↓ prostaglandin synthesis. Cause majority of non–H. pylori-related DU & GU. Regular use a/w 5–6× ↑ odds of GIB.

• Other: smoking, stress, excessive EtOH, gastric cancer/lymphoma, Crohn’s, viral infxn (eg, CMV/HSV in immunosupp), bisphosphonates, steroids (in combo w/ NSAIDs, but not risk factor alone); rarely gastrinoma (Zollinger-Ellison synd.), mastocytosis, idiopathic

• Stress ulcer: risk factors = ICU & coagulopathic, mech vent, h/o GIB, steroid use; Rx w/ PPI

Clinical manifestations

• Epigastric gnawing abdominal pain: relieved with food (DU) or worsened by food (GU)

• Complic.: UGIB, perf. & penetration, gastric outlet obstruction (due to edema & dysmotility)

Diagnostic studies

• Testing for H. pylori: stool Ag, urea breath testing (UBT) or EGD + rapid urease test (RUT) False ⊖ Ag, UBT, RUT if on abx, bismuth, PPI; ∴ stop prior to testing if possible Serology: ↓ utility, useful only to exclude infection in lower prevalence areas

• EGD (definitive dx): if fail empiric Rx or alarm features (see “GERD”); bx GU to r/o malig & H. pylori; repeat EGD in 6–12 wk if >2 cm, malig features, risk factors for gastric cancer (ie, ⊕ FHx, ⊕ H. pylori, atrophic gastritis, metaplasia on bx, >50 y), or sx persist

Treatment (Lancet 2016;388:2355; Gastro 2016;151:51; Gut 2017;66:6; AJG 2017;112:212)

• If H. pylori ⊕ → eradicate (“test and treat”); if ⊖ → gastric acid suppression w/ PPI

1^st line: Quad. Rx: 14d x [MNZ + TCN + bismuth + PPI] or [MNZ + amox + clarith + PPI]

Besides PUD, test & Rx if: gastric MALT lymphoma, s/p resection for early gastric ca, FHx gastric ca, unexplained iron def. anemia, ITP, uninvestigated dyspepsia in Pt <60 y, or when initiating long-term NSAIDs

• “Test-of-cure”: 4 wk after Rx, off PPI x 1–2 wk. Use stool Ag, EGD + RUT, or UBT.

• Lifestyle changes: d/c smoking and probably EtOH; diet does not seem to play a role

• Surgery: if refractory to med Rx (1^st r/o NSAID use) or for complic. (see above)

GI prophylaxis if taking ASA/NSAID (Am J Gastro 2009;104:728)

• PPI if h/o PUD/UGIB and either (a) on P2Y₁₂ inhib or anticoag, or (b) ≥2 of the following: >60 y, steroids or dyspepsia. Low bleeding risk Pts unlikely to benefit (Gastro 2019;157:403).

• Consider Δ non-selective NSAID to selective COX-2 inhibitor (↓ PUD & UGIB but ↑ CV events), if low CV risk & not on ASA

GASTROINTESTINAL BLEEDING

Definition

• Intraluminal blood loss anywhere from the oropharynx to the anus

• Classification: upper = above the ligament of Treitz; lower = below the ligament of Treitz

• “Severe” GIB: defined as having associated shock, orthostatic hypotension, ↓ Hct by 6% (or ↓ Hb by 2 g/dL), or requiring transfusion ≥2U PRBCs. Requires hospitalization.

Clinical manifestations

• Hematemesis = blood in vomitus (UGIB)

• Coffee-ground emesis = emesis of blood exposed to gastric acid (UGIB)

• Melena = black, tarry stools from digested blood (usually UGIB, but can be SB or R colon)

• Hematochezia = bloody or maroon-colored stools (LGIB or rapid UGIB)

Initial management (Am J Gastro 2021;116:899)

• Assess severity: VS including orthostatic Δs, JVP. Tachycardia (can be masked by βB use) suggests 10% volume loss, orthostatic hypotension 20% loss, shock >30% loss. Scoring predicts rebleeding & mortality: AIMS65, ABC Score & Glasgow-Blatchford.

• History: prior GIB, tempo of current bleed, specific bleeding manifestations (see above), other GI s/s (eg, abd pain, Δ in bowel habits, weight loss, N/V), ASA/NSAID or EtOH use, anticoag/antiplt drugs, h/o or risk factors for cirrhosis, radiation, prior GI or aortic surgery

• Physical exam: localizable abd tenderness, peritoneal signs, masses, LAN, prior surgery, signs of liver disease (hepatosplenomegaly, ascites, jaundice, telangiectasias), rectal exam: masses, hemorrhoids, anal fissures, stool appearance, color

• Resuscitation: placement of 2 large-bore (18-gauge or larger) intravenous lines. Volume replacement: NS or LR to achieve normal VS, UOP, & mental status.

• Lab studies: Hct (may be normal in first 24 h of acute GIB before equilibration) 2–3% → 500 mL blood loss; low MCV → Fe deficient and chronic blood loss; plt, PT/INR,

PTT; BUN/Cr (ratio >36 in UGIB b/c GI resorption of blood ± prerenal azotemia); LFTs

• Transfuse: type & cross; use O-neg if emerg; for UGIB (esp. w/ portal HTN) transfuse w/ more restrictive Hb goal (eg, >7 g/dL or >8 g/dL if CAD) (JAMA 2016;316:2025)

• Reverse coagulopathy: consider FFP to normalize INR (however caution in ESLD where INR does not correlate with bleeding risk); plts >50k, ddAVP if uremic, consider reversal agents if on anticoagulants (qv)

• Triage: alert endoscopist. Consider ICU if unstable VS or poor end organ perfusion.

Intubation for: emergent EGD, ongoing hematemesis, shock, poor resp status, Δ MS

OutPt management if SBP ≥110, HR <100, Hb ≥13 (♂) or ≥12 (♀), BUN <18, Ø melena, syncope, heart failure, liver disease (Clin Gastro Hepatol 2015;13:115)

Diagnostic studies (JACR 2021;18:S139)

• UGIB: EGD w/in 24 h (NEJM 2020;382:1299). If severe bleed, ↑ dx/Rx yield if erythro 250 mg IV given 30 min prior to endoscopy to clear stomach contents.

• LGIB: colonoscopy (identifies cause in >70%); early colo (w/in 24 h) unlikely to improve outcome vs. late (24-96 h) (Gastro 2020;158:168). If hematochezia a/w orthostasis, concern for brisk UGIB → exclude UGIB w/ EGD first. Push enteroscopy, anoscopy, capsule endoscopy in combo w/ urgent colo results in dx >95% of cases (GI Endo 2015;81:889).

• Imaging: if too unstable for endo or recurrent bleeding, consider IR embolization or surgery

tagged RBC scan: can identify general luminal location if bleeding rate ≥0.04 mL/min

CT angiography: faster to obtain than RBC scan, detects bleeding ≥0.3 mL/min

arteriography: can localize exact vessel if bleeding rates ≥0.5 mL/min, allows for IR Rx

• Emergent exploratory laparotomy (last resort) if no localization and life-threatening bleed

Etiology UGIB		Comment & Treatment (GI Endosc Clin N Am 2015;25:415)
PUD (20–60%; duodenal>gastric) (Am J Gastro 2021;116:899) See “PUD”		Treatment: PPI: 40 mg PO or IV BID Endoscopic therapy: epi inj + bipolar cautery or hemoclip. Bx for H. pylori and treat if ⊕. High-risk (for rebleeding) ulcer: arterial spurting, adherent clot, visible vessel. Endo Rx, IV PPI × 72 h post EGD, then Δ to high-dose oral PPI. If fail, arteriography w/ embolization; surgery (last resort). Intermediate-risk ulcer: oozing, in o/w stable Pt. Endo Rx, can Δ to oral PPI after EGD and observe 24–48 h. Low-risk ulcer: clean-based or flat. Oral PPI & discharge. Hold anticoag & antiplatelet Rx until hemostasis; can resume after hemostasis & PPI on board (Endoscopy 2015;47:a1)
Erosive gastropathy (4–30%)		Precipitants: ASA/NSAID, EtOH, cocaine, gut ischemia, XRT Stress-related mucosal injury in ICU Pts. Risk factors include severe coagulopathy, mech vent >48 h, high-dose glucocorticoids Treatment: high-dose PPI
Esophagitis (15%)		Rx offending cause + high-dose PPI; repeat EGD to r/o Barrett’s.
Esophageal or gastric varices (4–20%) (Clin Gastro Hepatol 2015;13:2109; J Gastro Hepatol 2016;31:1519; Hep 2017;65:310) See “Cirrhosis”		2° to portal HTN. If isolated gastric → r/o splenic vein thrombosis. Pharmacologic Start octreotide pending EGD if suspect varices: Rx for 2–5 d Abx: 20% cirrhotics p/w GIB have infxn, & ~50% develop infxn during hospitalization; Ppx w/ IV CTX, cipro, or levoflox × 7 d Nonpharmacologic Esophageal varices: endoscopic band ligation (>90% success). Covered esophageal stent placement or balloon tamponade if refractory as bridge to TIPS (consider early espec. if Child-Pugh C). Gastric varices: arteriography w/ coiling, or if available, endoscopic injection of cyanoacrylate (glue). If refractory: TIPS or balloon-retrograde transvenous obliteration (BRTO).
Portal HTN gastropathy		↑ portal venous pressure → ectatic vessels, hyperemia in gastric antrum. Rx: reduce portal HTN (octreotide), βB, TIPS.
Vascular (5–10%)	Angioectasia AVMs, HHT (see below)	AVMs congenital. Angioectasia (ectatic submucosal vessels) a/w ↑ age, CKD, cirrhosis, CTD, severe CV dis. Heyde syndrome: GIB due to angioectasias + aortic stenosis. Rx: endoscopic Rx.
	Dieulafoy’s lesion	Large (1–3 mm) submucosal artery protruding through fundal mucosa → sudden, massive UGIB. Difficult to identify. Endo Rx.
	Gastric antral vasc. ectasia (GAVE)	“Watermelon stomach”; ectatic gastric vessels, often a/w cirrhosis, CTD, typically older ♂. Rx w/ EGD w/ thermal hemostasis, repeat q4–8wk to eradicate lesions. TIPS does not improve outcomes.
	Aortoenteric fistula	AAA or aortic graft erodes into 3rd portion of duodenum. P/w “herald bleed.” If low suspicion → endoscopy; if high → CT angiography.
Malignancy (5%)		Endoscopic hemostasis of mass temporizing measure till cancer Rx
Mallory-Weiss tear (5–10%)		GE jxn lacerations due to vomiting → ↑ intraabd pressure & shearing Often self-resolve; Rx→ antiemetics, PPI, endoscopic therapy
Cameron’s lesions		Linear erosions in hiatal hernia due to mech trauma of diaphragm
Post-sphincter- otomy bleeding		Occurs in ~2% of ERCP w/ sphincterotomy; ↑ risk w/ more complic. procedure. Bleeding into duodenum. Rx w/ endo hemostasis.

Etiology LGIB	Comment & Treatment (NEJM 2017;376:1054)
Diverticular bleed (30%)	Pathophysiology: Intimal thickening and medial thinning of vasa recta as they course over dome of diverticulum → weakening of vascular wall → arterial rupture. Diverticula more common in left colon; but bleeding diverticula more often in right colon. Clinical: older, ASA/NSAIDs, usually painless hematochezia ± abd cramping Treatment: Usually stops spontaneously (~75%); ~20% recur. Can perform endoscopic hemostasis. Surgery (partial colectomy) last resort.
Polyp/Tumor (20%)	Typically slow ooze, p/w fatigue, weight loss, iron deficiency, anemia
Colitis (20%)	Infectious (see “Acute Diarrhea”), IBD, ischemic colitis, XRT
Anorectal disorders (20%)	Internal, external hemorrhoids; anal fissures, rectal ulcers, rectal varices (Rx by ↓ portal venous pressure in cirrhosis), XRT
Vascular (<10%)	Angioectasia & AVMs. Hereditary hemorrhagic telangiectasia (Weber-Osler-Rendu): diffuse AVMs throughout GI mucosa (also involve lips, oral mucosa, fingertips).
Meckel’s diverticulum	Congenital intestinal pouch due to incomplete obliteration of vitelline duct. 2% of pop, w/in 2′ of IC valve, 2″ long, ♂:♀ 2:1, can present as obscure GIB in adults. Dx w/ 99mTc-pertechnetate scintigraphy. Rx w/ angioembo, surgical resection.

Obscure GIB (Am J Gastro 2015;110:1265; Gastro 2017;152:497)

• Definition: continued bleeding (melena, hematochezia) despite ⊖ EGD & colo; 5% of GIB

• Etiologies: Dieulafoy’s lesion, GAVE, small bowel angiodysplasia, ulcer or cancer, Crohn’s disease, aortoenteric fistula, Meckel’s diverticulum, hemobilia

• Diagnosis: repeat EGD w/ push enteroscopy/colonoscopy when bleeding is active

If ⊖, video capsule to evaluate small intestine (contraindic. if stricture) (GIE 2015;81:889)

If still ⊖, consider ^99mTc-pertechnetate scan (“Meckel’s scan”), enteroscopy (single-balloon, double-balloon, or spiral), tagged RBC scan and arteriography

DIARRHEA

ACUTE DIARRHEA (<4 weeks’ duration)

Acute Infectious Etiologies (Am J Gastro 2016;111:602; JAMA 2019; 321:891)
NONINFLAMMATORY		Predom. disruption small intestine absorp. & secretion. Voluminous diarrhea, N/V. ⊖ Fecal WBC & FOB.
Preformed toxin		“Food poisoning,” <24 h dur. S. aureus (meats & dairy), B. cereus (fried rice), C. perfringens (rewarmed meats).
Viral (Lancet 2018; 392:175)	Rotavirus	Outbreak person to person (PTP), daycare; lasts 4–8 d.
	Norovirus	~50% of all diarrhea. Winter outbreaks; PTP & food/water; no immunity. Lasts 1–3 d. Vomiting prominent.
Bacterial	E. coli (toxigenic)	>50% of traveler’s diarrhea; cholera-like toxin; <7 d.
	Vibrio cholerae	Contam H2O, shellfish; “rice water” stools w/ dehydration
Parasitic (± malab for mos after Rx)	Giardia	Streams/outdoor sports, travel, outbreaks. Bloating. Acute (profuse, watery) → chronic (greasy, malodorous).
	Cryptosporidia	In soil; water-borne outbreak; usually self-limited, can → chronic infxn if immunosupp. Abd pain (80%), fever (40%).
	Cyclospora	Contaminated produce, intl travel (Latin America)
INFLAMMATORY		Predom. colonic invasion. Small-vol diarrhea. LLQ cramps, tenesmus, fever, typically ⊕ fecal WBC or FOB.
Bacterial	Campylobacter	Undercooked poultry, unpasteurized milk; carried by -puppies & kittens. Prodrome w/ abd pain, “pseudoappendicitis”; c/b GBS, reactive arthritis.
	Salmonella (nontyphoidal)	Eggs, poultry, milk, hamsters. Bacteremia in 5–10%. 10–33% of bacteremic Pts >50 y may develop aortitis.
	Shigella	Abrupt onset; no N/V; gross blood & pus in stool; ↑↑ WBC
	E. coli (O157:H7 & inv/hemorrhagic non-O157:H7)	Undercooked beef, unpasteurized milk, raw produce; PTP. O157 & non-O157 sp. (40%) produce Shiga toxin → HUS (typically in children). Gross blood in stool.
	C. difficile	Vide infra
	Vibrio parahaem.	Undercooked seafood
	Salmonella typhi	Travel to Asia, Africa, South America. Systemic toxicity, relative bradycardia, rose spot rash, ileus → ”pea-soup” diarrhea, bacteremia.
	Other	Yersinia: undercooked pork; unpasteurized milk, abd pain → ”pseudoappendicitis” (aka mesenteric adenitis) Aeromonas, Plesiomonas, Listeria (meats & cheeses)
Parasitic	E. histolytica	Contaminated food/water, travel (rare in U.S.); liver abscess
Viral	CMV	Immunosuppressed; dx by shell vial cx of colon bx

Evaluation (NEJM 2014;370:1532; Digestion 2017;95:293; PLOS One 2017;12:11)

• Ddx: hyperthyroid, adrenal insufficiency, meds (abx, antacids, immune checkpt inhibitors), appendicitis, diverticulitis, radiation, 1^st presentation of bowel disorder (eg, IBD, celiac)

• History: stool freq, blood, abd pain, duration of sxs [~1 wk for viral & bacterial (except C. diff), >1 wk for parasitic], travel, food, recent abx, immunocompromise

• PEx: vol depletion (VS, UOP, axillae, skin turgor, MS), fever, abd tenderness, ileus, rash

• Laboratory: calprotectin, stool cx, BCx, lytes, C. diff (if recent hosp/abx), stool O&P (if >10 d, travel to endemic area, exposure to unpurified H₂O, community outbreak, daycare, HIV ⊕ or MSM); ± stool ELISAs (viruses, Crypto, Giardia), serologies (E. histolytica); PCR available (but high ⊕ rate & unclear if true vs. colonized; consider if immunocompromised)

• Imaging/endoscopy: consider if warning signs (WS) of fever, severe abd pain, blood or pus in stool, >6 stools/d, severe dehydration, immunosupp, elderly, duration >7 d, hosp-acquired. CT/KUB if ? toxic megacolon; sig/colo if immunosupp or cx ⊖.

Treatment (Am J Gastro 2016;111:602; Clin Infect Dis 2017;65:e45)

• If no WS, nl PO intake → supportive: hydrate, loperamide, bismuth subsalicylate (Ø antichol)

• If mod. dehydration: 50–200 mL/kg/d of oral solution or Gatorade, etc. If severe: IV fluids.

• If suspect traveler’s diarrhea → azithro 1 g x 1 d (due to FQ resistance in Asia), rifaximin, or rifamycin; if suspect protozoal → flagyl or nitazoxanide

• Empiric abx for non–C. diff inflammatory diarrhea reasonable for severe disease (fever, >6 BMs/d, hospitalization, bloody or mucoid stools or high-risk Pt [> 70 yrs, immunosupp]: azithro 1 g x 1 d (preferred if fever or dysentery) or FQ × 3–5 d (↑ resistance)

• Avoid abx if suspect E. coli O157:H7 (exposure hx, gross blood) as may ↑ risk of HUS

CLOSTRIDIOIDES DIFFICILE INFECTION (CDI)

Pathogenesis & epidemiology (NEJM 2015;372:825)

• Ingestion of C. diff spores → colonization when colonic flora Δ’d by abx or chemo → release of toxin A/B → colonic mucosal necrosis & inflammation → pseudomembranes

• Most frequently reported nosocomial infxn; community-acquired w/o abx ~⅓of new cases. A/w any abx during or up to 10 wks post Rx (esp. β-lactams, clinda, FQ).

• Elderly, immunocompromised, and IBD Pts can develop CDI w/o recent abx exposure

Clinical manifestations (a spectrum of disease)

• Asx colonization: <3% healthy adults; ~20% in hospitalized patients on antibiotics

• Acute watery diarrhea (>3 stool/d), occ bloody ± mucus, lower abd pain, fever, ↑↑↑ WBC

• Pseudomembranous colitis: above sx + pseudomembranes + bowel wall thickening

• Fulminant colitis (2–3%): toxic megacolon (colonic atony/absence of BMs, colon dilatation ≥6 cm on KUB, systemic toxicity) and/or bowel perforation

Diagnosis (Ann Intern Med 2018;169:49)

• Only test if symptomatic (diarrhea, s/s of colitis); test liquid stool (unless concern for ileus)

• Stool toxin immunoassay (high Sp) + glutamate dehydrogenase (GDH) (high Se)

• Stool PCR: has ↑ Se, but ⊕ if colonized in absence of active infxn; should not necessarily Rx if ⊕ PCR w/ neg toxin assay (JAMA IM 2015;175;1792)

• Obtain CT abdomen/pelvis if suspect complication (toxic megacolon). Consider flex sig if dx uncertain and/or evidence of no improvement on standard Rx.

Initial treatment (CID 2021;73:5; Am J Gastro 2021;116:1124)

• If possible, d/c abx ASAP; stop antimotility agents & cholestyramine if using (binds vanco)

• Fidaxomicin is now preferred over vancomycin regardless of severity; may be limited by $

• Mild-mod: fidaxomicin 200 mg BID (↓ recurrence rate) or vanco 125 mg PO q6h × 10 d

• Severe (any of the following: >12 BM/d, Temp >103°F, WBC >15, HoTN, ICU care required, ileus): as above; could consider PO+PR vanco

• Fulminant disease: vanco 500 mg PO qid + MNZ 500 mg IV q8h; consider FMT

• If worsening (ileus, ↑ WBC, ↑ lactate, shock, toxic megacolon, peritonitis): abd CT & urgent surgical consult - subtotal colectomy, diverting loop ileostomy or colonic lavage

• If need to cont abx, cont C. diff. Rx for ≥7 d post-abx cessation (Am J Gastro 2016;111:1834)

• Stool carriage 3–6 wk postcessation; retesting for C. diff of limited utility during this time

Recurrent infection (15–30% risk after d/c of abx, most w/in 2 wk of stopping abx)

• 1^st recurrence: fidaxomicin 200 mg PO bid × 10 d or vanco 125 mg PO q6h × 10–14 d. Consider adding bezlotoxumab 10 mg/kg IV × 1 during abx Rx (mAb that binds toxin B) as ↓ recurrence; caution in CHF (NEJM 2017;376:305).

• Subsequent recurrences: fidaxomicin or vanco PO pulse → taper. Consult ID. Fecal microbial transplant (JAMA 2017;318:1985) recommended after 3 CDI.

• Prevention: vanco 125 mg PO QD ↓ risk of recurrence (CID 2016;65:651); consider for Pts needing abx w/ h/o severe or recurrent CDI. Avoid acid suppression/abx as able.

CHRONIC DIARRHEA (>4 wk)

General evaluation (JAMA 2016;315:2712; Gastro 2019;157:3)

• Clinically can be classified as watery, fatty, inflammatory

• Additional hx: timing (freq, relation to meals; nocturnal diarrhea a/w organic causes like IBD rather than IBS), abd pain, wt loss, prior surg, chemo/XRT, diet (incl caffeine or poorly absorbed carbs/sugars), infectious sxs, immunocompromise, travel, laxative use, stress

• Hx offending meds: PPI, colchicine, abx, H2RA, SSRIs, ARBs, NSAIDs, chemo, caffeine

• PEx: gen appearance (BMI), signs of systemic disease, surgical scars, rectal tone/DRE

• Lab testing: CBC, metabolic profile, alb, TSH, Fe, fecal calpro; see under each category

• Imaging/endoscopy: colonoscopy for chronic diarrhea of unknown cause. Abd CT/MRI usually warranted if systemic problem suspected.

Osmotic (watery; ⊖ fecal fat, ↑ osmotic gap, ↓ diarrhea w/ fasting)

• Caused by ingestion of poorly absorbed cations/anions (Mg, sulfate, phos; found in laxatives) or poorly absorbed carbs (eg, mannitol, sorbitol [found in chewing gum]) or lactose if lactose intolerant. Diarrhea resolves w/ cessation of offending substance.

• Dx: ↑ stool osmotic gap (see Figure); stool pH <6 if unabsorbed carbohydrates

• Lactose intolerance: can be acquired after gastroenteritis, med illness, GI surg. Clin: bloating, flatulence, discomfort, diarrhea. Dx: H⁺ breath test or empiric lactose-free diet. Rx: lactose-free diet & lactase tablets.

Secretory (watery; nl osmotic gap, no Δ diarrhea w/ fasting, nocturnal, cramps)

• Caused by secretion of anions or K+ into lumen or inhib of Na absorption → ↑ H₂O in stool. Most commonly caused by bacterial toxins from infxn (see above). Other causes:

• Endocrine: Addison’s, VIPoma, carcinoid, Zollinger-Ellison, mastocytosis, hyperthyroid (↑ motility). ✓ serum peptide levels (eg, gastrin, calcitonin, VIP) & urinary histamine.

• GI neoplasm: carcinoma, lymphoma, villous adenoma

• Microscopic colitis: common cause of chronic diarrhea w/ obscure origin. Often seen in middle-aged women w/ autoimmune disorders. NSAIDs, SSRIs, PPIs notable triggers. Grossly normal on colo but bx shows lymphocytic & plasmacytic infiltration of mucosa ± thickened submucosal collagen. Rx: budesonide (1^st line), antidiarrheals, cholestyramine, bismuth; consider anti-TNFs if refractory (Gastro 2016;150:242).

• Bile acid-induced diarrhea: ileal resection or disease (eg, Crohn’s) → bile acids in colon → electrolyte & H₂O secretion. Rx w/ empiric bile-acid binders (eg, cholestyramine).

Functional/IBS (normal osmotic gap, ↓ diarrhea with fasting): see “Dysmotility”

Malabsorption (fatty; ↑ fecal fat, ↑ osmotic gap, ↓ diarrhea w/ fasting)

• Defective mucosal absorption of nutrients b/c Δs in: mucosal surface (surgical resection) or gen. mucosal dis. (celiac, IBD). Bloating, foul-smelling, floating stools (steatorrhea).

• Celiac disease (JAMA 2017;318:647; Lancet 2018;391:70; Gastro 2019;156:4)

Immune rxn in genetically predisposed Pts (~1% pop) to gliadin, a component of gluten (wheat protein) → small bowel inflammatory infiltrate → impaired absorption

Other s/s: Fe/folate/B₁₂ defic anemia; osteoporosis; dermatitis herpetiformis; ↑ ALT/AST

Dx: best if eating gluten when tested; IgA anti-tissue transglutaminase Ab (most Se), IgA anti-deaminated gliadin peptide Ab; IgA α-endomysial Ab. Duodenal bx confirms dx (blunted villi, crypt hyperplasia, inflamm infiltrate); absence of HLA-DQ2/8 excludes dx.

Rx: gluten-free diet; 7–30% do not respond to diet → ? wrong dx or noncompliant

Complic: ~5% refractory sx, risk of T-cell lymphoma and small bowel adenocarcinoma

• Whipple’s disease: infxn w/ T. whipplei (Lancet 2016;16:13)

Other s/s: fever, LAN, edema, arthritis, CNS Δs, gray-brown skin pigmentation, AI & MS, oculomasticatory myorhythmia (eye oscillations + mastication muscle contract).

Dx: bx/path, IHC, PCR. Rx: PCN + streptomycin or 3^rd-gen ceph × 10–14 d → Bactrim ≥1 y.

• Small intestinal bacterial overgrowth (SIBO): colonic bacteria in SI → steatorrhea, B12/Fe defic, protein-losing enteropathy. A/w dysmotility (DM neuropathy, scleroderma), Δ’d anatomy (Crohn’s, surgery, fistulae), immune deficiency, celiac, CF. Dx w/ H⁺ or ¹⁴C -xylose breath testing or empiric abx. Rx w/ 7–10 d abx (rifaximin, MNZ, or FQ).

• Other: s/p short bowel resection (short bowel syndrome), chronic mesenteric ischemia, eosinophilic gastroenteritis, intestinal lymphoma, tropical sprue, Giardia infection

Maldigestion (fatty; ↑ fecal fat, ↑ osmotic gap, ↓ diarrhea w/ fasting)

• Defective intraluminal hydrolysis of nutrients, typ. 2/2 pancreatic/hepatobiliary pathology

• Pancreatic insufficiency: most commonly from chronic pancreatitis or pancreatic cancer. Test w/ stool elastase, chymotrypsin levels, fecal fat, or empiric pancreatic enzyme Rx.

• ↓ bile acids due to ↓ synthesis (cirrhosis), cholestasis (PBC), or s/p ileal resection. Test w/ empiric bile acid replacement therapy.

Inflammatory (⊕ fecal WBC, calprotectin, lactoferrin; ⊕ FOB; fever, abd pain)

• Infections: chronic C. diff, Entamoeba histolytica, Yersinia, CMV, TB especially in immunocompromised hosts. CMV, C. diff notorious for causing exacerbations of IBD.

• Inflammatory bowel disease (Crohn’s, UC); fecal calprotectin helpful for ruling out IBD

• Radiation enteritis, ischemic colitis, neoplasia (colon cancer, lymphoma)

DYSMOTILITY & NUTRITION

Functional GI disease (~30 types per Rome IV criteria; Gastro 2016;150:1257)

• Recurrent GI sx caused by disorders of gut-brain interaction rather than structural cause

• Irritable bowel syndrome (IBS) (JAMA 2015;313:949; Gastro 2015;149:1399 & 2018;154:1140)

Abd discomfort for 6+ mos a/w ≥2: improves w/ defecation, Δ stool frequency, Δ stool form

IBS-C (constipation predominant) vs. IBS-D (diarrhea predominant) vs. IBS-M (mixed) vs. IBS-U (unclassified). Sx may be affected by stress, diet, lifestyle, probably microbiome.

Treatment: cog. behavior Rx, probiotics, anti-spasmodics, exercise, neuromodulators (eg, TCA, SSRI), Δ diet (↓ fermentable carbs w/ low FODMAP diet, lactose-free diet)

IBS-C: ↑ fiber, laxatives (lubiprostone, linaclotide, tegaserod, tenapanor), biofeedback

IBS-D: loperamide, rifaximin, eluxadoline, bile acid sequestrants, alosetron

• Cyclic vomiting syndrome (CVS): acute recurrent vomiting; a/w marijuana use, personal or FHx of migraine. Acute Rx: antiemetics, IVF, sumatriptan (1^st line, followed by aprepitant x 3 d), BDZs; prevention: TCAs/AEDs; avoid marijuana.

Gastroparesis (Nat Rev Dis Primers 2018;4:41)

• Delayed gastric emptying w/o mechanical obstruction, typically p/w nausea (>90%), vomiting (>80%), early satiety (60%), postprandial fullness/pain

• Etiol: DM, post-surg, post-viral, crit. illness, Parkinson’s, opiates, CCB, anti-cholin, idiopath

• Dx: r/o mechanical cause then gastric emptying scintigraphy; (⊕ if retained solids >4 h)

• Treatment: prokinetics (metoclopramide or erythromycin), antiemetics for sx; feeding tube if refractory; consider pyloromyotomy, botox injection, pyloroplasty, or gastric stimulator

Paralytic ileus of the colon & small bowel (Dis Colon Rectum 2021;64:1046)

• Definition: loss of intestinal peristalsis in absence of mechanical obstruction

• Abd discomfort & distention, ↓ or absent bowel sounds, ± N/V, hiccups

• Typically in elderly, hospitalized, ill Pts; precipitated by: intra-abd process (surgery, pancreatitis, peritonitis, intestinal ischemia), severe illness (eg, sepsis), meds (opiates, CCB, anticholin.), metab/endo abnl (thyroid, DM, kidney failure, liver failure, hypoK), spinal cord compression/trauma, neurologic d/o (Parkinson’s, Alzheimer’s, MS)

• KUB/CT w/ colonic dilatation (in ileus, dilated loops of SB) w/o mech obstruction; cecal diam >12 cm a/w high-risk perf in Ogilvie’s syndrome (colonic pseudo-obstruction)

• Treatment: NPO, avoid offending meds, IV neostigmine (monitor for bradycardia), methylnaltrexone; bowel decompression w/ NGT, rectal tube, nutrition support. Ogilvie’s only: colonoscopic decompression; if refractory, colostomy or colectomy.

Constipation (Annals 2015;162:ITC1, Nat Rev Dis Primers 2017;3:17095; JAMA 2019;322:2239)

• Defined as dissatisfaction w/ defecation or (per Rome IV): ≥2 of following during last 3–6 mos ≥25% of the time: straining, lumpy/hard stools, incomplete evacuation, sensation of anorectal obstruction, manual maneuvers to facilitate defecation, stool frequency <3/wk

• Primary etiologies: slow transit vs. pelvic floor dyssynergia

• Secondary etiologies (4 Ms; JAMA 2016:315:185)

Mech obstruction: malignancy, compression, rectocele, strictures

Meds: opioids, TCAs, anticholinergics, CCB, NSAIDs, diuretics, Ca²⁺, Fe, low fiber diet

Metabolic/endo: DM, hypothyroid, uremia, preg, panhypopit, porphyria, ↑ Ca, ↓ K, ↓ Mg

Myopathy/Neuro: Parkinson’s, Hirschsprung’s, amyloid, MS, spinal injury, dysautonomia

• Dx: H&P w/ DRE. Labs: consider CBC, electrolytes w/ Ca, TSH. Colonoscopy if alarm sx. Anorectal manometry/balloon expulsion test; colonic transit study; defecography.

• Treatment: 1^st line: ↑ fluid, fiber, & exercise; emollient laxative (docusate) to soften stool.

2^nd line: Bulk laxatives (psyllium, methylcellulose) to ↑ colonic residue, ↑ peristalsis. Stimulant laxatives (senna, castor oil, bisacodyl) to ↑ motility & secretion. Osmotic laxatives (Mg, NaPO₄ [avoid in CKD], PEG) to ↑ H₂O in colon.

3^rd line: Enema/suppository (phosphate, mineral oil, tap water, soapsuds, bisacodyl)

After above failed: linaclotide ↑ stool freq, ↓ straining/bloating (Am J Gastro 2018;113:105).

Lubiprostone (↑ secretion); methylnaltrexone and alvimopan for opioid-induced.

Plecanitide (cGMP agonist) for chronic idiopathic constipation (Gastroenterol 2016;150:S317)

Nutrition in critical illness (also see “Mech Ventilation”) (Crit Care 2015;19:35)

• Enteral & parenteral with similar clinical outcomes (Lancet 2018;391:133)

• Enteral (EN): starting w/in 48 h of ICU admit may ↓ infection & mortality. Contraindic. if bowel obstruction, major GIB, uncontrolled shock. Possible complic: ischemic bowel b/c ↑ demand for splanchnic blood, aspiration PNA, metabolic abnormality.

• Parenteral (PN): start after 7 d if unable to tolerate EN; no clear benefit to early initiation. Contraindic: hyperosmolality, severe electrolyte disturbances, severe hyperglycemia; sepsis is relative contraindication. Complications: hyperglycemia, sepsis (↑ risk of fungal infections), catheter-associated thrombus, refeeding syndrome, abnl LFTs (steatosis, cholestasis, gallbladder sludge due to lack of enteric stimulation).

DISORDERS OF THE COLON

DIVERTICULOSIS

Definition & pathophysiology (Aliment Pharm Ther 2015;42:664)

• Acquired herniations of colonic mucosa & submucosa in areas where vasa recta penetrate

• Abnormal motility and ↑ intraluminal pressure cause protrusion of colonic wall

Epidemiology

• Risk factors: ↓ fiber, chronic constipation, obesity, smoking, physical inactivity, EtOH, NSAIDs, ↑ age (10% if <40 y; 50–66% if >80 y); ↑ red meat consumption

• Left side (90%, mostly sigmoid) >R side of colon (except in Asia where 75–85% R-sided)

Clinical manifestations

• Usually asx; 5–15% develop diverticular hemorrhage (see “GIB”) and 10–25% diverticulitis

• Limited data for ↑ fiber diet or avoiding nuts/seeds (Thera Adv Gastro 2016;9:213)

DIVERTICULITIS

Pathophysiology (NEJM 2007;357:2057; Gastro 2015;149:1944)

• Retention of undigested food and bacteria in diverticulum → fecalith formation → obstruction → compromise of diverticulum’s blood supply, infection, microperforation

• Uncomplicated (75%): microperforation → localized infection, LLQ pain, fever, ↑ WBC

• Complicated (25%): macroperf → abscess, peritonitis, fistula (65% w/ bladder), obstrxn

Clinical manifestations

• LLQ abdominal pain, fever, nausea, vomiting, constipation or diarrhea

• PEx ranges from LLQ tenderness ± palpable mass to peritoneal signs & septic shock

• Ddx includes IBD, infectious colitis, PID, tubal pregnancy, cystitis, colorectal cancer

Diagnostic studies

• Abdominal CT (I⁺O⁺): diverticula, bowel wall thickening, pericolic fat ± abscess, fistula

• Colonoscopy contraindic. acutely as ↑ risk of perforation; for Pts w/o colonoscopy in the past year, perform 6–8 wks after to r/o neoplasm

Treatment (JAMA 2017;318:291; NEJM 2018;379:1635; Gastro 2021;160:906)

• Mild: outPt Rx indicated if Pt has few comorbidities and can tolerate POs

PO abx: (MNZ + FQ) or amox/clav for 7 d; liquid diet until clinical improvement

No abx is noninferior to abx in uncomplicated diverti (Clin Gastroenterol Hepatol 2021;19:503)

• Severe: inPt Rx if cannot take POs, narcotics needed for pain, or complications

NPO, IVF, NGT (if ileus); IV abx (GNR & anaerobic coverage; eg, CTX/MNZ or pip-tazo)

• Abscesses >4 cm should be drained percutaneously or surgically

• Surgery: if progression despite med Rx, undrainable abscess, free perforation

After source control, 4 d abx may be sufficient (NEJM 2015;372:1996)

Resection for recurrent bouts of diverticulitis on a case-by-case basis

Consider lower threshold for urgent & elective surgery for immunocompromised Pts

Prevention (Gastro 2021;160:906)

• Avoid smoking and NSAIDs; insufficient evidence to recommend mesalamine or rifaximin

• Risk of recurrence 10–30% w/in 10 y of 1^st episode; nuts, seeds ∅ increase risk

POLYPS

Pathophysiology & epidemiology (NEJM 2016;374:1065)

• Accumulation of mutations in colonic epithelial cell DNA affecting oncogenes & tumor suppressor genes → tumor initiation (formation of adenoma; APC loss of fxn) → tumor progression (adenoma → carcinoma; K-ras gain of fxn, DCC, p53 loss of fxn)

• Risk factors: ↑ age, FHx (sporadic in 1° relatives, Lynch, FAP), IBD, ↑ dietary fat, central adiposity, ↑ EtOH, ↓ fiber, ↑ red meat, smoking, DM

• Protective factors: ↑ physical activity, ASA/NSAIDs, Ca²⁺ intake, HRT, ↓ BMI; possibly ↑ fiber, vitamin D, fish oil, statins, selenium

• Neoplastic polyps: adenomas (tubular, villous, tubulovillous dysplasia), sessile serrated adenomas/polyps (concern for interval CRC), carcinomas

• Non-neoplastic polyps: hyperplastic, juvenile, Peutz-Jeghers (can undergo malignant transformation), inflammatory

CRC screening (JAMA 2021;325:1978)

• Colonoscopy gold standard. Other options: FOBT/FIT yearly, flex sig q5y or flex sig q10y + FIT every year, fecal DNA testing (eg, Cologuard) q3y or CT colonography q5y

• Start screening in average risk Pts at age 45 (typically q10y unless abnl found)

• If ⊕ FHx, start age 40, or 10 y before age of dx in youngest family member, repeat q5y

INFLAMMATORY BOWEL DISEASE

Definition (NEJM 2020;383:2652)

• Ulcerative colitis (UC): inflammation of the colonic mucosa; contiguous, starting at rectum

• Crohn’s disease (CD): transmural inflammation anywhere along GI tract, skip lesions

Epidemiology & pathophysiology (Lancet 2016;387:156 & 2017;390:2769)

• Age of onset 15–30 y; bimodal w/ 2^nd peak at 50–70 y; 1:1 M:F in N America

• Genetic predisposition (↑ Caucasian/Jewish) + environmental risk factors (smoking ↑ risk for CD, defective mucosal barrier) → T cell dysregulation → inflammation

ULCERATIVE COLITIS (Lancet 2018;389:1756; Am J Gastro 2019:114:384)

Clinical manifestations

• Grossly bloody diarrhea, lower abdominal cramps, tenesmus, small, frequent BM

• Extracolonic (>25%): erythema nodosum, pyoderma gangrenosum, aphthous ulcers, uveitis, episcleritis, thromboembolic events (esp. during a flare; Lancet 2010;375:657), AIHA, seroneg arthritis (most common), PSC (↑ risk cholangio CA, CRC)

• Several scores for severity assessment: Truelove & Witts; Mayo Score/DAI; Montreal

Diagnosis

• Colonoscopy: involves rectum (95%) & extends prox., circumfer., & contig. w/in colon

• Location: proctitis (30–60%), L-sided (15–45%) and extensive (pancolitis; 15–35%)

• Appearance: vascularity loss, friable mucosa, diffuse ulceration, pseudopolyps (chronicity)

• Histology: superficial chronic inflammation; crypt abscesses & architectural distortion

• Barium enema with featureless and tubular appearance of colon (leadpipe appearance)

• Flares: ↑ ESR & CRP (not Se or Sp); ⊕ fecal calprotectin helpful in distinguishing IBD vs. IBS and monitoring for IBD flare (Gastro Hep 2017;13:53); must rule out infection

Complications

• Toxic megacolon (5%): colon dilatation (≥6 cm on KUB), colonic atony, systemic toxicity, & ↑ risk of perf. Rx w/ IV steroids & broad-spectrum abx; surgery if needed.

• Stricture (rectosigmoid), dysmotility, anorectal dysfxn after recurrent inflammation

• ↑ Risk of CRC and dysplasia (see below) after 8 years of active disease

• For Pts s/p surgery w/ ileal pouch, may develop pouchitis (inflammation of ileal pouch, up to ½ of Pts). Rx w/ abx (MNZ, cipro), probiotics.

Prognosis

• 50% in remission at any given time. Intermittent exacerbations in 90%; continual active disease in ~18%. Prox progression in 25% at 10 y. Rate of colectomy at 10 y is 24%.

• Mortality rate of severe UC flare is <2%, & overall life expectancy in UC = non-UC Pts

CROHN’S DISEASE (Lancet 2017;389:1741)

Clinical manifestations (Nat Rev Gastro Hep 2016;13:567)

• Abdominal pain, loose/frequent stools (up to 50% ⊕ FOBT), malaise, wt loss

• Mucus-containing, often nonbloody diarrhea

• N/V, bloating, obstipation if presence of obstruction; extracolonic manifestations as in UC

• Several scoring systems: CD Activity Index (CDAI), Harvey-Bradshaw Index

Diagnosis

• Ileocolonoscopy + bx along w/ small bowel assessment (eg, MR-enterography)

• Small bowel/ileitis (~25%), ileocolonic (~50%), colonic (~25%); isolated upper tract rare

• Appearance: nonfriable mucosa, cobblestoning, aphthous ulcers, deep & long fissures

• Histology: transmural inflammation with mononuclear cell infiltrate, noncaseating granulomas (seen in <25% of mucosal biopsies), fibrosis, ulcers, fissures, skip areas

• Montreal classification: age at dx, disease location & behavior (stricturing vs. nonstricturing, penetrating vs. nonpenetrating), plus modifiers for upper tract & perianal disease

Complications

• Perianal disease: fissures, fistulas, skin tags, perirectal abscesses (in 24% of Pts; perianal disease precedes intestinal symptoms)

• Stricture: small bowel, postprandial abd pain; can lead to complete SBO & require surgery

• Fistulas: perianal, enteroenteric, rectovaginal, enterovesicular, enterocutaneous

• Abscess: fever, tender abd mass, ↑ WBC; steroids mask sx, ∴ need high level of suspicion

• Malabsorption: ileal disease/resection: ↓ bile acids abs → gallstones; ↓ fatty acid abs → Ca oxalate kidney stones; ↓ fat-soluble vitamin abs → vit D deficiency → osteopenia

Prognosis

• Variable at 1 y: ~50% in remission, ~20% flare, ~20% low activity, ~10% chronic active

• At 20 y, majority will have required some surgery; overall life expectancy is slightly ↓

MANAGEMENT (Lancet 2017;398:1756; Mayo 2017;92:1088)

Initial evaluation

• H&P (✓ for intestinal & extraintestinal manifestations) and dx studies as above

• Lab: consider CBC/diff, LFTs, iron studies, B12, folate, vit D, ESR, CRP, fecal calprotectin

• Exclude other etiologies: infectious (espec. TB), ischemic colitis, intestinal lymphoma, CRC, IBS, vasculitis, Behçet’s, celiac disease, small intestinal bacterial overgrowth

• R/o infection (esp. TB, HBV, CMV, O&P) before treating with immunosuppressants and biologics (although not all acutely hospitalized Pts w/ IBD need infxn r/o prior to Rx)

Goals of treatment (Ther Adv Gastro 2015;8:143)

• Induce remission of acute flare → maintain remission; mucosal healing 1° goal

• Step-up Rx (least → most toxic) vs. top-down; (strongest → de-escalate) approach; consider early biologic if severe disease

Medical Therapy for IBD (NEJM 2021;385:1302)
Ulcerative Colitis (Am J Gastrol 2019:114:384)
Mild	Rectal mesalamine or glucocorticoids as suppository or enema
Mild- moderate	Oral 5-ASA: many formulations (sulfasalazine, mesalamine, olsalazine, balsalazide) depending on disease location. Used for induction & maintenance of remission. Complications: pancreatitis, abd pain, diarrhea. MMX-budesonide: PO budesonide released throughout colon for flare. 1st-pass metab ↓ systemic steroid adverse effects of steroid.
Moderate- severe	PO prednisone: 40–60 mg w/ taper over several wks to induce remission AZA/6-MP: 0.5–1 mg/kg and uptitrate over several wks for maintenance Complications: BM suppression, lymphoma, pancreatitis, hepatitis ✓ TPMT levels prior to dosing to ↓ risk of generation of toxic metabs. In selected cases, add allopurinol to boost activity in non-responders. Anti-TNF: ↑ remission rate when AZA combined w/ IFX (Gastro 2014;146:392)
Severe or refractory disease (Lancet 2017; 389:1218; NEJM 2016; 374:1754 & 2017; 76:1723; JAMA 2019; 321:156)	IV steroids: 100 mg hydrocort q8h or 16–20 mg methylpred q8h to induce remission w/ plan to taper & switch to non-steroid maintenance. Cyclosporine: for severe flares refractory to steroids, 2–4 mg/kg infusion × 7 d w/ goal to Δ to maintenance medication (eg, AZA/6-MP) Anti-TNF (infliximab, adalimumab & golimumab): for steroid-refractory flares or to maintain remission. Complic: reactivation of TB (✓ PPD prior to Rx) or viral hepatitis; small ↑ risk NHL; lupus-like rxn, psoriasis, MS, CHF. Alternative agents: vedolizumab (α4β7 integrin inhibitor); tofacitinib (JAK inhibitor); ustekinumab (IL-12/23 inhibitor); ozanimod (sphinosine-1- phosphate receptor agonist) Investigational: fecal microbiota transplant; etrolizumab (α4β7 inhibitor)
Crohn’s Disease (JAMA 2021;325:69)
Mild	Oral 5-ASA: for colonic Crohn’s disease Symptom control: loperamide/cholestyramine for diarrhea management.
Mild-mod	PO budesonide: enteric-coated for ileal release (taper over 3 mos)
Moderate- severe	PO prednisone: same as UC, for inducing remission, not maintenance AZA/6-MP: same as UC; ↑ remission w/ AZA+IFX (NEJM 2010;362:1383) MTX: 15–25 mg IM/SC or PO qwk for maintenance; 1–2 mo to take effect
Severe or refractory disease (NEJM 2016; 375:1946)	IV steroids: same as UC, for inducing remission, not maintenance Anti-TNF: infliximab, adalimumab or certolizumab (pegylated); consider combination therapy with AZA/6-MP Alternative agents: vedolizumab (α4β7 integrin inhibitor); ustekinumab (IL-12/23 inhibitor); natalizumab (α4 integrin inhibitor) Investigational: tofacitinib (JAK inhibitor); ozanimod (S-1-P receptor agonist)

Surgery

• UC: colectomy if sx refractory to or intolerable side effects from meds, CRC, perforation, toxic megacolon, uncontrolled hemorrhage. Often ileal pouch-anal anastomosis (IPAA).

• CD: resection if refractory; surgery for strictures; diverting ileostomy for perineal disease

Cancer screening (NEJM 2015;372:1441)

• Colon cancer: risk in UC ~2% at 10 y, ~8% at 20 y, ~18% at 30 y. Similar for pancolonic CD, plus risk of small bowel cancer as well. Dysplasia best marker for risk. Other risk factors include: PSC, ⊕ FHx, greater extent of disease, stricture, & pseudopolyps.

• Surveillance: colonoscopy w/ random bx 8 y after dx to eval for dysplasia, q1–3y thereafter based on risk factors. Chromoendoscopy using dye to stain high-risk lesions for targeted bx may be preferable. If high-grade dysplasia or dysplasia-assoc. lesion/mass → colectomy.

INTESTINAL ISCHEMIA

ACUTE MESENTERIC ISCHEMIA

Definition and causes (NEJM 2016;374:959)

• Reduced or absent blood flow to small intestine, typically caused by arterial (ie, SMA or its branches) occlusion or transient hypoperfusion or less often by venous occlusion

• Arterial embolism (~40–50%): embolic occlusion to SMA (has narrow take-off angle), often in setting of AF, valvular disease incl. endocarditis, atherosclerotic plaque in aorta

• SMA thrombosis (~20–30%): typically due to atherosclerosis at origin of SMA; other risk factors incl. vascular injury from abd trauma, infxn, or mesenteric dissections/aneurysms

• Nonocclusive mesenteric ischemia (~10%): transient intestinal hypoperfusion due to ↓ CO, athero, sepsis, drugs that ↓ gut perfusion (pressors, cocaine, amphetamines)

• Mesenteric venous thrombosis (MVT, ~5%): a/w hypercoag. states, portal hypertension, IBD, malignancy, inflammation (pancreatitis, peritonitis), pregnancy, trauma, surgery

• Focal segmental ischemia of small bowel (<5%): vascular occlusion to small segments of small bowel (vasculitis, atheromatous emboli, strangulated hernias, XRT)

Clinical manifestations

• Arterial occlusion: sudden intense abd pain out of proportion to tenderness on exam

• Venous occlusion: often more insidious in onset, intermittent pain with peaks and valleys

• Nonocclusive: abd distention & pain, n/v, lower GI bleeding due to mucosal sloughing; often occurring after episode of hypoperfusion (eg, cardiac event or shock)

• Exam ranges: unremarkable ± abd distention to peritoneal (infarction); ⊕ FOBT ~75%

Diagnostic studies

• Dx relies on high level of suspicion; rapid dx essential to avoid infarction (occurs w/in hrs)

• Mortality 20 to >70% if bowel infarcted; dx prior to infarction strongest predictor of survival

• Laboratory: often nl; ~75% ↑ WBC; ↑ amylase, LDH, PO₄, D-dimer; ~50% ↑ lactate (late)

• KUB: nl early before infarct; “thumbprinting,” ileus, pneumatosis in later stages

• CT angiography (arterial phase): noninvasive test of choice; venous phase for dx MVT

• Angiography: gold standard; potentially therapeutic; indicated if vasc occlusion suspected

Treatment (NEJM 2016;374:959; World J Emerg Surg 2017;12:38)

• IVF, NPO, optimize hemodynamics (minimize pressors), broad-spectrum abx, anticoagulation w/ heparin ± tPA (for occlusive disease), IV papaverine (vasodilator; for non-occlusive mesenteric ischemia)

• If evidence of peritonitis: to OR for surgical endovascular therapies & bowel resection

• SMA thrombosis: percutaneous (stenting) or surgical revascularization

• SMA embolism: embolectomy (catheter-based aspiration vs. surgical)

• Nonocclusive: correct underlying cause (esp. cardiac)

• Mesenteric venous thrombosis: 3–6 mo anticoag after initial heparinization. Fibrinolysis or thrombectomy typically reserved for Pts w/ hemodynamic instability or refractory sx.

• Focal segmental ischemia: typically surgical resection

CHRONIC MESENTERIC ISCHEMIA

• Pathophysiology: ↓ blood flow to gut typically because of mesenteric atherosclerosis

• Sx: “intestinal angina” = postprandial abd pain, early satiety, & ↓ wt due to fear of eating. If pain becomes constant → could represent acute thrombosis (see above).

• Dx: duplex U/S or CTA; angiography gold stnd; gastric tonometry exercise testing

• Treatment: surgical revascularization (1^st line); angioplasty ± stenting; TPN for nutrition

ISCHEMIC COLITIS

Definition & pathophysiology

• Nonocclusive disease 2° to Δs in systemic circulation or anatomic/fxnal Δs in local mesenteric vasculature; often underlying etiology unknown, frequently seen in elderly

• “Watershed” areas (splenic flexure & rectosigmoid) most susceptible; 25% involve R side; confers worse prognosis (Clin Gastroenterol Hepatol 2015;13:1969)

Clinical manifestations, diagnosis, & treatment

• Usually p/w cramping LLQ pain w/ overtly bloody stool; fever and peritoneal signs should raise clinical suspicion for infarction

• Disease spectrum: reversible colopathy (35%), transient colitis (15%), chronic ulcerating colitis (20%), resulting stricture (10%), gangrene (15%), fulminant colitis (<5%)

• Dx: flex sig/colonoscopy or CT abd/pelvis to make diagnosis; r/o IBD, infectious colitis

• Treatment: bowel rest, IV fluids, broad-spectrum abx, serial abd exams; surgery for infarction, fulminant colitis, hemorrhage, failure of med Rx, recurrent sepsis, stricture

• Resolution w/in 48 h w/ conservative measures occurs in >50% of cases

PANCREATITIS

ACUTE PANCREATITIS (Lancet 2020; 396:726; JAMA 2021;325:382)

Pathogenesis

• Pancreatic duct and acinar injury via direct or indirect toxicity → impaired secretion and premature activation of digestive enzymes → autodigestion and acute inflammation

Etiologies (JAMA 2021;325:382)

• Gallstones (40%): ♀ >♂; usually due to small stones (<5 mm) or microlithiasis/sludge

• Alcohol (30%): ♂ >♀; 4–5 drinks/day over ≥5 yrs; usually chronic w/ acute flares

• Metabolic: hypertrig. (2–5%; TG >1000; type I & V familial hyperlipemia); hyperCa

• Drugs (<5%): 5-ASA, 6-MP/AZA, ACEI, cytosine, didanosine, dapsone, estrogen, furosemide, isoniazid, MNZ, pentamidine, statins, sulfa, thiazides, tetracycline, valproate

• Anatomic: divisum, annular pancreas, duodenal duplication cysts, Sphincter of Oddi dysfxn

• Autoimmune (vide infra)

• Familial: suspect if age <20 y; (often a/w mutation in PRSS1, SPINK1 or CFTR gene)

• Infections: ascaris, clonorchis, coxsackie, CMV, EBV, HIV, mumps, mycoplasma, TB, toxo

• Ischemia: shock, vasculitis, cholesterol emboli

• Neoplastic: panc/ampullary tumors, mets (RCC most common, breast, lung, melanoma)

• Post ERCP (5%): Ppx w/ PR indomethacin can ↓ sx; temporary panc duct stent if high risk

• Trauma: blunt abdominal trauma, post-pancreatic/biliary surgery

Clinical manifestations

• Epigastric abdominal or LUQ pain (90%), only ½ w/ bandlike pain radiating to back

• 10% pain-free (due to analgesic/steroid use, immunosuppressed, ΔMS, ICU); ∴ ✓ lipase in unexplained shock, periumbilical or flank (Cullen or Grey Turner signs) bruising

• N/V (90%), abd tenderness/guarding, ↓ bowel sounds, jaundice if biliary obstruction

• Ddx: acute cholecystitis, perforated viscus, SBO, mesenteric ischemia, IMI, AAA leak, distal aortic dissection, ruptured ectopic pregnancy

• Early phase (<1 wk): possible SIRS ± organ failure; late (>1 wk): local complications (qv)

Diagnostic studies (Am J Gastro 2013;108:1400)

• Dx requires 2 of 3: characteristic abd pain; lipase or amylase >3× ULN; ⊕ imaging

• Laboratory: levels of amylase & lipase do not correlate w/ severity of disease

↑ amylase: rises w/in hrs, normalizes w/in 3–5 d (faster than lipase)

false ⊖: 20% EtOH pancreatitis; 50% hypertriglyceridemia (assay interference)

false ⊕: other abd or salivary gland process, acidemia, ↓ GFR, macroamylasemia

↑ lipase: longer t_½ than amylase

>3× ULN 99% sensitive, 99% specific for acute pancreatitis

>10k has 80% PPV for biliary dx, 99% NPV for EtOH (Dig Dis Sci 2011;56:3376)

false ⊕: renal failure, other abd process, DKA, HIV, macrolipasemia

ALT >3× ULN has 95% PPV for gallstone pancreatitis (Am J Gastro 1994;89:1863)

• Imaging studies (Am J Gastro 2013;108:1400)

Abd U/S: bowel gas often obscures pancreas visualization; however should be ordered to r/o biliary etiology (ie, gallstones, BD dilatation)

Abd CT: not rec for first 3 days (local complic. not yet visible & concern for AKI w/ IV contrast). However, if persistent pain and/or clinical deterioration after 48–72 h, CT(I⁺) useful to r/o local complications (necrosis, fluid collections).

MRI/MRCP: Can detect necrosis, assess for stones & ductal disruption earlier than CT

Endoscopic U/S (EUS): useful for occult biliary disease (microlithiasis)

Severity (Gut 2013;62:102; Gastro 2018;154:1096)

• Severity defined by presence of organ failure (AKI, resp failure, GIB, shock) & local or systemic complic. (panc necrosis, fluid collections, gastric outlet obstrxn, splenic & PVT).

Mild: 80% of cases; no organ failure or local/systemic complications; low mortality

Moderate: transient (<48 h) organ failure ± local/systemic complications, high morbidity

Severe: persistent (>48 h) organ failure, very high mortality

Prognosis (NEJM 2016;375:1972)

• Ranson’s, APACHE II: predict severity at 48 h using multiple physiolog. criteria; poor PPV

• BISAP: simple 5-point scoring system (BUN >25, impaired MS, SIRS, age >60 y, pleural effusion) used w/in first 24 h; score ≥3 predicts ↑ risk of organ failure, mortality

• CTSI: CT data at 48–72 h (fluid collect., necrosis) to predict mortality; lags behind clinical sx

Treatment (Am J Gastro 2017;112:797; JAMA 2020;323:2331)

• Fluid resusc.: aggressive in 1^st 24 hrs, even if mild. 20 mL/kg IVB → 3 mL/kg/hr. Goal ↓ BUN & Hct over 12–24 h. ✓ UOP (goal 0.5–1 cc/kg/hr); LR superior to NS (↓ SIRS; avoid if ↑ Ca).

• Nutrition (NEJM 2014;317:1983)

Early enteral feeding encouraged, though not superior to oral feeding at 72 h

Mild: Start feeding once without N/V or ileus; may not need to be completely pain free. Low-fat low-residue diet as safe as liquid diet and a/w shorter LOS.

Severe: early (w/in 48–72 h) enteral nutrition indicated and preferred over TPN b/c ↓ infectious complications. Nasogastric non-inferior to nasojejunal feeding.

• Analgesia: IV opioids (monitor respiratory status, adjust dosing if ↑ renal impairment)

• Gallstone pancreatitis: urgent (w/in 24 h) ERCP w/ sphincterotomy if cholangitis, sepsis, or Tbili ≥5. If mild, CCY during initial hosp. to ↓ risk of recurrence (Lancet 2015;386:1261); defer surgery if necrotizing panc. until improvement in inflam. & fluid collections.

• Hypertriglyceridemia: insulin gtt (activates lipoprotein lipase), fibrates, ± apheresis

• No role for Ppx abx in absence of infectious complications (World J Gastro 2012;18:279)

Complications

• Systemic: ARDS, abdominal compartment syndrome, AKI, GIB (pseudoaneurysm), DIC

• Metabolic: hypocalcemia, hyperglycemia, hypertriglyceridemia

• Fluid collections:

Acute fluid collection: seen early; not encapsulated; asymptomatic; resolve in 1–2 wk

Pseudocyst: ~4 wk after initial attack, encapsulated. No need for Rx if asx (regardless of size/location). If sx → endoscopic (Gastro 2013;145:583) vs. perc/surg drainage.

• Pancreatic necrosis: Nonviable pancreatic tissue. CT-guided FNA if infection suspected.

Sterile necrosis: if asx, can be managed expectantly, no role for Ppx abx

Infected necrosis: most often GN gut organism; high mortality. Rx w/ carbapenem, pip/tazo, or [(3^rd gen ceph or FQ) + MNZ]. If stable, defer drainage to >4 wk to allow liquefication & WOPN (qv). If sx or unstable, perc. drainage & minimally invasive surgical debridement or endoscopic necrosectomy superior to open necrosectomy.

WOPN (walled off panc. nec.): fibrous wall surrounds necrosis over ≥4 wk; endoscopic or perc. drainage (preferred over open necrosectomy) if infected or symptomatic

• Peripancreatic vascular complications: pseudoaneurysm, abdominal compartment syndrome, splanchnic venous thrombosis (splenic vein most common site)

CHRONIC PANCREATITIS (Lancet 2020;396:499)

Pathogenesis & etiology (Gastro 2013;144:1292; JAMA 2019;322:2422)

• Often recurrent acute attacks → inflam infiltrate → fibrosis → loss of exocrine & endocrine tissue. Pancreatic insufficiency (DM, fat/protein malabsorption) when 90% panc fxn lost.

• TIGAR-O: Toxins (60–80% due to EtOH; smoking), Idiopathic, Genetic (PRSS1, SPINK1, CFTR, CTRC, CASR), Autoimmune, Recurrent panc., Obstruction

Clinical manifestations

• Epigastric pain, N/V; over time can be painless; signs of exocrine insuff (steatorrhea, wt loss) or endocrine insuff (DM: polydipsia, polyuria); 13× ↑ risk of pancreatic cancer

Diagnostic studies (Pancreas 2014;43:1143; Am J Gastro 2020;115:322)

• Labs: amylase/lipase ↑ early, may be nl later. ⊕ fecal fat, ↓ stool elastase & A1AT. Mixed TG breath test alternative to stool elastase. ✓A1c, consider IgG4/ANA & genetic testing if young or ⊕ FHx. If dx w/ CP, measure baseline fat-soluble vitamins (ADEK).

• Imaging: Ca²⁺ on KUB/CT. ERCP/MRCP/EUS: high sens for dx; may show stricture, dilated ducts. IV secretin stim w/ MRI may ↑ dx yield. Panc fxn testing not widely available.

Treatment (JAMA 2019;322:2422; Lancet 2020;396:499)

• Pancreatic enzyme replacement (may ↓ pain by reducing CCK). Rx routine vitamin D & Ca.

• Pain control: smoking & EtOH cessation, analgesics (start with non-opioids; eg, pregabalin), endoscopy (stone removal or stenting strictures), celiac nerve plexus block, surgery

AUTOIMMUNE PANCREATITIS

Pathogenesis (Am J Gastro 2018;113:1301)

• Type 1: lymphoplasmacytic sclerosing panc. w/ dense fibrosis; ↑ IgG4; high relapse

• Type 2: idiopathic duct-centric pancreatitis; minimal ↑ IgG4; a/w IBD; fewer relapses

Clinical manifestations

• Abdominal pain, can p/w obstructive jaundice and panc mass mimicking panc Ca

• Can be primary, or in a/w IgG4 cholangiopathy, salivary gland disease (eg, Sjögren’s), mediastinal or RP fibrosis, interstitial nephritis, autoimmune thyroiditis, UC/PSC, RA

Diagnosis

• Labs: cholestatic LFTs (↑ Aϕ >AST/ALT), ↑ γ-globulins and IgG4, ⊕ ANA, RF

• HISORt criteria: Histology, Imaging (“sausage pancreas,” bile duct stricture), Serology, other Organ involvement, Response to therapy

Treatment

• Glucocorticoids 1^st-line; immunomod. (AZA, MMF, cyclophosphamide, rituximab) if relapse

ABNORMAL LIVER TESTS

Tests of hepatocellular injury or cholestasis (J Clin Transl Hepatol 2017;5:394)

• Aminotransferases (AST, ALT): intracellular enzymes released 2° necrosis/inflammation

ALT more specific for liver than is AST (heart, skeletal muscle, kidney, brain, RBC/WBC)

↑ levels seen w/ most types of hepatocellular injury; AST >ALT → MSK injury, MI

• Alkaline phosphatase (Aϕ): enzyme bound in hepatic canalicular membrane ↑ levels seen w/ biliary obstrxn, intrahepatic cholestasis or infiltration of the liver also found in bone, intestines, kidney, placenta; confirm from liver w/: ↑ GGT (or ↑ 5′-NT)

• Bilirubin: product of heme metab (unconjugated, “indirect”) carried by alb to liver where taken up for conjugation (“direct”) to make soluble, then excreted into bile.

↑ indirect hyperbili seen with hemolysis, enzymatic disorders (eg, Crigler-Najjar, Gilbert’s)

↑ direct hyperbili seen with cholestasis, enzymatic disorders (eg, Dubin-Johnson, Rotor’s)

jaundice seen when bili >2.5 mg/dL (esp. in sclera or under tongue); direct ↑ urine bili

Tests of hepatic function

• Albumin: marker for liver protein synthesis, can help differentiate acute vs. chronic liver failure, may be normal in acute hepatocellular injury (t_1/2 ~15–18 d)

• Prothrombin time (PT): depends on synthesis of coag factors by liver (except FVIII); b/c t_1/2 of some factors (eg, V, VII) is short, ↑ PT can occur w/in hrs of liver dysfxn

• R-value = ratio of ALT:Aϕ normalized to ULN for each = (ALT/ULN) ÷ (Aϕ/ULN)

R >5 suggests hepatocellular injury, <2 suggests cholestatic injury, 2–5 suggests mixed

Acute mild-to-moderate elevation in ALT/AST (<15× ULN)

• Assess risk of EtOH/drug/toxin: H&P; in EtOH AST:ALT ratio >2:1

• Obtain abdominal imaging to r/o cirrhosis, congestion, or biliary obstruction (mixed LFTs)

• Other infectious etiologies: tick borne illnesses, CMV/EBV, COVID-19, others

• Can be initial manifestation of chronic etiologies noted below

Chronic mild-to-moderate elevation in ALT/AST (<15× ULN)

• Viral hepatitis: ✓ HBsAg, anti-HBs, anti-HBc, anti-HCV, IgM anti-HAV

• NAFLD: consider BMI, ✓ lipid panel, Hb_A1c, liver U/S or elastography

• Other etiologies of cirrhosis (qv)

Hemochromatosis: ✓ TIBC, serum iron, serum ferritin

Wilson disease: serum ceruloplasmin, urine Cu

α-1 antitrypsin (can cause liver disease w/o lung involvement)

• Chronic autoimmune hepatitis ✓ ANA, ASMA, anti-LKMA, IgG, SPEP

• TSH (both hypo & hyperthyroidism associated with abnormal LFTs), celiac disease

• If workup negative, consider biopsy

Acute severe elevation in ALT/AST (>1000)

• Massive elevations (>5000) usually due to ischemic injury or drug-induced hepatitis

• Ischemia: hypotension, shock or severe HF (often >50× ULN), Budd-Chiari: usually diagnosed based on clinical hx, U/S w/ Doppler; ratio ALT:LDH <1.5 if ischemic because of concomitant ↑ LDH (vs. ratio >1.5 w/ toxins, viruses)

• Meds/toxins: acetaminophen, meds (eg, INH, amio, nitrofuratonin), OTC/herbal, cocaine (nb, EtOH should not produce this degree of elevation). Obtain acet. level, tox screen.

• Acute viral infection: hepatitis A–E or reactivation of HBV, EBV/CMV

• Acute autoimmune hepatitis (qv): ✓ IgG, ANA, ASMA

• Acute biliary obstruction (often with sig drop in ALT/AST the next day, Aϕ takes longer to rise & fall): start w/ liver U/S, if unrevealing obtain CT or MRCP

• Rhabdomyolysis and heat stroke

HEPATITIS

VIRAL

Hepatitis A (ssRNA; 30–45% of acute viral hepatitis in U.S; MMWR 2018;67:1208)

• Transmission & RFs: fecal–oral route; contam. food, water, shellfish; daycare ctr; intl travel

• Incubation: 2–6 wk; no chronic carrier state; once antibody forms → lifelong immunity

• Sx: ↓ appetite, malaise, fever, N/V, RUQ pain, jaundice; rarely ALF (↑ w/ chronic HCV)

• Diagnosis: acute hepatitis = ⊕ IgM anti-HAV; past exposure = ⊕ IgG anti-HAV (⊖IgM)

• Rx for acute HAV: supportive care; refer to liver txplnt center if acute liver failure

• Vaccinate if: MSM, IVDU, chronic liver disease, international travel; Havrix (2 doses)

Hepatitis B (dsDNA; ~45% of acute viral hepatitis in U.S.; JAMA 2020;324:2452)

• Transmission: blood (IVDU, transfusion), sexual, perinatal (vertical)

• Incubation: 6 wk–6 mo (mean 12–14 wk)

• Acute infxn: 70% subclinical, 30% jaundice, <1% acute liver failure (up to 60% mortality)

• Chronic infxn: HBsAg ⊕ >6 mo in <5% of adult-acquired (↑ if immunosupp), >90% of perinatal; ~40% chronic HBV → cirrhosis (↑ risk w/ HCV, HDV, or HIV coinfxn, EtOH)

• HCC: ↑ risk if cirrhosis, ⊕ FHx HCC, African >20 y old, Asian ♂ >40 y old or ♀ >50 y old, or >40 y old w/ ↑ ALT ± HBV DNA >2000. Screen w/ AFP & U/S q6mo.

• Extrahepatic syndromes: PAN (<1%), membranous nephropathy, MPGN, arthritis

• Serologic and virologic tests (screening guidelines: Hepatology 2018:67:1560)

HBsAg: appears before sx; used to screen blood donors; persists >6 mo = chronic HBV

HBeAg: evidence of viral replication and ↑ infectivity

IgM anti-HBc: 1^st Ab to appear; indicates acute infection window period = HBsAg becomes ⊖, anti-HBs not yet ⊕, anti-HBc only clue to infxn

IgG anti-HBc: indicates previous (HBsAg ⊖) or ongoing (HBsAg ⊕) HBV infection

anti-HBe: indicates waning viral replication, ↓ infectivity

anti-HBs: indicates resolution of acute disease & immunity (sole marker after vaccination)

HBV DNA: presence in serum correlates w/ active viral replication in liver

^*Precore mutant: HBeAg not made, but anti-HBe can develop due to x-reactivity w/ HBcAg; a/w ↑ HBV DNA

• Treatment for acute HBV: supportive; hospitalize for Δ MS or ↑ INR (liver transplant center); consider antiviral therapy if severe or protracted course

^*ALT ULN <35 U/L for ♂, <25 U/L for ♀. Adapted from Hepatology 2018;67:1560

• When to treat chronic HBV with anti-virals? (1) immune active phase; (2) HBeAg ⊖ chronic hepatitis B; (3) cirrhosis w/ HBV DNA ≥2K; (4) decomp. cirrhosis due to hep B; (5) acute liver failure due to acute hepatitis B; (6) special pop: preg (3^rd trimester w/ HBV DNA ≥200k), inactive carriers treated w/ immunosuppression, HCC, HCV co-infection

• Entecavir or tenofovir: nucleo(s/t)ide analogs, well tolerated, low resistance; at 5 y, HBeAg seroconversion is 30–40% & loss of HBsAg is 5–10% (Lancet Gastro Hep 2016;1:185). Tenofovir preferred if h/o lamivudine resistance; no known tenofovir resistance to date.

• Rx duration: (1) HBeAg ⊕ immune active w/o cirrhosis: if seroconversion (HBeAg ⊖, anti- HBe ⊕), can stop after 1 y if ALT nl & HBV DNA suppressed or until HBsAg clears; (2) HBeAg ⊖ immune reactivation: indefinite; (3) cirrhosis: indefinite

• If undergo liver transplant: HBIG + nucleo(s/t)ide analogue effective in preventing reinfection

• HIV/HBV coinfection: Rx w/ 2 drugs active against both HBV & HIV (https://aidsinfo.nih.gov)

• Immunosuppression: prior to initiating chemoRx, anti-TNF, rituximab, steroids (>20 mg/d >1 mo), screen for HBV; Rx if mod-to-high risk of reactive (incl anti-HBs ⊕ getting rituximab)

• Postexposure (risk infxn ~30%) Ppx: HBIG → vaccine (if unvac or known nonresponder)

Hepatitis C (ssRNA; ~10% of acute viral hepatitis in U.S.; Lancet 2015;385:1124)

• Transmission: blood (IVDU, transfusion before 1992) >sexual; 20–30% w/o clear precipitant

• Incubation: 1–5 mo; mean 6–7 wk

• Acute infxn: 80% subclinical; 10–20% sx hepatitis w/ jaundice; acute liver failure rare; prob of spont clearance a/w IL28B & HLA class II genotypes (Annals 2013;158:235)

• Chronic: up to 85% → chronic hepatitis, 20–30% of whom develop cirrhosis (after ~20 y)

↑ risk of cirrhosis in men, EtOH, HIV; HCC in 1–4% of Pts w/ cirrhosis per year

• Extrahepatic syndromes: mixed cryoglobulinemia, porphyria cutanea tarda, lichen planus, leukocytoclastic vasculitis, thyroiditis, MPGN, IPF, NHL and monoclonal gammopathies

• Serologic, virologic, & genetic tests (screen all adults [✓ anti-HCV] JAMA 2020;323:970)

anti-HCV (ELISA): ⊕ in 6 wk, does not = recovery or immunity; can be ⊖ after recovery

HCV RNA: ⊕ w/in 2 wk, marker of active infection

HCV genotype (1–6): guides duration & predicts response to Rx; geno. 3 a/w ↑ risk HCC

• Dx: acute hepatitis = ⊕ HCV RNA, ± anti-HCV; resolved = ⊖ HCV RNA, ± anti-HCV; chronic = ⊕ HCV RNA, ⊕ anti-HCV

• Treatment indications (www.hcvguidelines.org) (Lancet 2019;393:1453; Hepatology 2020;71:686)

Acute: if no spont. clearance at 12–16 wk, can Rx w/ same regimens for chronic HCV

Chronic: ↓ HCC & mortality. Recommended for all except if ↓ life expectancy.

Recommended First-Line Oral Direct-Acting Antiviral (DAA) Regimens
Regimen (simplified)	Indication
Sofosbuvir & velpatasvir	Genotypes 1–6, 12 weeks Rx
Glecaprevir & pibrentasvir	Gentotypes 1–6; 8 weeks Rx
Simplified treatment: adults w/ HCV w/o cirrhosis or w/ compensated cirrhosis & no prior HCV treatment; cannot have HIV, HBsAg ⊕, pregnancy, HCC, ESRD, or liver transplant; if decompensated or previously treated, refer to GI for assistance.

Based on Hepatology 2020;71:686. Antiviral classes: RNA polymerase inhibitor (“…buvir”); NS5a inhibitor (“…asvir”); NS3/4A protease inhibitor (“…previr”).

• Monitoring on Rx: CBC, INR, LFTs, GFR, HCV VL prior to starting Rx. PIs contraindicated if decomp. liver dx (ascites, encephalopathy) or CPS ≥7. D/c Rx if jaundice, N/V, weakness, 10x ↑ in ALT, or significant ↑ in bili, Aϕ, INR after 4 wks.

• Goal is sustained virologic response (SVR) = Ø viremia 12 wks after completion of Rx. Success depends on genotype but SVR rates >90% with current regimens.

• Special populations (HCV/HIV coinfection, decompensated cirrhosis, s/p liver transplant, renal impairment): www.hcvguidelines.com for updated recs on mgmt

• Vaccinate all chronic HCV patients against HBV and HAV if not immune

• Postexposure (needlestick risk ~3%) Ppx: none, although sofosbuvir-velpatasivir under investigation in clinical trial; if HCV RNA → ⊕, consider Rx w/in 3 mos

Hepatitis D (RNA; Gastro 2019:156;461)

• Transmission: blood or sexual; endemic in Africa & E. Europe. Generally requires host to already have HBV infxn in order to cause co-infection or superinfection; in rare cases (immunosupp s/p liver transplant) can replicate autonomously.

• Natural hx: acute HBV–HDV coinfection resolves in >80% of cases; however, acute HDV superinfection leads to chronic HBV–HDV in most cases (↑ progression to cirrhosis, HCC)

• Dx: ✓ total anti-HDV once in all HBV-infected patients, if antibody ⊕, confirm w/ HDV RNA

Hepatitis E (ssRNA; World J Gastro 2016;22:7030; Gastro Clin N Am 2017;46:393)

• Most common cause of acute viral hepatitis in endemic areas

• Transmission: fecal–oral; travelers to central & SE Asia, Africa and Mexico, exposure to swine. ↑ rates of cases in Europe.

• Natural hx: often asx, sometimes causes acute hepatitis w/ ↑ mort. (10–20%) if pregnant; rarely can become chronic in transplant Pts

• Dx: IgM anti-HEV (through CDC), HEV RNA; treatment is generally supportive only

• Extrahepatic sx: arthritis, pancreatitis, anemia, neuro (GBS, meningoencephalitis)

Other viruses (human pegivirus, CMV, EBV, HSV, VZV)

AUTOIMMUNE HEPATITIS (AIH)

Classification (J Hep 2015;62:S100, World J Gastro 2015;21:60)

• Type 1: anti-smooth muscle Ab (ASMA), ANA; anti-soluble liver antigen (anti-SLA), a/w more severe disease and relapsing disease (found in 10–30% Pts), IgG often ↑

• Type 2: anti-liver/kidney microsome 1 (anti-LKM1); anti-liver cytosol type 1 (anti-LC-1)

• Overlap syndrome: AIH + PBC (suspect if ⊕ AMA or ⊕ histology → “autoimmune cholangitis”)

• Drug-induced: minocycline, nitrofurantoin, infliximab, hydralazine, α-methyldopa, statins

Diagnosis and treatment (J Hepatol 2015;63:1543, Clin Liver Dis 2015;19:57)

• 70% female; bimodal presentation in the second and fifth decades of life

• 40% present w/ severe AIH (3% ALF) w/ ALT >10 × ULN; 34–45% asx

• Extrahepatic syndromes: thyroiditis, arthritis, UC, Sjögren’s, Coombs’ ⊕ anemia, celiac

• Dx: scoring system combining serologies, ↑ IgG, Ø viral hepatitis, & liver bx (interface hepatitis & lymphoplasmacytic infiltrate) has high Sp & mod Se (Dig Dis 2015;33[S2]:53)

• Rx: (1) ALT or AST >10× ULN (2) IgG >2× ULN + ALT >5× ULN (3) bridging/multiacinar necrosis (4) cirrhosis w/ inflammation on biopsy (5) AST/ALT >2x ULN + symptoms

• Induction Rx: (1) prednisone monoRx; (2) prednisone + AZA, or (3) budesonide (if non-cirrhotic) + AZA → 65–80% remission (asx, nl LFTs, bili, & IgG, none-to-minimal interface hepatitis); taper steroids as able; relapse rate of 50–80% (J Hep 2015;62:S100)

• Nonresponders or AZA intolerant: cyclosporine, tacrolimus, MMF, rituximab, infliximab

OTHER CAUSES OF HEPATITIS OR HEPATOTOXICITY

Alcohol-associated hepatitis (J Hepatol 2016;69:154; Am J Gastro 2018;113:175)

• Sx: progressive jaundice, tender hepatomegaly, fever, ascites, GIB, encephalopathy

• Labs: ALT usually <300–500 w/ AST:ALT > 2:1, ↓ plt, ↑ Tbili & INR indicate severe hepatitis

• Prognosis: scoring systems include Maddrey’s discriminant fxn (MDF), Lille model, MELD

MDF (4.6 × [PT – control] + Tb) ≥32 w/ 30–50% 1-mo mortality if unRx’d (Gastro 1996;110:1847)

Lille model: predicts nonresponse to steroids after 1^st week of Rx; score >0.45 predicts poor response to further steroid Rx and a/w ↓ in 6-mo survival (Hep 2007;45:1348)

Combination of Lille + MELD scores best predictor of mortality (Gastro 2015;149:398)

• Rx: consider if MDF ≥32, MELD >18, or presence of encephalopathy

Glucocorticoids (eg, methylprednisolone 32 mg/d or prednisolone 40 mg/d × 4 wk → 4–6 wk taper) may ↓ 1-mo but not 6-mo mortality, a/w ↑ infection (NEJM 2015;372:1619, CD001511)

Contraindic: active GIB, pancreatitis, untreated HBV, uncontrolled bact/fungal/TB infxn

Addition of NAC to steroids ↓ 1-mo but not 6-mo mortality (NEJM 2011;365:1781)

• Consider early transplantation in carefully selected Pts (Gastro 2018;155:422)

Acetaminophen hepatotoxicity (Clin J Transl Hepatol 2016;4:131; BMJ 2016;353:i2579)

• Pathophysiology: >90% of acetaminophen (N-acetyl-p-aminophenol, APAP) metab into nontoxic metab, but ~5% metab by CYP2E1 into NAPQI, a hepatotoxic metab detoxified by glutathione conjugation; APAP overdose (>10 g) depletes glutathione stores → injury

• CYP2E1 induced by fasting, alcohol, certain anticonvulsants and anti-TB drugs, resulting in injury with even low doses (2–6 g) of acetaminophen

• Liver dysfunction may not be apparent for 2–6 d; nausea, vomiting & abdominal pain 1^st sx

• Rx: NG lavage, activated charcoal if w/in 4 h. Consider early transfer to transplant ctr

N-acetylcysteine: administer up to 72 h after ingestion, if time of ingestion unknown or chronic ingestion >4g/d; low threshold to start NAC w/ low or undetectable APAP levels

PO NAC (preferred): 140 mg/kg loading dose → 70 mg/kg q4h × 17 additional doses

IV NAC: 150 mg/kg × 1 h → 50 mg/kg × 4 h → 100 mg/kg × 16 h; risk of anaphylaxis (↓ w/ 12-h regimen; Lancet 2014;383:697); use if unable to tolerate POs, GIB, pregnancy, liver injury

Ischemic hepatitis

• “Shock liver” w/ AST & ALT >1000 + ↑↑ LDH (ALT:LDH ratio often <1:5); delayed ↑↑ Tbili

• Seen in HoTN & CHF; often requires ↑ venous + ↓ portal/arterial pressure + hypoxia

Nonalcoholic fatty liver disease (NAFLD) (JAMA 2020;323:1175; Lancet 2021;397:2212)

• Definition: fatty infiltration of liver + absence of EtOH or other cause of steatosis (HCV, etc.)

NAFL = steatosis, Ø inflam; NASH = steatosis + inflam ± fibrosis on bx

• NAFLD: 25% of U.S. pop. & over 60% in T2DM & obesity

• NASH: 2–5% of NAFLD & risk of cirrhosis in NASH w/ fibrosis on bx is 30% at 10 y

• Clinical: 80% asx, ↑ ALT > AST, but nl ALT/AST does not exclude poss. of NASH on bx

• Dx: liver bx remains gold standard. VCT elastography emerging alternative (J Hepatol 2017;66:1022). FIB-4/NAFLD fibrosis score predicts NASH w/ advanced fibrosis w/ PPV >80%.

• Rx (Gastro 2021;161:1657): wt loss (≥10%), exercise, DM control, liraglutide (Lancet 2016;387:679), statins (Metabolism 2017;71:17), vit E in Pts w/o DM (Hepatol 2018;67:328), bariatric surgery (World J Hepatol 2019;11:138). New therapies (eg, PPAR agonist lanifibranor, NEJM 2021;385:1547) emerging. HCC a complication of NAFLD, usually in setting of NASH cirrhosis.

ACUTE LIVER FAILURE (ALF)

Definition

• Acute liver injury + coagulopathy + encephalopathy w/o preexisting liver dis. (<26 wks)

• Fulminant if encephalopathy <8 wks from jaundice onset, subfulminant if 8–26 wks

• Acute on chronic liver failure: acute insult to liver in Pt w/ underlying chronic liver disease

Etiology (J Hepatol 2015;62:S112)

• Drugs/toxins (nearly 80% of cases in U.S.; Gastro 2015;148:1353, Clin Liver Dis 2017;21:151)

Dose-dependent: acetaminophen (most common cause; >40% of cases in U.S.)

Idiosyncratic, not dose related: anti-TB drugs (INH, RIF, PZA); AEDs (phenytoin, valproate, carbamazepine); NSAIDs; abx (eg, fluoroquinolones, macrolides, nitro-furantoin); drugs of abuse (MDMA & cocaine); others (amiodarone, TCAs)

Toxins: Amanita phalloides (mushroom sp. in West Coast), certain herbal preparations

• Viral: HAV, HBV, HCV (rare), HDV + HBV, HEV (esp. if pregnant). In immunosupp: HSV (50% have skin lesions), EBV, VZV, CMV, HHV6

• Vascular: Budd-Chiari, ischemic hepatitis, hepatic sinusoidal obstruction syndrome

• Other: Wilson disease, pregnancy-related ALF (acute fatty liver, preeclampsia, HELLP), initial presentation of autoimmune hepatitis; idiopathic

Clinical manifestations

• Initial presentation: N/V, malaise, RUQ pain, jaundice, encephalopathy, multiorgan failure

• Neurologic: encephalopathy: grade 1 = attn deficit, disordered sleep; grade 2 = asterixis, confusion; grade 3 = somnolence, rigidity; grade 4 = coma; ↑ ICP w/ bradycardia & HTN

cerebral edema: astrocyte swelling related in part to ↑ ammonia levels

• Cardiovascular: hypotension with low SVR, shock

• Pulmonary: respiratory alkalosis, impaired peripheral O₂ uptake, pulm edema, ARDS

• GI: GI tract bleed common (need PPI Ppx), pancreatitis (due to ischemia, drugs, infxn)

• Renal: ATN, hepatorenal syndrome, hyponatremia, hypokalemia, hypophosphatemia

• Hematology: bleeding diathesis w/ thrombocytopenia, ↑ PT/PTT, ↓ fibrinogen, ↓ synthesis of coag factors balanced by ↓ protein C/S; bleeding mostly due to low platelet count, DIC

• Infection: espec. with Staph, Strep, GNRs, and fungi (↓ immune fxn, invasive procedures); fever and ↑ WBC may be absent, most common sites are respiratory, urinary & blood

• Endocrine: hypoglycemia (↓ glc synthesis), metabolic acidosis (↑ lactate), adrenal insuf.

Workup (Clin Liver Dis 2017;21:769)

• CBC, PT/PTT, LFTs, lytes, BUN/Cr, NH₃, pH, arterial lactate, acetaminophen level, HIV, amylase/lipase, viral serologies (qv) in all Pts, with additional labs as below if suspected

• Autoimmune hep serologies & IgG levels, ceruloplasmin & serum/urine copper, preg test

• Imaging studies (RUQ U/S or abd CT, Doppler studies of portal and hepatic veins)

• Liver biopsy if underlying etiology remains elusive after initial testing

Management (J Clin Exp Hepatol 2015;5:S104; Gastro 2017;152:644)

• ICU care at liver transplant center for hemodynamic & ventilatory support; CVVH for AKI

• Early listing for liver transplantation in selected Pts (see below)

• Cerebral edema: consider ICP monitoring if grade 3/4 enceph; if ↑ ICP → mannitol 0.5–1.0 mg/kg; if arterial NH₃ >150, grade 3/4 enceph, AKI or on vasopressors → prophylactic 3% saline with goal Na 145–155 mEq/L; barbiturates & hypothermia if refractory ↑ ICP

• Encephalopathy: intubate for grade 3 or 4; lactulose is of little benefit & may be detrimental

• Coagulopathy: vit K, FFP/plts/cryo only if active bleeding (↑ risk of volume overload)

• Infection: low threshold for abx (broad spectrum, eg, vancomycin & 3^rd-gen ceph.) if suspect infection; anti-fungal coverage in high-risk Pts (TPN, CVVH)

• Rx of specific causes: NAC if acetaminophen; antiviral for HBV; plasma exchange can be temporizing measure for Wilson disease; IV acyclovir for HSV; PCN-G for A. phalloides; delivery of child for pregnancy-related; TIPS, anticoag for Budd-Chiari. Lack of data for use of steroids in autoimmune, but often given (Hepatology 2014;59:612).

• NAC may benefit Pts w/ non-APAP ALF but data inconclusive (Clin Drug Investig 2017;37:473)

• King’s College Criteria for Liver Transplantation consideration:

Acetaminophen ALF: arterial pH <7.30 or Grade III/IV enceph + INR >6.5 + Cr >3.4

Non-acetaminophen ALF: PT >100 or any 3: age <10 or >40 y, jaundice >7 d prior to onsent of encephalopathy, PT >50 or INR >3.5, Tbili >18, unfavorable disease (viral hepatitis, DILI, Wilson’s disease, or low factor V level)

Prognosis (Ann Intern Med 2016;164:724; World J Gastro 2016;22:1523)

• Non-acetaminophen ALF mortality ~70%, acetaminophen-induced ALF mortality ~25–30%

• HBV, Wilson’s, AIH, DILI, Budd-Chiari ~ associated with ↓ prognosis

• Factor V level <20% in Pts <30 yrs or <30% in >30 yrs associated w/ poor prognosis

CIRRHOSIS

Definition (Dig Dis 2016;34:374; NEJM 2016;375:767; J Hep 2016;64:717)

• Definition fibrosis & regenerative nodules causing distortion of hepatic architecture

• Decompensated = complication due to ↑ portal pressure such as: variceal bleed, HCC, SBP, encephalopathy, ascites, hepatorenal or hepatopulmonary syndrome

Etiologies

• Alcohol, toxins (eg, arsenic)

• Nonalcoholic fatty liver disease (NAFLD) is the cause of most “cryptogenic cirrhosis”

• Viral hepatitis: chronic HBV, HCV, HDV infection

• Autoimmune hepatitis: ♀, ↑ IgG, ⊕ ANA, ASMA, anti-LKM-1, anti-LC1

• Metabolic diseases: hemochromatosis, Wilson disease, α₁-AT deficiency

• Biliary tract diseases: primary biliary cholangitis, secondary biliary cirrhosis (calculus, neoplasm, stricture, biliary atresia), primary sclerosing cholangitis

• Vascular diseases: Budd-Chiari syndrome, R-sided CHF, constrictive pericarditis, SOS

• Medications: amiodarone, methotrexate, vitamin A, valproic acid, isoniazid

Clinical manifestations

• Nonspecific sx (anorexia, fatigue) or jaundice, encephalopathy, ascites, variceal bleeding

Physical exam

• Liver: initially enlarged, palpable (L lobe predom), firm; eventually shrunken, nodular

• Signs of liver failure: jaundice (bili >2.5), spider angiomata & palmar erythema (↑ estra- diol), Dupuytren contractures, white nail lines (Muehrcke lines) & proximal nail beds (Terry nails), ↑ parotid & lacrimal glands, gynecomastia, testicular atrophy, asterixis, encephalopathy, clubbing, hypertrophic osteoarthropathy, anovulation in women

• Signs of portal HTN: splenomegaly, ascites, dilated superficial abd veins (caput medusae), epigastric Cruveilhier-Baumgarten venous hum (flow through recanalized umbilical vein)

Laboratory studies

• LFTs: ↑ bili, ↑ PT/INR (poor correlation w/ bleeding; factor VIII nl b/c not synthesized by liver), ↓ alb, ± ↑ aminotransferases (AST >ALT if late) and ↑ Aϕ (variable)

• Hematologic tests: anemia (marrow suppress., hypersplenism, Fe ± folate defic.), neutro-penia (hypersplenism), thrombocytopenia (hypersplenism, ↓ Tpo production, EtOH tox)

• Chem: ↓ Na (↑ ADH due to ↓ EAV); ↑ Fe/TIBC, ↑ ferritin (released from hepatocytes)

• Lab indices predictive of cirrhosis: AST/plt >2; Lok index; Bonacini score (JAMA 2012;307:832)

• Indirect markers of fibrosis: FibroTest/FibroSURE, Hepascore (good at differentiating significant fibrosis F2 to F4), FIB-4 index (NAFLD, HCV), NAFLD fibrosis score, APRI (HCV), non-invasive imaging (eg, U/S or MR elastography)

Workup (Am J Gastro 2017;112:18; Lancet 2021;398:1359)

• Abd U/S w/ Doppler: liver size & echotexture, r/o HCC, ascites, ✓ patency of vasculature

• Determine etiology: hepatitis serologies (HBsAg, anti-HBs, anti-HCV), autoimmune hepatitis studies (IgG, ANA, ASMA), Fe and Cu studies, α₁-AT, AMA

• Assess fibrosis: biomarkers (FibroSURE = panel of 5 markers validated in HCV, ↑ score predictive of fibrosis); elastography (U/S or MR-based; measurement of liver stiffness)

• Liver bx (gold standard): percutaneous or transjugular (consider if ascites or coagulopathy), used to confirm presence of cirrhosis and dx etiology, not always needed

Prognosis (www.mdcalc.com/child-pugh-score-cirrhosis-mortality)

• Modified Child-Turcotte-Pugh (CPS) score based on ascites, enceph., & labs (bili, alb & INR; see Appendix). CPS A (5–6 pts): 1-y survival 100%, B (7–9): 80%; C (10–15): 45%.

• MELD-Na (Model for End-Stage Liver Disease; Gastro 2011;14:1952): used to stratify liver Tx list & predict 3-mo survival in cirrhosis and some acute forms of liver dis. Based on Cr, INR, total bili, Na. Calculator: https://optn.transplant.hrsa.gov/resources/allocation-calculators/meld-calculator/.

If MELD <21, additional predictors of mortality include refractory ascites, ↑ HVPG & ↓ QoL.

MELD-Plus includes alb, chol, LOS, age, WBC (PLOS One 2017;12:e0186301).

Ascites (see “Ascites” for diagnostic eval; Dig Dis 2017;35:402; Hepatology 2021;74:1014)

• Due to portal HTN (defined as hepatic venous pressure gradient [HVPG] >5 mmHg)

• Develops in 60% w/in 10 y; often first decompensating event

• Treatment: ↓ Na intake (1–2 g/d); restrict intake of free water if Na <125

Diuretics: goal diurese ~1 L/d. Use spironolactone ± furosemide in 5:2 ratio (uptitrate as able); urine Na/K >1 implies effective natriuresis if Pt compliant w/ low-Na diet

Avoid NSAIDs/ACEI/ARBs in cirrhosis because interfere w/ diuretic action

Long-term albumin infusions ↓ mortality (Lancet 2018;391:2417), but not widely adopted

• Refractory ascites: seen in 5–10% of Pts; 2-y survival 25%

Defined as diuretic-resistant if on 2-g Na diet w/ minimal weight loss on max diuretics, or diuretic-induced complications (AKI, Na <125, ↑ K, encephalopathy)

Conflicting evid. for d/c’ing βB (Hep 2016;63:1968; J Hepatol 2016;64:574). Discontinue if SBP <90 or MAP ≤82 mmHg, serum Na <120 mEq/L, AKI, HRS, SBP, sepsis, severe alcohol-assoc hepatitis, or poor follow-up. If limited by HoTN, can add midodrine.

Large-volume paracenteses (LVP; >5 L fluid removal): give 6–8 g albumin per L fluid removed (above 5 L) as colloid replacement a/w ↓ risk of post-para circulatory dysfxn & possibly ↓ mortality (Hep 2012;55:1172). Avoid LVP if SBP present because ↑ risk of AKI.

Transjugular intrahepatic portosystemic shunt (TIPS) (Gastro 2017;152:157)

↓ ascites in 75%; ↑ CrCl, ↑ enceph, survival benefit over LVP remains controversial

Contraindic: grade II enceph, CHF or pulm HTN, active infxn or biliary obstruction

Complications: bleeding, fistula; stent thrombosis (1-y patency w/ coated stents ~80%); infxn (“endotipsitis”); new or ↑ enceph in 20–30% (Am J Gastro 2016;111:523), hemolysis

Consider for liver transplant if above fail

• Hepatic hydrothorax: 2° diaphragmatic defect; often unilateral, R >L, ± ascites

Treatment: avoid chest tube (↑ complications); Rx same as ascites (TIPS if refractory). Indwelling pleural catheter potential option if refractory for palliation (Chest 2019;155:307)

Spontaneous empyema can occur (even w/o SBP) → dx thoracentesis; Rx abx

Spontaneous bacterial peritonitis (SBP; see “Ascites”; Hepatology 2021;74:1014)

• High mortality rate; risk factors include ascitic TP <1 g/dL, hx of SBP, current GIB

• Can p/w encephalopathy, abd pain, fever, but often (25%) asx; perform diagnostic paracentesis in all hospitalized patients with cirrhosis and ascites

• Micro: typically, monobacterial GNRs (E. coli, Klebs) >GPCs (S. pneumo, enterococcus)

• Rx: 3^rd-gen. ceph is 1^st line; consider pip/tazo or mero if ↑ risk of MDRO; vanc if prior MRSA ⊕; IV albumin 1.5 g/kg at time of dx & 1 g/kg on day 3 → ↑ survival (NEJM 1999;341:403)

• Repeat paracentesis at 48 h: expect 25% ↓ in PMNs if Rx working.

• Indefinite Ppx if (1) h/o SBP or (2) ascitic TP <1.5 plus: Na ≤130 or Cr ≥1.2 or BUN ≥25 or [CPS ≥9 + Tbili ≥3] (Am J Gastro 2009;4:993) → cipro 500 mg qd or Bactrim DS qd. Short-term Ppx: CTX 1 g IV × 7d if GIB (Δ to cipro 500 bid/Bactrim DS bid when eating).

Gastroesophageal varices  UGIB (see also “GIB”; Hepatology 2017;65:310)

• Presence of varices correlates w/ severity of liver dis (40% of Child A Pts → 85% Child C)

• ↑ varix size, child B/C, & red wale marks assoc w/ ↑ risk of bleeding

• UGIB 1° prevention: screen at time of dx w/ EGD; data best for Pts w/ med-large varices

Nonselective β-blockers: ~50% ↓ risk of bleeding & ↓ mortality if med-large varices. Nadolol, propranolol, or carvedilol; latter ↓ MAP & HVPG more than propranolol; delays progression of varices (Gut 2017;66:1838); may use in Pts w/ HTN. Titrate to max tolerated dose; EGD not req. to document improvement. Hold for criteria listed above.

Endoscopic variceal ligation (EVL): superior to βB in ↓ risk of 1^st bleed but no diff in mortality (Ann Hep 2012;11:369); risk of serious complications (esoph perf, ulcers). Repeat q1–4wk until varices gone, w/ f/u EGD at 3 mo then q6–12mo.

βB vs. EVL: choice based on Pt/physician preference; βB often 1^st for small varices; larger varices may benefit more from EVL; both for 1° Ppx currently not recommended

• 2° prevention: for all Pts after 1^st bleed, given ~50% risk of rebleed & ~30% mortality; βB + EVL >either alone; TIPS if refractory, or consider in child B/C w/in 72 h of admission for EV bleed (↓ rebleeding, ↑ enceph., Ø Δ mort.) (Hepatology 2017;65:310)

Hepatic encephalopathy (HE) (NEJM 2016;375:1660; Hepatology 2014; 60:715)

• Pathogenesis: failure of liver to detoxify NH₃ + other substances (eg, ADMA; J Hepatol 2013;58:38) that cause cerebral edema, ↓ O₂ consumption, ↑ ROS → brain dysfxn

• Precipitants: bleeding, infxn, med nonadherence, ↓ K, ↓ Na, dehydration, hypoxia, portosystemic shunt (eg, TIPS), meds (eg, sedatives), acute insult to liver (eg, PVT)

• Stages: see section in “Acute Liver Failure”

• Dx: serum NH₃ levels have poor Se for dx & monitoring Rx; remains a clinical dx

• Rx: identify/correct precipitants; lactulose (acidification of colon: NH₃ → NH₄⁺) w/ goal 2–4 stools/d (PEG may be as effective; JAMA IM 2014;174:1727); add rifaximin 550 mg bid (↓ gut bacteria → ↓ NH₃ prod) if refractory or after 2^nd recurrence HE on lactulose (NNT=3) (Am J Gastro 2013;108:1458); FMT, oral branched-chain AAs, probiotics may have a role (Cochrane Reviews 2017;2; Gastro 2019;156:1921); maintain K >4, avoid alkalosis as able

Hepatorenal syndrome (HRS) (Hepatology 2021;74:1014, Gastro 2016;150:1525)

• Pathophys: splanchnic vasodilation and renal vasoconstriction w/ ↓ renal blood flow

• Criteria: (1) cirrhosis w/ ascites; (2) acute kidney injury (serum Cr ↑ ≥0.3 mg/dL w/in 48 h or ≥50% ↑ in serum Cr from baseline; Gut 2015;64:531); (3) Ø improvement in Cr after d/c diuretic & volume expansion (1 g/kg/d of albumin × 2 d); (4) Ø shock (prerenal azotemia/ATN); (5) Ø nephrotoxic meds; (6) Ø intrinsic kidney disease

HRS-AKI: development in <2 wk; usually occurs in severe liver failure, often following precipitating event (see later); median survival 2 wk

HRS-CKD: more indolent, median survival 6 mo; liver failure present <than in HRS-AKI

• Precipitants: GIB, overdiuresis, infection, serial LVP, drugs (aminoglycosides, NSAIDs)

• Rx: if critically ill → vasopressor (eg, norepinephrine or vasopressin) + albumin (1 g/kg, max 100 g, bolus daily) to ↑ MAP 10 mmHg. If not critically ill → octreotide (100–200 mcg SC tid) + midodrine (max 15 mg PO tid) + 1 g/kg (max 100 g) albumin on day of presentation followed by 20–60 g albumin qd to ↑ MAP. Terlipressin + albumin ↑ 10 d survival (not yet approved in U.S. but now recommended by AASLD) (NEJM 2021;384:818). May need dialysis or TIPS as bridge to liver transplant.

Hepatocellular carcinoma (HCC; qv in Heme-Onc) (Nature Reviews 2021;7:6)

• ↑ risk w/ cirrhosis of any type (leading cause of death in cirrhosis, 1–6%/y) but esp. ↑ w/ viral (Hep B/C~3–8%/y), concomitant EtOH use, obesity related NASH, HFE or diabetes

• Clinical: asx vs. hepatic decompensation (eg, ascites, HE), PVT w/ tumor thrombus

• Dx: screen Pts w/ cirrhosis q6mo w/ U/S ± AFP; alternative is dual-phase CT/MRI

• Rx: see “HCC” in Heme-Onc

Other complications

• Hepatopulmonary syndrome (HPS) (Dig Dis Sci 2015;60:1914, Hepatology 2021;74:1014)

Abnl gas exchange (A-a gradient ≥15 or P_aO₂ <80) caused by intrapulmonary vascular dilatations leading to intrapulmonary shunting (improves with O₂)

S/S: platypnea-orthodeoxia (dyspnea & hypoxia w/ sitting up), clubbing, spider angiomas

Dx w/ contrast echo showing “late” A-V shunting (contrast in LA 3–6 cycles after RA)

Rx: O₂; potential embolization if large vessel on CT, TIPS, liver tx only definitive Rx

• Portopulmonary hypertension (POPH) (Expert Rev Gastro Hepatol 2015;9:983)

Pulm HTN in Pt w/ portal HTN w/o other cause. ESLD→ ↑ endothelin→ pulm vasoconst.

Rx w/ same therapies as for idiopathic PAH, incl prostacyclin analogs, endothelin receptor antagonists, sildenafil; liver transplant is often curative

• Cirrhotic cardiomyopathy: ↓ inotropic & chronotropic response, ↓ systolic & diastolic fxn, ↑ QT, hyperkinetic circulation, high output; ↑ troponin & BNP

• Infxns: unless immune, vaccinate for HAV, HBV, PCV13, PPSV23, COVID-19; flu yearly. Cellulitis in ~20% of Pts hospitalized w/ cirrhosis, often in abd or LE a/w edema.

• Endocrine: diabetes (15–30%), ↑ frequency of adrenal insuffic. (Dig Dis Sci 2017;62:1067)

• Coagulopathy: balanced defects w/ ↓ synth of coag factors, hyperfibrinolysis, ↓ plt balanced by ↓ synthesis anticoag factors (protein C/S), defic. of profibrinolytic factors, ↑ levels of vWF. No support for routine administration of FFP, plt, cryo unless DIC.

• Nutrition: monitor and supplement fat-soluble vitamins, zinc, screen for malnutrition, sarcopenia & fraility; ensure protein intake 1.2–1.5 g/kg/d (Hepatology 2021;74:1611)

• Meds: acetaminophen can be used up to 2 g/d; avoid ASA/NSAIDs; aminoglycosides contraindicated; oral hypoglycemics if compensated but insulin if decompensated

Liver transplantation (Hepatology 2014;59:1144)

• Undertake evaluation when MELD ≥15. Exception points added if HCC, HPS

• Indic: recurrent/severe enceph, refractory ascites, recurrent variceal bleeding, HRS, HPS, PPH, HCC (if no single lesion is >5 cm or ≤3 lesions with largest ≤3 cm), ALF

• Contraindic: inadequate social support, active substance abuse (some exception), sepsis, advanced cardiopulm dis., extrahepatic Ca, cholangio Ca, hemangiosarcoma, persistent noncompliance, AIDS, ALF w/ sustained ICP >50 mmHg or CPP <40 mmHg

• Survival: 1-y up to 90%, 5-y up to 80%, though lower with autoimmune liver disease, such as AIH/PBC/PSC may recur in 10–30% (or more) of allografts

OTHER ETIOLOGIES OF CIRRHOSIS

Hemochromatosis & iron overload syndromes (Am J Gastro 2019;114:1202)

• Recessive disorder of iron sensing or transport leading to tissue iron deposition

• HFE mutations (85% of cases): typically C282Y homozyg. (~0.5% of N. Europeans), rarely C282Y/H63D compound heterozyg. C282Y homozygotes: 28% of ♂ & 1% of ♀ develop sx (delayed since menses ↓ Fe load). C282Y/H63D: only 1.5% manifest dis.

• Non-HFE mutations: hemojuvelin, hepcidin, transferrin receptor 2, & ferroportin

• 2° causes of iron overload: iron-loading anemias (eg, thalassemia major, sideroblastic anemia, aplastic anemia), parenteral iron overload (RBC transfusions, long-term HD), chronic liver disease (due to EtOH, HBV, HCV, NASH, etc.), dietary iron overload

• Sx: fatigue & arthralgias, loss of libido in ♂. In advanced disease (rare): bronze skin (melanin + iron), hypogonadism (esp. in juvenile onset), DM, arthropathy (MCP), CHF, infxns (↑ risk Vibrio, Listeria, Yersinia), cirrhosis (↑ risk if EtOH/fatty liver disease; 15% risk of HCC). Disease also a/w ALS (H63D homozygotes) & porphyria.

• Dx: iron sat >45% (iron/TIBC × 100%); ↑ ferritin (acute phase reactant, so poor Sp; often nl in young Pts). If ↑ iron sat. → ✓ HFE to confirm dx, imaging by MRI (black liver). If HFE ⊕ & ferritin >1000 ng/mL or ↑ LFTs → liver bx for quant Fe index & to stage fibrosis

• Treatment: phlebotomy (250 mL = 1 unit, ~250 mg of Fe) qwk until Fe sat <50% & ferritin 50–100 µg/L, then q3–4mo; PPI ↓ intestinal Fe absorption & may ↓ need for phlebotomy; avoid vit C & uncooked seafood; deferoxamine if phleb. contraindic.; genetic counseling

Wilson disease (World J Hepatol 2015;7:2859)

• Recessive disorder of copper transport (mutation in ATP7B) → copper overload

• Epidemiology: 1 in ~30,000 w/ age of presentation generally ranging from 3 to 55 y

• Extrahepatic s/s: neuro ψ disease, parkinsonism, movement disorder (hepatolenticular disease), Kayser-Fleischer rings (⊕ in 99% w/ neuro ψ but in <50% w/ hepatic disease), Coombs ⊖ hemolytic anemia, renal disease

• Dx: ↑ 24-h urine Cu, ↓ serum ceruloplasmin (Se 90%), liver bx w/ hepatic Cu content, genetic testing for ATP7B gene helpful if unclear dx. In acute liver failure, Aϕ/bili <4 + AST/ALT >2.2 better Se & Sp than urine Cu or ceruloplasmin (Hepatology 2008;4:1167).

• Treatment: chelation w/ D-penicillamine (supplement B6 as D-pen inactivates); alternative is trientine (↓ toxicity w/ ≈ efficacy, but $$), ammonium or bis-choline tetrathiomolybdate (investigational) may ↓ neurologic deterioration compared to trientine. Zinc: ↓ intestinal Cu transport & can help delay disease; best used in conjunction w/ chelation (give 5 h after chelators). Eliminate Cu-rich foods. Transplant for ALF or unresponsive to Rx.

α₁-antitrypsin deficiency (α₁-AT) (J Hepatol 2016;65:413; NEJM 2020;382:1443)

• Abnl α₁-AT → polymerization in liver (cirrhosis) & uninhibited protease activity in lung (emphysema). Affects 1/3000 of European ancestry. Varied presentations: neonatal hepatitis; cholestatic jaundice in children; ↑ AST/ALT or cirrhosis in children/adults.

• Extrahepatic disease: panlobular emphysema, necrotizing panniculitis, ANCA vasculitis

• Dx: serum α₁-AT (acute phase reactant) w/ CRP level (to ensure not ↑ due to inflamm.)

gold standard = phenotyping of protease inhibitor (Pi). Alleles most a/w hepatic dis.: Z (63% of ZZ adults have chronic liver dis. and liver fibrosis, may be present in 35% of ZZ individuals w/o overt liver disease) & M (malton) (J Hepatol 2018;69:1357). Liver bx shows characteristic PAS ⊕ cytoplasmic inclusion bodies.

• Treatment: ↓ risk by avoiding EtOH, maintaining a normal BMI; liver transplant if severe

Primary biliary cholangitis (PBC) (Hep 2019;69:394; Nat Rev 2020;17:93; Lancet 2020;396:1915)

• Autoimmune destruction of intrahepatic bile ducts

• Epi: ♀ 40–60 y; a/w Sjögren’s (50%), Raynaud’s, scleroderma, celiac & thyroid disease; may be triggered by infxns or toxins; a/w X monosomy, variants in IL12α & IL12R genes

• Sx: fatigue/sleep disturbance, pruritus, jaundice, 50% asx w/ only LFT abnormalities

• Ddx: PSC, AIH, hepatic sarcoidosis, meds, idiopathic adult ductopenia, biliary stricture/Ca

• Dx: ↑ Aϕ, ↑ bili, ↑ IgM, ↑ chol (mainly HDL-C), ⊕ (AMA) in 95%. If ⊕ AMA, liver bx not needed due to high Se & Sp. 0.5% gen pop ⊕ AMA & nl LFTs → 10% develop PBC at 6 y. If AMA ⊖, liver bx (Pts often ⊕ ANA, smooth muscle Ab; same prognosis as ⊕ AMA).

• Rx: ursodeoxycholic acid (UDCA) (13–15 mg/kg bid), monitor for 3–6 mos → ~25% complete response, ↑ survival & ↓ histologic change & ↓ complications (varices). Biochemical response predicts clinical outcome.

Obeticholic acid (FXR agonist): monoRx if cannot tolerate UDCA (but not in decompen cirrhosis) or if no Δ w/ UDCA after 1 y; found to ↓ Aφ, ↑ pruritus (NEJM 2016;375:631)

Bezafibrate (not available in U.S. but fenofibrate similar) appears to be effective 2^nd-line agent in combo w/ UDCA if inadequate response to UDCA (NEJM 2018;378:2171)

Pruritus: cholestyramine (give 2–4 h after UDCA); if refractory sx: naltrexone, rifampin

If ESLD: liver tx; ~20% recur but no impact on long-term survival

Primary sclerosing cholangitis (PSC) (NEJM 2016;375:1161; Clin Liver Dis 2020;15:125)

• Diffuse inflammation of intrahepatic and extrahepatic bile ducts leading to fibrosis & stricturing of biliary system. A/w HLA-B8 and -DR3 or -DR4, frequent ⊕ autoantibodies.

• Epi: ♂ >♀ (20–50 y) ~70% Pts w/ PSC have IBD (usually UC); only 1–4% w/ UC have PSC. ⊕ prognostic factors: ♂, absence of IBD, small duct PSC (Gastro 2017;152:1829).

• Symptoms: fatigue, pruritus, jaundice, fevers, RUQ pain, IBD; 50% of Pts asymptomatic

• Ddx: extrahepatic obstruction, PBC, overlap w/ AIH, IgG4 autoimmune cholangitis, etc.

• Dx: cholangiography (MRCP ± ERCP) → multifocal beaded bile duct strictures; exclude 2^° cause; may miss dx if confined to small intrahepatic ducts (“small duct PSC”).

Liver bx if unclear: “onion-skin” fibrosis around bile ducts + some findings similar to PBC.

• Treatment: supportive care, fat-soluble vitamins; no meds have improved survival

UDCA may ↓ Aϕ & improve Sx, but unclear if beneficial

If dominant stricture → endoscopic dilation, stenting or surgical resection can help

Cholangiocarcinoma: 15% lifetime risk; annual surveillance w/ MRCP or U/S & CA19-9

Liver transplantation: ~30% recurrence, though if UC, colectomy may ↓ recurrence

HEPATIC VASCULAR DISEASE

(Modified from The Nature of Disease Pathology for the Health Professions, 2007. Hepatology 2009;49:1729.)

Portal vein thrombosis (PVT) (Clin Liver Dis 2017;10:152; Gastro 2019;156:1582)

• Definition: thrombosis of portal vein often w/ extension into mesenteric vein/splenic vein

• Etiologies: commonly due to cirrhosis or hypercoaguable state (cancer, infection, OCP, collagen vascular diseases, Behçet’s, IBD, surgery, trauma, OCPs, preg)

• Clinical manifestations

acute: abd pain, fever, variceal bleed or asx w/ incidental finding on U/S or CT. If mesenteric vein involved may p/w intestinal infarct. If fever, consider pylephlebitis.

chronic: asx/incidental finding; may p/w s/s of portal HTN → hematemesis 2° variceal bleeding, splenomegaly, encephalopathy; ascites uncommon unless cirrhosis

• Dx: LFTs usually nl; begin w/ U/S w/ Doppler, confirm w/ MRA or CT (I⁺), angio; consider hypercoag w/u. “Portal cavernoma”: network of hepatopetal collaterals in chronic PVT—can rarely cause biliary obstruction & cholestatic LFTs = portal cholangiopathy.

• Treatment: Acute: If noncirrhotic, LMWH → warfarin or DOAC × 6 mo, or indefinitely if irreversible cause. If cirrhotic, anticoag ↑ recanalization w/o ↑ bleeding (Gastro 2017;153:480); screen for high-risk varices prior to Rx (Nat Rev Gastro Hep 2014;11:435).

Chronic: Anticoag if noncirrhotic or hypercoag state. If cirrhotic, consider txp if sx or progression. In all, screen for varices; if present, variceal bleed Ppx prior to anticoag.

Splenic vein thrombosis

• Can occur 2/2 local inflam. (eg, panc.). Can p/w isol. gastric varices. Splenectomy curative.

Budd-Chiari syndrome (World J Hepatol 2016;8:691)

• Hepatic outflow obstruction 2/2 occlusion of hepatic vein(s) or IVC → sinusoidal congestion and portal HTN. Can be 1° (eg, thrombosis) or 2° (eg, extravascular compression).

• Etiol.: ~50% due to myeloprolif. d/o a/w JAK2 mutations (P. vera, etc.), hypercoag states (systemic, OCP, pregnancy), tumor invasion (HCC, renal, adrenal), trauma, idiopathic

• Symptoms: hepatomegaly, RUQ pain, ascites, dilated venous collaterals, acute liver failure

• Dx: ± ↑ AST, ALT & Aϕ; Doppler U/S of hepatic veins (85% Se & Sp); CT (I⁺) or MRI/MRV → vein occlusion or ↑ caudate lobe (separate venous drainage); hepatic venography gold standard w/ “spider- web” pattern + assess venous pressure; biopsy only if unclear

• Treatment: Rx underlying condition, anticoag (LMWH → warfarin); consider thrombolysis if acute; angioplasty & stent if short stenosis; consider TIPS or DIPS (U/S-guided direct intrahepatic portosystemic shunt) (if other methods fail to treat sx of portal HTN); liver transplant if ALF or failed other options

Sinusoidal obstruction syndrome (SOS) (Bone Marrow Transplant 2020:55:485)

• Occlusion of hepatic venules & sinusoids (formerly veno-occlusive disease) 2/2 toxic insult

• Etiologies: post HSCT (15%), chemo (cyclophosphamide, cytarabine), XRT, bush tea

• Clinical manifestations: painful hepatomegaly, RUQ pain, ascites, weight gain, ↑ bilirubin

• Dx: U/S w/ reversal of portal flow; dx made clinically (early weight gain, ↓ plt refractory to transfusion, ↑ bili, hx of recent toxins); if necessary, liver bx or HVPG (>10 mmHg)

• Rx: supportive, diuretics; if severe → early defibrotide ↑ survival, but side effects & expensive

• Ppx: defibrotide; ursodeoxycholic acid for high-risk HSCT pop; ? use of low-dose heparin

ASCITES

Pathophysiology (Hepatology 2021;74:1014)

• Portal HTN → ↑ NO & prostaglandins → splanchnic vasodilatation→ ↓ effective arterial volume → ↑ RAAS & ADH → renal Na & H₂O retention → volume overload and ascites

• In malignant or inflammatory ascites, leaking of proteinaceous material occurs from tumor or from inflamed/infected/ruptured intraabdominal structures

Symptoms

• ↑ abd girth, wt gain, new abd hernia, abd pain, dyspnea, nausea, early satiety

Evaluation (World J Hepatol 2013;5:251; JAMA 2016;316:340)

• Physical exam: flank dullness (>1500 mL needed), shifting dullness (Se ~83%)

• Radiologic: U/S detects >100 mL fluid; MRI/CT (also help with Ddx)

• Paracentesis: perform in all Pts w/ new ascites, suggested in all hosp. Pts w/ cirrhosis + ascites. Low complic. rate (~1% hematoma formation). Prophylactic FFP or plts does not ↓ bleeding complic. Most useful tests: cell count, alb, total protein (for SAAG), & culture

• Serum-ascites albumin gradient (SAAG): serum alb (g/dL) – ascites alb (g/dL)

SAAG ≥1.1 diagnoses portal HTN with ~97% accuracy (Ann Intern Med 1992;117:215)

If portal HTN + another cause (seen in ~5% of cases) SAAG still ≥1.1

Etiologies
Portal HTN Related (SAAG ≥1.1)	Non–portal HTN Related (SAAG <1.1)
Presinusoidal obstruction portal or splenic vein thrombosis, schisto- somiasis, sarcoidosis Sinusoidal obstruction: cirrhosis, acute hepatitis (including EtOH), malignancy (HCC or mets) Postsinusoidal obstruction right-sided CHF (ex: constriction, TR), Budd-Chiari syndrome, SOS	Malig: peritoneal carcinomatosis; chylous ascites from malignant lymphoma (↑ TG); Meigs’ syndrome (ovarian tumor) Infection: TB, chlamydia/gonorrhea (ie, Fitz-Hugh-Curtis syndrome) Inflam: pancreatitis, ruptured pancreatic/biliary/lymph duct; bowel obstrxn, serositis (SLE) Hypoalbuminemic states: nephrotic syndrome, protein-losing enteropathy

• Ascites fluid total protein (AFTP): useful when SAAG ≥1.1 to distinguish cirrhosis (AFTP <2.5 g/dL) from cardiac ascites (AFTP ≥2.5 g/dL). Low AFTP (<1 g/dL) assoc. w/ ↑ risk of SBP (see “Cirrhosis” for guidelines on SBP Ppx based on AFTP).

• Cell count: normal limit of PMNs in ascitic fluid up to 250 PMNs/mm³. Bloody tap (typically from traumatic para) can skew cell count; subtract 1 PMN for every 250 RBCs to correct PMN count. Ascitic PMNs ≥250 suggest infection.

• Other tests: amylase (pancreatitis, gut perforation); bilirubin (test in dark brown fluid, suggests bile leak or proximal intestinal perf); TG (chylous ascites); BNP (HF); cytology (peritoneal carcinomatosis, ~95% Se w/ 3 samples). SBP a/w ↓ glc & ↑ LDH. Ascites culture (prior to abx if possible, should have both aerobic & anerobic w/ 10 cc per bottle)

Treatment (see “Cirrhosis” for details)

• If 2° to portal HTN: ↓ Na intake (<2 g/d) + diuretics; if refractory → LVP (serial) or TIPS

• If non–portal HTN related: depends on underlying cause (TB, malignancy, etc.)

Bacterial peritonitis (Gut 2012;61:297; Hepatology 2021;74:1014)

Ascites PMN	⊕ Ascites Culture	⊖ Ascites Culture
≥250/µL	Spontaneous bacterial peritonitis (SBP): gut bacterial translocation to ascites. In cirrhosis, ↓ ascites opsonins (esp. if ↓AFTP) ↑ risk of infxn. Infection usually monomicrobial: most common → E. coli, Klebs, S. pneumo; rarely Staph & Pseudo. Rx 3rd-gen ceph; carbapenem if critically ill. 2° bacterial peritonitis: 2/2 intra-abd abscess, perf. Runyon’s criteria: AFTP >1 g/dL, glc <50 mg/dL, LDH >ULN for serum. Cx polymicrobial. Rx 3rd-gen ceph. + MNZ; urgent abd imaging ± ex lap.	Culture-⊖ neutrocytic ascites (CNNA): cell counts suggest infxn but cx ⊖. No recent abx, w/o other explan. for counts. Often do have SBP and should be treated with empiric regimen.
<250/µL	Nonneutrocytic bacterascites (NNBA): ⊕ cx w/o ↑ PMNs. Natural course may resolve w/o Rx. Start abx if symptomatic; if asymptomatic repeat para in 48 hrs. Cx w/ 1 org.: Misc. GPC, E. coli, Klebs, misc. GNR.	(Normal)
Peritoneal dialysis-associated: cloudy fluid, abd pain, fever, nausea. Dx can be made with >50 PMNs. Culture most often GPC (50%) or GNR (15%). Rx: vanc + gent (IV load, then administer in PD).

BILIARY TRACT DISEASE

CHOLELITHIASIS (GALLSTONES)

Epidemiology & pathogenesis (J Hepatol 2016;65:146; Gastro 2016;151:351)

• Affects ~10% of Western populations, 15–25% of people develop sx over 10–15 y

• Bile = bile salts, phospholipids, cholesterol; ↑ cholesterol saturation in bile + accelerated nucleation + gallbladder hypomotility → gallstones

• Risk factors: ♀; South, Central, Native American; ↑ age (>40 y); obesity, TPN, rapid ↓ wt; dyslipidemia; preg., drugs (OCPs, estrogen, clofibrate, octreotide); ileal dis., genetics

• Statin use ↓ risk of sx gallstones & cholecystectomy (Hepatol Res 2015;45:942)

Types of gallstones (J Hepatol 2016;65:146)

• Cholesterol (90%): 2 subtypes

mixed: contain >50% cholesterol; typically smaller, multiple stones

pure: 100% cholesterol; larger, yellow, white appearance

• Pigment (10%)

Black: unconjugated bili & calcium; seen w/ chronic hemolysis, cirrhosis, CF, Gilbert synd

Brown: stasis & infxn in bile ducts → bacteria deconjugate bilirubin → precipitates w/ Ca; found pred in bile ducts; seen w/ biliary strictures, parasites, post-cholecystectomy

Clinical manifestations

• Asx in ~80%. Biliary pain develops in 1–4%/y. Once sx, rate of complications ~1–3%/y.

• Biliary pain = episodic RUQ or epigastric pain; begins abruptly, continuous, resolves slowly and lasts 30 min–3 h; ± radiation to scapula; precip by fatty foods; nausea

• Physical exam: afebrile, ± RUQ tenderness or epigastric pain

Diagnostic studies

• Labs normal in most

• RUQ U/S: Se & Sp >95% for stones >5 mm; should be performed after ≥8 h fast for distended, bile-filled gallbladder. If ⊖, repeat in 1 mo to detect missed stones

• Endoscopic U/S (EUS): Se 94–98% in Pts w/ biliary pain but nl U/S (J Hepatol 2016;65:146)

• CT scan/KUB is less Se; stones often isodense w/o enough calcium & will be missed

Treatment (Am Fam Physician 2014;89:795; J Hepatol 2016;65:146)

• Cholecystectomy (CCY), usually laparoscopic, if symptomatic (earlier is better)

• CCY in asx Pts if: GB calcification (↑ risk of cancer), GB polyps >10 mm, stones >3 cm; Pts undergoing bariatric surgery, cardiac Tx candidates, hemolytic anemia (sickle cell)

• Options if ↑ risk for surgery: percutaneous drainage, endoscopic transpapillary drainage

• UDCA can be trialed for cholesterol stones w/ biliary pain or if poor surgical candidate, but takes ~3 mo to work; ↓ risk of gallstone formation that occurs w/ rapid wt ↓

• Pain: NSAIDs drugs of choice, efficacy ≈ opiates & avoids ↑ sphincter of Oddi pressure

Complications

• Cholecystitis: 20% of Pts with symptomatic biliary pain progress to cholecystitis w/in 2 y

• Choledocholithiasis → cholangitis or gallstone pancreatitis

• Mirizzi syndrome: hepatic duct compression by GB stone → jaundice, biliary obstruction

• Cholecystenteric fistula: stone erodes through gallbladder into bowel, ~15% w/ colon

• Gallstone ileus: SBO (usually at term ileum) due to stone in intestine that passed thru fistula

• Gallbladder carcinoma: ~1% in U.S., often found late stage, a/w poor prognosis

CHOLECYSTITIS (JAMA 2022;327:965)

Pathogenesis

• Acute cholecystitis: stone impaction in cystic duct → inflammation behind obstruction → GB swelling ± secondary infection (50%) of biliary fluid

• Acalculous cholecystitis: GB stasis & ischemia (w/o cholelithiasis) → necroinflammation. Occurs in critically ill. A/w postop major surgery, TPN, sepsis, trauma, burns, opiates, immunosuppression, infxn (eg, CMV, Candida, Crypto, Campylobacter, typhoid fever).

Clinical manifestations

• History: RUQ/epigastric pain ± radiation to R shoulder/back, nausea, vomiting, fever

• Physical exam: RUQ tenderness, Murphy’s sign = ↑ RUQ pain and inspiratory arrest with deep breath during palpation of R subcostal region, ± palpable gallbladder

• Laboratory evaluation: may see ↑ WBC, ± mild ↑ bilirubin, Aϕ, ALT/AST, amylase; if AST/ALT >500 U/L, bili >4 mg/dL or amylase >1000 U/L → choledocholithiasis

Diagnostic studies

• RUQ U/S: high Se & Sp for stones, but need specific signs of cholecystitis: GB wall thickening >4 mm, pericholecystic fluid and a sonographic Murphy’s sign

• HIDA scan: most Se test (80–90%) for acute cholecystitis. IV inj of HIDA (selectively secreted into bile). ⊕ if HIDA enters BD but not GB. 10–20% false ⊕ (cystic duct obstructed 2/2 chronic cholecystitis, lengthy fasting, liver disease).

Treatment (Ann Surg 2013;258:385; NEJM 2015;373:357)

• NPO, IV fluids, nasogastric tube if intractable vomiting, analgesia

• Antibiotics (E. coli, Klebsiella and Enterobacter sp. are usual pathogens) ([2^nd- or 3^rd-generation cephalosporin or FQ] + MNZ) or piperacillin-tazobactam

• CCY (typically laparoscopic) w/in 24 h ↓ morbidity vs. waiting 7–45 d

• If unstable for surgery, EUS-guided transmural, ERCP-guided transcystic duct drainage, or percutaneous cholecystotomy (if w/o ascites or coagulopathy) are alternatives to CCY

• Intraoperative cholangiogram or ERCP to r/o choledocholithiasis in Pts w/ jaundice, cholangitis or stone in BD on U/S (see below)

Complications

• Gangrenous cholecystitis: necrosis w/ risk of empyema and perforation

• Emphysematous cholecystitis: infection by gas-forming organisms (air in GB wall)

• Perforation: ~10% of cases, due to delay in diagnosis; pericholecystic abscess forms

• Post CCY: bile duct leak, BD injury or retained stones, cystic duct remnant, sphincter of Oddi dysfxn

CHOLEDOCHOLITHIASIS

Definition

• Gallstone lodged in common bile duct (CBD)

Epidemiology

• Occurs in 15% of Pts w/ gallbladder stones; can form de novo in CBD due to biliary stasis

Clinical manifestations

• RUQ/epigastric pain 2° obstrxn of bile flow → ↑ CBD pressure, jaundice, pruritus, nausea

• Rarely asymptomatic

Diagnostic studies (J Hepatol 2016;65:146; Gastrointest Endosc 2019;89:1075)

• Labs: ↑ bilirubin, Aϕ; transient spike in ALT or amylase suggests passage of stone

• RUQ U/S: BD stones seen ~50–80% of cases; usually inferred from dilated CBD (>6 mm)

• ERCP preferred modality when likelihood high (eg, visualized stone, cholangitis, bili >4, or dilated CBD on U/S + bili 1.8–4 mg/dL); cholangiogram (percutaneous, operative) if ERCP unavailable or unsuccessful; EUS/MRCP to exclude BD stones if suspicion intermediate (eg, no stone, dilated ducts on U/S, bili 1.8–4 mg/dL, gallstone panc., age >55, or abnl non-bili LFT)

Treatment

• ERCP & papillotomy w/ stone extraction (± lithotripsy)

• CCY w/in 6 wk unless contraindication (>15% Pts develop indication for CCY if unRx’d)

Complications

• Cholangitis, cholecystitis, pancreatitis, stricture

CHOLANGITIS

Definition & etiologies (World J Gasrointest Pathophysiol 2018:9:1)

• Bile duct obstruction causes stasis → infection proximal to the obstruction

• Etiologies: BD stone (~85%); malignant (biliary, pancreatic) or benign stricture; infection w/ fluke (Clonorchis sinensis, Opisthorchis viverrini); recurrent pyrogenic cholangitis

Clinical manifestations

• Charcot’s triad: RUQ pain, jaundice, fever/chills; present in ~70% of Pts

• Reynolds’ pentad: Charcot’s triad + shock and Δ MS; present in ~15% of Pts

Diagnostic studies

• RUQ U/S: often demonstrates dilation of bile ducts

• Labs: ↑ WBC (with left shift), bilirubin, Aφ, amylase; may see ⊕ BCx

• ERCP; percutaneous transhepatic cholangiogram if ERCP unsuccessful

Treatment

• Antibiotics (broad spectrum) to cover common bile pathogens (see above) ampicillin + gentamicin (or levofloxacin) ± MNZ (if severe); carbapenems; pip/tazo

• ~80% respond to conservative Rx and abx → biliary drainage on elective basis

• ~20% require urgent biliary decompression via ERCP (papillotomy, stone extraction, and/or stent insertion). If sphincterotomy cannot be performed (larger stones), decompression by biliary stent or nasobiliary catheter can be done; otherwise, percutaneous transhepatic biliary drainage or surgery.