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GASTROENTEROLOGY

CIRRHOSIS

Definition (Hep 2011;54:1864 & 2012;56:1983; J Hep 2012;56:S13)

•  Definition: fibrosis and regenerative nodules resulting from hepatocellular injury

•  Decompensated = jaundice, variceal bleed, encephalopathy, ascites; worse prognosis

Etiologies

•  Alcohol (~60–70%): Laennec’s cirrhosis; micronodular

•  Viral hepatitis (~10%): chronic HBV, HCV, HDV infection

•  Autoimmune hepatitis: female, ↑ IgG,  ANA, antismooth muscle Ab

•  Metabolic diseases (~5%): hemochromatosis, Wilson’s disease, ɑ1-AT deficiency

•  Biliary tract diseases (~5%): primary biliary cirrhosis, secondary biliary cirrhosis (calculus, neoplasm, stricture, biliary atresia), primary sclerosing cholangitis

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

•  Nonalcoholic fatty liver dis. (NAFLD, 10–15%) cause of most “cryptogenic cirrhosis”

Clinical manifestations

•  Subclinical or may p/w liver dysfunction (jaundice, coagulopathy, encephalopathy) and/or portal HTN (ascites, varices); 35% p/w fever (SBP, acute EtOH); 25% p/w hematemesis

Physical exam

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

•  Signs of liver failure: jaundice (bili >2), spider angiomata & palmar erythema (↑ estra- diol), Dupuytren’s contractures, white nail lines (Muehrcke’s lines) & proximal nail beds (Terry’s nails), ↑ parotid & lacrimal glands, gynecomastia, testicular atrophy, asterixis, encephalopathy, fetor hepaticus, clubbing, hypertrophic osteoarthropathy

•  Signs of portal hypertension: splenomegaly, ascites, dilated superficial abdominal veins (caput medusae), epigastric Cruveilhier-Baumgarten venous hum

Laboratory studies

•  ↑ bilirubin, ↑ PT (poor correlation w/ bleeding; factor VIII nl as not synthesized by liver), ↓ alb, ± ↑ aminotransferases (AST > ALT if late) and ↑ AΦ (variable), ↓ Na, ↑ γ-glob

•  Anemia (marrow suppression, hypersplenism, Fe and/or folate defic.), neutropenia (hypersplenism), thrombocytopenia (hypersplenism, ↓ Tpo production by liver, EtOH tox)

Workup

•  Abdominal U/S w/ Doppler: liver size (↑ L & caudate lobe), r/o HCC, ascites, ✓ patency of portal, splenic and hepatic veins

•  Assess fibrosis: biomarkers (eg, FibroSURE = panel of 6 markers validated in HCV, ↑ score predictive of fibrosis); U/S or acoustic radiation force impulse or MR elastography

•  Determine etiology: hepatitis serologies (HBsAg, anti-HBs, anti-HCV), autoimmune hepatitis studies (IgG, ANA, anti–smooth muscle Ab), Fe and Cu studies, ɑ1-AT, AMA

•  ± Liver bx: percutaneous or transjugular (consider if ascites or coagulopathy) used to dx etiology and presence of cirrhosis

Ascites (see “Ascites” for details on dx eval; Hep 2009;29:2087)

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

•  Develops in 60% w/in 10 y; ~50% mortality at 5 y

•  Treatment (Am J Gastro 2009;104:1802): ↓ Na intake (1–2 g/d); free H2O restrict if Na <125

Diuretics: goal 1 L/d; urine Na/K >1 implies effective aldo block; spironolactone ± furosemide in 5:2 ratio (eg, 100 & 40 mg daily); ↑ doses in proportion

 NSAID as interferes w/ diuretic action (common cause of refractory ascites)

•  Refractory ascites (Clin Gas Hep 2011;9:931): seen in 5–10% of Pts; 2-y survival is 25%

Diuretic resistant on 2g Na diet or diuretic-induced complic (Cr >2, Na <125, ↑ or ↓ K, enceph)

Large-volume paracentesis (LVP); if >5 L, replace w/ 8–10 g/L of alb → ↓ risk of paracentesis-induced circ. dysfxn (AKI & lyte abnl) & ? ↓ mortality (Hep 2012;55:1172)

Beware LVP if SBP as ↑ risk of ARF → consider dx tap to r/o SBP first

Transjugular intrahepatic portosystemic shunt (TIPS) (Clin Gas Hep 2011;9:936)

↓ 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 include technical: bleeding, fistula; related to stent: thrombosis w/in 24 h rare, 1 y patency w/ coated stents ~80%, infxn (endotipsitis); shunting: new or ↑ enceph in 20–30%, hemolysis (Hep 2010;51:306)

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

Treatment:  chest tube due to ↑ complications; Rx same as ascites

Spont empyema can occur (even w/o SBP) → dx thoracentesis; Rx same as for SBP

Spontaneous bacterial peritonitis (SBP; see “Ascites” for details; J Hep 2010;53:397)

•  Develops in ~20%; 20% mortality; risk factors: AFTP <1 g/dL, hx of SBP, current GIB

•  Can p/w encephalopathy, abd pain, fever, but often (25%asx; consider paracentesis in all hospitalized cirrhotics w/ ascites

•  Micro: 70% GNR (E. coliKlebs), 30% GPC (EnterococcusS. pneumo), nosocomial (fungi, Pseud); ~40% culture 

•  Rx: 3rd gen. ceph (eg, cefotaxime 4g/d total dose) or amox/clav × 5 d, if  enceph/AKI can use FQ (cipro/oflox) but avoid if already on for ppx or in ↑ FQ resist. areas IV albumin 1.5 g/kg at time of dx & 1 g/kg on day 3 → ↑ survival (NEJM 1999;341:403) If not improving, repeat paracentesis at 48 h: ~25% ↓ PMN count = Rx success

•  Ppx: if h/o SBP or AFTP <1.5 + Na <130, Cr >1.2 or Child-Pugh B (Am J Gastro 2009;4:993) norfloxacin 400 mg PO qd or Bactrim DS qd

Gastroesophageal varices ± UGIB (see also “GIB”; NEJM 2010;362:823)

•  Present in 60% of decompensated cirrhotics; incidence of bleeding is 24% by 2 y; bleeding risk if HVPG >12 mmHg; screen all cirrhotics at time of dx

•  1° prevention of UGIB: med-to-large varices or “red wale” marks or Child-Pugh B or C

nonselective b-blockers: ~50% ↓ risk of bleeding ± ↓ mortality; typically nadolol or propranolol (consider carvedilol if systemic HTN as ɑ1 blockade ↓ intrahepatic vasc resist.; Hep 2010;54:2214); titrate to 25% ↓ HR; EGD  req. to document improvement

endoscopic variceal ligation (EVL): ↓ bleeding & death  bB (Ann Hep 2012;11:369) q1–2wk until gone → survey EGD at 3 mo → q6–12mo; adding bB only ↑ side effects

bB vs. EBL: choice based on Pt/physician preference, bB often 1st (Hep 2008;47:1764)

•  2° prevention: for all Pts after 1st bleed b/c ~50% rebleed & ~30% mortality bB + EBL > either alone (Annals 2008;149:109); TIPS if refractory or consider in Child-Pugh B or C w/in 72 h of admission for esoph variceal bleed (↑ 1-y survival; NEJM 2010;362:2370)

Portosystemic (hepatic) encephalopathy (PSE) (Clin Gas Hep 2012;10:1208)

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

•  Precipitants: ↑ dietary protein, constip., GIB, med nonadherence, infxn, azotemia, ↓ K, Δ volume/water, hypoxia, HCC, portosystemic shunt, meds, PVT

•  Stages: (1) confusion; (2) drowsiness; (3) stupor; (4) coma

•  Dx: asterixis can be seen; NH3 poor Se for dx & monitoring Rx; remains a clinical dx

•  Treatment: identify/correct precipitants, restrict dietary protein acutely (60–80 g/d), lactulose (acidification of colon: NH3 → NH4+) w/ goal 2–4 stools/d ± rifaximin 550 mg bid (↓ gut bacteria → ↓ NH3prod); correct zinc deficiency

•  2° prevention: lactulose ± rifaximin 550 bid (Gastro 2009;137:885; NEJM 2010;362:1071)

Hepatorenal syndrome (HRS) (NEJM 2009;361:1279; Crit Care 2012;16:R23(1))

•  Pathophys: renal vasoconstriction w/ ↓ renal blood flow; kidney histologically nl

•  Criteria: (1) cirrhosis w/ ascites; (2) Cr >1.5 mg/dL; (3)  improvement in Cr (to ≤1.5) after d/c diuretic & volume expansion (1 g/kg/d of albumin × 2 d); (4)  shock (prerenal azotemia/ATN); (5)  nephrotoxic meds; (6)  organic kidney dis (eg, GN) or obstruction

Type I: Cr >2.5 or 1.5× baseline in <2 wk; usually occurs in severe liver failure, often following precipitating event (see later); median survival 2 wk

Type II: more indolent course, median survival 6 mo; liver failure present < in type I

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

•  Rx: Type 1: octreotide (100–200 mcg SC tid) + midodrine (7.5–12.5 mg PO tid, titrate to ↑ MAP 15 mmHg) + 20–40 g/d albumin or terlipressin + albumin (Hep 2010;51:576); definitive Rx = liver tx. Type 2 w/ refractory ascites → TIPS.

Hepatocellular carcinoma (HCC) (Hep 2011;53:1020; Lancet 2012;379:1245)

•  Epi: worldwide, 6th most prevalent cancer, 3rd most frequent cancer-related death, 80% of cases due to HCV/HBV cirrhosis, in which annual risk of HCC is ~3–8% (Gastro 2012;142:1264). ↑’d risk w/ cirrhosis of any type but esp. w/ viral, HFE, PBC, ?ɑ1-AT.

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

•  Dx: screen cirrhotics q6mo w/ U/S ± AFP, though many centers choose dual phase CT/MRI (if arterial enhancing & venous phase or delayed washout, no bx req for dx)

•  Rx: radiofrequency ablation (RFA) for HCCs <3 cm in size; consider resection if single lesion <2 cm and Child-Pugh A w/o portal HTN; transarterial chemoembolization (TACE) preferred for large cancers (not curative) or if not amenable to RFA (near IVC/lung); consider liver transplant if up to 3 HCCs ≤3 cm or 1 HCC ≤5 cm

•  Complications of Rx in 2–11%, procedure mortality ~0.5%. RFA → PVT, colon perforation, abscess, skin burn, PTX, subcapsular hematoma, AKI, diaphragm injury. TACE → postembolization syndrome (PES) = nausea, RUQ pain, ileus, fever, ↑ ALT/AST; self-limited, resolves w/in 1 wk. Other: hepatic ischemia, abscess (2%), biliary tree injury, cholecystitis, gastroduodenal ulceration (~5%), kidney injury (2%).

Other complications

•  Coagulopathy (NEJM 2011;365:147): complex balance of pro- & anti-hemostatic drivers ↑ bleeding: ↓ plts (sequestration & ↓ Tpo) & ↓ clotting factors, renal dysfxn ↑ clotting: ↑ vWF & factor VIII, ↓ protein C, S, ATIII

•  Hepatopulmonary syndrome (HPS) (NEJM 2008;358:2378)

Definition/etiology: abnl pulm gas exchange (A-a gradient ≥15 or PaO2 <80) + intrapulm vascular shunting w/o intrinsic pulm disease; ? due to ↑ pulmonary NO

S/S: platypnea-orthodeoxia, clubbing, cyanosis

Dx w/ contrast echo showing pulm A-V shunt (opac. 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) ( J Clin Gastr 2011;45:703): ↑ PAP (MPAP >25 mmHg), PVR >240 dyns/cm5 and PAOP <15 mmHg. Due to pulm vasoconstriction from ↑ endothelin in ESLD. If PASP ≥40 mmHg by TTE → RHC.

•  Cirrhotic cardiomyopathy: ↓ inotropic & chronotropic response, ↓ systolic and diastolic fxn, prolonged QT, hyperkinetic circulation; ↑ troponin, BNP (JACC 2010;56:539)

•  Infxn: Kupffer cell (hepatic mΦ) dysfxn, ↓ opsonic activity; vaccinate for HAV & HBV, influenza yearly, pneumococcal vaccine, avoid PPIs? (Alim Pharm Ther 2012;36:866)

•  Endocrine: diabetes (15–30%) due to altered glc & insulin metabolism; ↑ frequency of adrenal insufficiency in ESLD (Hep 2012;55:1282)

Prognosis

•  MELD (Model for End-Stage Liver Disease): used to stratify Pts on liver tx list & to predict 3-mo survival in Pts w/ cirrhosis and some acute forms of liver disease. Based on Cr, INR, & total bili. Calculator: www.mayoclinic.org/meld/mayomodel6.html (Gastro 2011;14:1952). If MELD <21 additional predictors of mortality include Na <130 (NEJM 2008;359:1018; Clin Gastro Hep2009;7:1236), refractory ascites, ↑ HVPG and low QoL.

Liver transplantation

•  Undertake evaluation when MELD ≥15

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

•  Contraindic: inadequate social support, active substance abuse (EtOH w/in 6 mo), sepsis, significant comorbidity (eg, PoPH w/ MPAP ≥45 mmHg refractory to Rx), extrahepatic cancer, persistent noncompliance

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

OTHER ETIOLOGIES OF CIRRHOSIS

Hemochromatosis (Hep 2011;54:328; BMJ 2011;342:218)

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

•  HFE mutations (85% of cases), typically C282Y homozygotes (~0.5% of N. European Caucasians), rarely C282Y/H63D compound heterozygotes; C282Y homozygotes: 28% of  develop sx (88% lab abnl), and 1% of  develop sx (due to menses ↓ Fe load → later presentation). C282Y/H63D: only 1.5% manifest dis.

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

•  2° Fe overload: thalassemia, PRBC transfusion, MDS, EtOH, NASH (NEJM 2012;366:348)

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

•  Dx: fasting 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; avoid vit C, PPI (↓ intestinal iron transport); deferoxamine or deferasirox if phleb. contraindic.; genetic counseling

Wilson’s disease (J Hep 2012;56:671)

•  Recessive disorder of copper transport (mutation in ATP7B) → copper overload; primarily affects liver, but also other tissues (brain, eye)

•  Epidemiology: 1 in 40,000, majority present b/t 5 & 35 y/o, only 3% of Pts present >40 y/o

•  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%), rarely penicillamine challenge w/ ↑ urine Cu excretion, liver bx w/ hepatic Cu content. 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/ penicillamine + pyridoxine; 2nd line trientine (↓ toxicity w/ similar efficacy). Zinc: ↓ intestinal Cu transport and can help delay disease; best used if asx or in conjunction w/ chelation (must give 4–5 h apart from chelators).

ɑ1-antitrypsin deficiency (ɑ1-AT) (NEJM 2009;360:2749; Clin Gas Hep 2012;10:575)

•  Abnl ɑ1-AT → polymerization in liver (cirrhosis) & uninhibited protease activity in lung (emphysema). Affects 1/3000 of European ancestry. Varied presentations: neonatal hepatitis in infants; cholestatic jaundice in kids; ↑ AST/ALT or cirrhosis in kids/adults.

•  Extrahepatic disease: emphysema, necrotizing panniculitis, ANCA vasculitis (Wegener)

•  Dx: serum ɑ1-AT level (acute phase reactant), level <50% of nl typically diagnostic;

gold standard = phenotyping of protease inhibitor (Pi); Z is high-risk allele (ZZ = liver dis); S is “slow” allele (SZ = liver or lung dz); M is nl (MZ ? ↑ risk of dis); null/null → no ɑ1-AT protein, ∴ only emphysema and not liver dis (no polymerization)

liver bx shows characteristic PAS  cytoplasmic inclusion bodies

•  Treatment: standard Rx for cirrhosis/chronic liver dis.; ɑ1-AT replacement for emphysema

Primary biliary cirrhosis (PBC) (Hepatology 2009;50:291; Lancet 2011;377:1600)

•  Autoimmune destruction of intrahepatic bile ducts; may be triggered by certain infxns or toxins; a/w X monosomy, variants in IL12ɑ & IL12 receptor genes (NEJM 2009;360:2544)

•  Epi:  40–60 y/o; a/w Sjögren’s, Raynaud’s, scleroderma, celiac & thyroid disease

•  Sx (late): fatigue, pruritus, jaundice, steatorrhea, xanthelasma, autonomic & cog dysfxn

•  Ddx: PSC, autoimmune hepatitis (overlap syndrome), sarcoid, meds, idiopathic adult ductopenia, biliary stricture/cancer

•  Dx: ↑ AΦ, ↑ bili, ↑ IgM, ↑ chol,  antimitochondrial Ab (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 (13–15 mg/kg/d) regardless of stage

~25% complete response, ↑ survival & ↓ histologic change & complications (eg, varices) (Gastro 2005;128:297). Trials of colchicine, MTX, budesonide if refractory to urso.

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

Fat-soluble vitamins; screen/Rx osteoporosis (risk independent of vit Δ deficiency)

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

Primary sclerosing cholangitis (PSC) (Liver Transpl 2008;14:735)

•  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 but poor response to immunomodulator Rx suggesting nonautoimmune pathogenesis.

•  Epi: >(20–50 y). ~70% of Pts w/ PSC have IBD (usually UC); only 1–4% w/ UC get PSC.

•  Clinical sx: fatigue, pruritus, jaundice, fevers, RUQ pain, cholangioca., ↑ Tb, ↑ AΦ

•  Ddx: extrahepatic obstruction, PBC, may also have overlap w/ AIH and similar presentation to IgG4 autoimmune cholangitis (steroid responsive) (Gastro 2008;134:706)

•  Dx: MRCP ± ERCP → multifocal beaded bile duct strictures, but may miss dx if confined to small intrahepatic ducts (~2% “small duct PSC”: better prognosis,? different disease). Liver bx may show “onion-skin” fibrosis around bile ducts, but not necessary for dx, plays role in excluding autoimmune sclerosing cholangitis.

•  Treatment: supportive care, fat-soluble vitamins; no meds have improved survival Ursodeoxycholic acid may ↓ colon CA risk in Pts w/ UC & improve LFTs in Pts w/o UC Dominant stricture: endoscopic dilation, short-term stenting or surgical resection Cholangiocarcinoma (20%): ? biannual surveillance w/ MRCP/RUQ U/S and CA19-9 Liver transplantation: ~30% recurrence, though if UC, colectomy may ↓ recurrence