LIVER DISEASES AND COMPLICATIONS
Educational Objectives
| The goal of this program is to improve the management of complications of cirrhosis and alcoholic liver disease. After hearing
and assimilating this program, the clinician will be better able to:
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 | 1. Distinguish between compensated and decompensated cirrhosis.
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| 2. Recognize and recommend treatment for ascites, spontaneous bacterial peritonitis, hepatorenal syndrome (HRS),
esophageal varices, variceal bleeding, and hepatic encephalopathy.
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| 3. Differentiate discriminant function (DF) from model for end-stage liver disease (MELD).
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| 4. Review definition of ascites and its assessment.
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| 5. Differentiate types 1 and 2 HRS and treatment.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest.
Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a
proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose.
Acknowledgements
Dr. O’Leary was recorded at the 33rd Annual Texas Program, held September 19-21, 2008, in Austin, TX, and sponsored
by the Texas Society for Gastroenterology and Endoscopy, the American College of Gastroenterology, and the
Society of Gastroenterology Nurses and Associates Texas Regional Societies. Drs. Shah and Perri were recorded at
Gastroenterology and Hepatology Update 2008, held September 19, 2008, in Nashville, TN, and sponsored by
Vanderbilt University School of Medicine, Department of Medicine, Division of Gastroenterology, Hepatology, and
Nutrition, and Division of Continuing Medical Education. The Audio-Digest Foundation thanks the speakers and the
sponsors for their cooperation in the production of this program.
Management of Complications of Cirrhosis
Jacqueline O’Leary, MD, MPH, Hepatologist, Baylor University Medical Center, Liver Consultants of Texas, Dallas
| Compensated vs decompensated cirrhosis: decompensated cirrhosis—clinical diagnosis; includes findings of
ascites, hepatorenal syndrome (HRS), variceal hemorrhage, hepatic encephalopathy, and synthetic dysfunction (eg, hypoalbuminemia
or elevated prothrombin time [PT]); compensated cirrhosis—absence of above features
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| Natural history: compensated cirrhosis— patients with hepatitis C, cirrhosis, and no additional risk factors have ≈3%
annual risk for decompensation, 1% to 6% risk annually of developing hepatocellular carcinoma, and 15% risk of dying
within 5 yr; decompensated cirrhosis—model for end-stage liver disease (MELD) score best predictor of 90-day mortality;
50% to 72% of patients with untreated decompensated cirrhosis die in ≤5 yr; treatment improves outcome, even in
decompensation
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| Ascites: paracentesis performed at diagnosis and on admission to hospital in patients with gastrointestinal (GI) bleeding or
encephalopathy; serum-ascites albumin gradient (SAAG) ≥1.1 g/dL in patients with ascites due to liver dysfunction;
treatment—salt restriction (<2 g/day); spironolactone plus furosemide (Lasix) used commonly in ratio of 100/40 mg, with
maximum of 400/160 mg; no limit on daily weight loss for those with lower extremity edema; those without lower extremity
edema should not lose >0.5 kg/day; to determine whether ascites refractory, maximize diuretics and check for dietary noncompliance;
if spot urine sodium greater than spot urine potassium, patient secreting 2 g/day of sodium; nonsteroidal anti-inflammatory
drugs (NSAIDs) nephrotoxic and common cause of refractory ascites; refractory ascites—indication for
urgent transplantation evaluation; can apply for MELD exception of 16 points if >3 L/wk removed; large-volume paracentesis
vs transjugular intrahepatic portosystemic shunt (TIPS)—provides better control of ascites, has increased risk for
hepatic encephalopathy, and has been associated with improved survival in only one meta-analysis; varying results due to
patient selection; contraindicated in heart failure (HF) or pulmonary hypertension, high MELD score, and bilirubin >5 mg/
dL
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| Spontaneous bacterial peritonitis (SBP): complication of ascites; defined as polymorphonuclear (PMN) cell count
>250/mm3 in ascitic fluid; paracentesis safely performed in patients with low platelets and high international normalized
ratio; suspect secondary SBP when infection polymicrobial, anaerobes or fungi isolated, and response to therapy inadequate;
most common organisms Escherichia coli, Klebsiella pneumoniae, and Enterococcus; treatment—third-generation
cephalosporin, eg, cefotaxime 2 g intravenously (IV) q8h, if renal function adequate; in high-risk patients, repeat
paracentesis recommended after 48 hr; if significant improvement (>50% decrease) in PMN count seen, switch to oral
antibiotics for 5 to 10 days; IV albumin—for all patients with SBP; decreases risk for HRS and improves mortality;
prophylaxis—essential after episode of SBP and in cirrhotic patients with fluid in abdomen and GI bleeding; decreases
rate of SBP (from 45% to 14%) and mortality (from 24% to 15%); IV antibiotics possibly superior to oral antibiotics;
70% risk for recurrence of SBP without prophylaxis; daily norfloxacin or weekly quinolone therapy equally efficacious;
primary SBP prophylaxis—indicated if ascitic fluid total protein <1.5 g/dL and Child-Turcotte-Pugh (CTP) score >9
and bilirubin >3 mg/dL or in renal impairment (defined as increased creatinine, increased serum urea nitrogen [BUN],
and hyponatremia)
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| Hepatorenal syndrome: defined as cirrhosis with ascites, serum creatinine >1.5 mg/dL, absence of shock, no treatment
with nephrotoxic drugs (eg, aminoglycosides, IV contrast, NSAIDs), absence of parenchymal liver disease (ie, no proteinuria,
no hematuria, and normal renal ultrasonography [US]), and no improvement after 48 hr of diuretic withdrawal
and volume expansion with IV albumin; oliguria and low urine sodium no longer part of definition but often found;
type 1—doubling of creatinine to >2.5 mg/dL in <2 wk; median survival 2 wk without transplantation or adequate
treatment; type 2—moderate and slowly progressive renal failure with creatinine of 1.5 to 2.5 mg/dL; dominant clinical
feature refractory ascites; median survival 6 mo; annual incidence of HRS in patients with cirrhosis and ascites, 8%
(higher in refractory ascites); infection due to SBP most common cause of HRS
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| Treatment: liver transplantation—only true cure; all patients with HRS should be immediately referred for transplantation,
unless absolute contraindications exist; as bridge to transplantation, midodrine, octreotide, and IV albumin used;
studies show 64% response rate, although survival still dismal; levarterenol (Levophed)—second option; goal to
raise mean arterial pressure (MAP) by 10 points; speaker’s MAP goal 65 mm Hg (combined with IV albumin); pressor
of choice in hypotensive cirrhotic patients; TIPS—only for patients who are not transplant candidates; MELD score
predicts mortality
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| Esophageal varices: screen all patients with cirrhosis using upper endoscopy; rate of developing varices, 8%/yr; new
classification—small varices <5 mm and flatten (previously, grade 1); large varices everything else; patients with small
varices develop large varices at rate of 8%/yr; repeat endoscopy indicated every 2 to 3 yr in patients with no varices and
compensated cirrhosis, every 1 to 2 yr in patients with small varices and compensated cirrhosis, and yearly for decompensated
cirrhosis; patients without varices shown not to benefit from β-blockade; primary prophylaxis—indicated in
patients with large varices or small varices with high-risk lesions; improves mortaloty; methods include nonselective β-
blockade or banding to obliteration; both methods equally efficacious, although β-blockade more cost-effective;
nadolol—once-daily dosing; decreased crossing of blood-brain barrier (patients less likely to develop depression);
propranolol—short- and long-acting forms; if short-acting form used, tid dosing; banding—every 2 wk until obliterated,
with surveillance at 1 to 3 mo, then every 6 to 12 mo indefinitely
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| Variceal bleeding: if acute, transfuse to hemoglobin of 8 g/dL; overtransfusion increases rate of rebleeding; antibiotic
prophylaxis always indicated; IV octreotide initiated immediately; banding superior to sclerotherapy; balloon tamponade
used when control of bleeding not achieved, for maximum of 24 hr (>24 hr increases risk for esophageal necrosis); TIPS
treatment of choice for refractory bleeding in patients with reasonable MELD scores; secondary prophylaxis—
indicated in untreated individuals (60% risk of rebleeding); nonselective β-blockade used with banding to obliteration
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| Hepatic encephalopathy: mental status evaluation sufficient for diagnosis; venous ammonia levels unreliable and
poorly correlate with symptoms; elevated ammonia in absence of symptoms does not justify treatment; ammonia level
helpful only when diagnosis unclear; evaluate patient for precipitating causes (eg, infection); paracentesis to rule out
SBP; look for urinary tract infection and pneumonia; patients immunosuppressed; intravascular volume depletion common,
even in presence of massive extravascular volume overload; commonly caused by excess lactulose, overdiuresis,
and GI bleeding; even small doses of narcotics and benzodiazepines not cleared by liver; hypokalemia increases genesis
of ammonia in kidney, leading to worsening encephalopathy; “lactulosopenia” (patient stops taking it); worsening hepatic
function; TIPS; treatment—determine and treat underlying causes; treat infection; volume expansion for dehydrated
patients; replete potassium to 4 mEq/L; lactulose; bowel movement superior on lactulose; 2 to 3 soft bowel
movements goal of therapy; nonabsorbable antibiotics another option; neomycin causes ototoxicity and nephrotoxicity;
metronidazole causes neuropathy; rifaximin efficacious and has no side effects, but expensive; speaker does not restrict
protein (worsens malnutrition)
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Alcoholic Liver Disease (ALD)
Vijay Shah, MD, Professor of Medicine, Mayo Clinic, Rochester, MN
| Diagnosis: steatohepatitis on liver biopsy in ALD identical to that of nonalcoholic steatohepatitis; laboratory parameters
provide limited discrimination; to distinguish etiology, consider mean corpuscular volume (MCV), aspartate aminotransferase
(AST)/alanine aminotransferase (ALT) ratio, body mass index (BMI), and sex; ALD/nonalcoholic fatty liver disease
(NAFLD) index (ANI) score compares favorably to other scores for detecting source of steatohepatitis
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| Prognosis: discriminant function (DF)—used to determine risk for death; 4.6 multiplied by sum of (PT less control) plus
total bilirubin; DF value >32 indicates >50% mortality; 32 derived as cutoff point for treatment with corticosteroids; issue of
using PT rather than INR (more commonly reported); decision for therapy influenced by toxicity of treatment; patients without
ascites or encephalopathy unlikely to die; MELD score—predicts risk for death from acute liver failure or chronic cirrhosis;
compares favorably to DF for predicting mortality in patients with alcoholic hepatitis; creatinine usually drives
mortality rate
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| Causes of ALD: genes related to alcohol addiction, genetic polymorphisms, and sex (women more predisposed to developing
ALD at any given level of alcohol consumption); bad habits related to alcohol intake, hepatitis C, as well as nutrition and
obesity; most people who drink excessive amounts of alcohol for short periods develop fatty liver; however, more advanced
lesions not as predictable (only 20% of those who continually drink in excess develop alcoholic hepatitis, only 15%-30% develop
cirrhosis); cutoff point in men, 40 to 60 g/day of ethanol (10-20 g/day in women)
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| Treatment: corticosteroids—several trials and meta-analyses support use in patients with DF >32 and/or patients with
encephalopathy; need to treat 5 patients to save one; has infectious sequelae, and long-term survival benefit not well established;
inhibition of tumor necrosis factor (TNF)-α—corticosteroids and other drugs, including pentoxifylline, infliximab,
and etanercept; TNF thought to kill hepatocytes; study showed pentoxifylline associated with significant
improvement in survival; benefit achieved largely through protection of renal function (key determinant of survival in alcoholic
hepatitis); infliximab and etanercept ineffective
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| Liver transplantation for ALD: survival similar, regardless of cause; rate of recidivism ≈20%; pros—excellent
long-term survival, low rate of rejection and alcohol-related graft problems; cons—patient selection
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Ascites and Hepatorenal Syndrome
Roman Perri, MD, Assistant Professor of Medicine, Division of Gastroenterology, Hepatology, and Nutrition,
Vanderbilt University Medical Center, Nashville, TN
Ascites
| Definition: most common manifestation of decompensated liver disease; heralds ≈50% risk for mortality over 2 yr; average
amount of fluid in peritoneal cavity, ≈150 mL (undetectable); requires ≈3 L of ascites for detection on physical examination
(PE); common signs of ascites on PE (eg, bulging flanks, fluid wave, shifting dullness) unreliable (accuracy 50%-
70%); imaging techniques (US and computed tomography [CT]) specific and sensitive for ascites; consequence of portal
hypertension; formation governed by capillary permeability, oncotic pressures, and hydrostatic forces; renal retention of
sodium—precedes formation of ascites; importance supported by finding of resolution of ascites with dietary sodium restriction
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| Assessment: paracentesis; typical laboratory tests include cell count and differential, albumin level (with concomitant serum
albumin level), and total protein level (TPL); cirrhosis and portal hypertension most likely causes; if unexpected
findings result or other etiology suspected, additional tests warranted; SAAG >1.1 g/dL consistent with ascites secondary
to portal hypertension; seen in patients with cirrhosis, alcoholic hepatitis, sinusoidal obstruction, or right-sided HF; ascites
TPL helpful in differentiating HF from cirrhosis (in HF, ascites TPL often >2.5 g/dL)
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| Management: significant improvement of ascites seen with treatment of reversible liver disease; main principle managing
sodium balance by diuresis or restriction of dietary sodium
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Hepatorenal Syndrome
| Manifestations: low systemic arterial pressures, multiorgan dysfunction, marked increases in renin and antidiuretic hormone
levels, and very low glomerular filtration rate (GFR), due to intense renal vasoconstriction and sodium retention;
because of low GFR, response to diuretics poor
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| Definition: functional renal failure that develops in advanced cirrhosis and in setting of circulatory dysfunction
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| Diagnosis: demonstration of reduced GFR difficult in cirrhotic patients because muscle mass reduced, production of creatinine
decreased, and urea synthesis by liver reduced; important to demonstrate no improvement after volume expansion;
criteria—cirrhosis with ascites; serum creatinine >1.5 mg/dL, no improvement in creatinine during ≤2 days of
diuretic withdrawal and volume expansion, no recent episodes of shock, no recent treatment with nephrotoxic drugs, absence
of significant kidney parenchymal disease
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| Type 2 HRS: moderate and steady decline in renal function; significant circulatory dysfunction; primary problem ascites
refractory to diuretics; median survival 6 mo; management—diuretics continued if natriuresis induced; maintain dietary
sodium restriction; serial large-volume paracentesis safe (IV albumin administered; defined as >5 L of ascitic fluid removed);
TIPS option, but rarely results in prompt resolution, and survival benefit uncertain
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| Type 1 HRS: rapidly progressive acute renal failure that often develops after precipitating event, eg, SBP; median survival
10 days; spontaneous improvement rare; prompt improvement of portal hypertension due to abstinence in patients
with alcoholic hepatitis or antiviral treatment of hepatitis B often results in its resolution; however, treatment usually difficult;
surgical therapy—liver transplantation (treatment of choice for patients with advanced cirrhosis, including those
with type 1 HRS); moderate renal insufficiency typically endures, even after liver transplantation; death sometimes occurs
before liver transplantation (therefore, medical support imperative); medical therapy—midodrine and octreotide;
survival significantly better than with low-dose dopamine therapy; norepinephrine (NE) and albumin used by speaker;
have patient in intensive care unit to monitor central venous pressure; NE administered as tolerated; monitor urine output
and blood pressure closely; IV albumin and furosemide administered to keep CVP between 4 and 10 mm Hg; TIPS—
rarely used; takes months to see improvement in GFR; if MELD score >18, median survival after TIPS <3 mo;
dialysis—bridge to transplantation; typical indications used; patient tolerance poor; prevention— IV albumin typically
administered at diagnosis of SBP and on day 3 (reduces risk for HRS); pentoxifylline beneficial in patients with alcoholic
hepatitis, due to reduction in risk for HRS; recently demonstrated that patients with low ascites protein level with markers
of significant liver dysfunction, renal dysfunction, and jaundice tend to develop fewer episodes of HRS with primary prophylaxis
against SBP with oral quinolone
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Suggested Reading
Bambha K et al: Predictors of early re-bleeding and mortality after acute variceal haemorrhage in patients with cirrhosis. Gut
57:814, 2008; De Gottardi A et al: Transplantation for alcoholic liver disease. Gut 56:735, 2007; Ferguson JW et al: Inducible
nitric oxide synthase activity contributes to the regulation of peripheral vascular tone in patients with cirrhosis and ascites.
Gut 55:542, 2006; Fernández J et al: Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis
and hemorrhage. Gastroenterology 131:1049, 2006; Fernández J et al: Primary prophylaxis of spontaneous bacterial
peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 133:818, 2007; Ferral H et al:
Survival after elective transjugular intrahepatic portosystemic shunt creation: prediction with model for end-stage liver disease
score. Radiology 231:231, 2004; Gildea TR et al: Predictors of long-term mortality in patients with cirrhosis of the liver admitted
to a medical ICU. Chest 126:1598, 2004; Groszmann RJ et al: Beta-blockers to prevent gastroesophageal varices in
patients with cirrhosis. N Engl J Med 353:2254, 2005; Leevy CB et al: Hospitalizations during the use of rifaximin versus
lactulose for the treatment of hepatic encephalopathy. Dig Dis Sci 52:737, 2007; Londoño MC et al: MELD score and serum
sodium in the prediction of survival of patients with cirrhosis awaiting liver transplantation. Gut 56:1283, 2007; Ripoll C et al:
Hepatic venous pressure gradient predicts clinical decompensation in patienSalerno F et al: Transjugular intrahepatic portosystemic
shunt for refractory ascites: a meta-analysis of individual patient data. Gastroenterology 133:825 (Erratum: 133:1746),
2007; Selcuk H et al: Factors prognostic of survival in patients awaiting liver transplantation for end-stage liver disease. Dig
Dis Sci 52:3217, 2007; Terra C et al: Renal failure in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis:
value of MELD score. Gastroenterology 129:1944, 2005; Tong W et al: Reconsidering hepatorenal syndrome. Throw
in the towel? Not so fast! Postgrad Med 116:15, 2004.
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