LIVER DISEASE
From the 5th Annual Update in Gastroenterology and Liver Disease, sponsored by the University of Wisconsin School of
Medicine and Public Health and Office of Continuing Professional Development in Medicine and Public Health, Madison,
WI
| HOW DO YOU KNOW IT’S NASH ?—Michael R. Lucey, MD, Professor and Vice-Chair, Department of Medicine,
and Chief, Section of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public
Health, Madison
|
| Case: 42-year-old ballet dancer presents with abnormal liver tests and fatigue; appears well
|
| Alcoholic liver disease: most common cause; screen for alcohol abuse or addiction (CAGE questions)—have you
ever felt you should cut back on your drinking? ever angry with family because they say you drink too much? ever
felt guilty about drinking? ever take “eye-opener” (drink in morning)? historical features in alcohol abuse—history
of rehabilitation, attendance at Alcoholics Anonymous (AA), or arrests for driving under the influence (DUIs),
especially in adulthood (age >27 yr); detailed history—if 2 positive CAGE answers; ask about daily intake, blackouts
(forgetting events of previous day), delirium tremens (DTs), morning shakiness; polysubstance abuse often
present; aspartate transaminase (AST) higher than alanine aminotransferase (ALT) by 2:1 suggests recent alcohol
excess; study—16% to 34% prevalence of alcohol problems among hospital inpatients, depending on how answers
interpreted
|
| Patient evaluation: ballet dancer—not on medication; has had no alcohol for years; iron studies normal, no autoantibodies,
no markers for viral disease; physical examination—look for features of chronic liver disease, presence
of alcohol, social circumstances, markers for hemachromatosis, autoimmune hepatitis, and viral hepatitis;
more on ballet dancer —body mass index (BMI) 38, central obesity, random blood glucose (BG) 148 mg/dL, elevated
triglycerides
|
| Liver studies: imaging—ultrasonography (US) to look for fat (sonographer dependent); computed tomography
(CT) has disadvantage of high radiation and risk to kidney function if contrast used; magnetic resonance imaging
(MRI) best test for semiquantitative assay of fat; biopsy—difficult to distinguish histopathologically nonalcoholic
steatohepatitis (NASH) from alcoholic liver disease; both have fat, fibrosis, Mallory’s hyaline, and leukocytes; patient
may have both (history helps); look for other causes, eg, autoimmune hepatitis, primary biliary cirrhosis, Wilson’s
disease, hepatoma, iron overload, cirrhosis (patient with ascites, spider angioma, enlarged spleen, low
platelets), and hepatitis C
|
| Prevalence: NASH and nonalcoholic fatty liver disease (NAFLD) most common causes of persistently elevated
liver tests in United States and those with Western lifestyle
|
| Obesity in United States: Americans eating more calories (15% more in 1997 than in 1984); prevalence of
NAFLD—≈30% of population; related to body mass (16% in lean persons, 76% in obese); differs by ethnic
group (45% of Hispanics, 33% of white, 21% of blacks), and by sex (42% of white men, 24% of white women);
based partly on body size and poverty (healthy food more expensive than junk food and takes more time to prepare)
|
| Insulin resistance: underlying pathophysiology in NASH; endocrinologists considered fatty liver part of diabetes;
not clear that liver phenomena main problem; higher mortality in metabolic syndrome probably due to cardiovascular
risk; definition—impaired tissue response to insulin, manifested by reduced uptake of glucose by muscle and
adipose tissue; insulin fails to stimulate glycogen synthesis and to suppress gluconeogenesis; to counter problem—
exercise and reduce caloric intake; stimulate body to convert stored fat to energy; truncal fat (middle of abdomen)
leads to insulin resistance
|
| Metabolic syndrome: NAFLD (just fat), may progress to NASH (fat plus inflammation and fibrosis), but most patients
remain at NAFLD; NASH progressive, damages liver, findings—hypertension, insulin resistance, type 2 diabetes,
hypertriglyceridemia, and truncal obesity; associated conditions—include polycystic ovary syndrome
(PCOS) and sleep apnea
|
| Disease progression: patients progressing from NAFLD to NASH may progress to liver failure; predicted to be
most common indication for liver transplantation; recurs after transplantation unless patient controls diet and maintains
exercise; posttransplant medications support metabolic syndrome, eg, corticosteroids (increase appetite, insulin
resistance, and put fat into liver); progression of NASH to cirrhosis to liver cancer to need for transplantation
|
| Weight loss: treatment of choice; done by controlling food intake throughout day and avoiding accidental eating;
requires lifelong discipline; study with pioglitazone—improved liver tests and fibrosis in diabetes and NASH; may
be possible to use insulin sensitizers; study with exercise and weight loss—10% weight loss maintained over duration
of study improved ALT and insulin sensitivity; suggests moderate reduction in weight helps; study involving
gastric bypass surgery—decreased hepatic steatosis but did not change histologic assessment of inflammation or fibrosis
at 1 yr; want to change course of liver injury; unknown whether surgery does this
|
| Advice to patients: lifestyle modification—reduce fat intake; replace saturated with unsaturated fat; replace fat fiber
with standard fiber (fruit and vegetables); 140 min of exercise weekly; if weight has caused joint problems making
exercise problematic, work with case manager or trainer to keep on track; involve family; quit smoking
|
| COMPLICATIONS OF END-STAGE LIVER DISEASE —Norman L. Sussman, MD, Associate Professor of Surgery
and Medicine, Baylor College of Medicine, Houston, TX
|
Hepatopulmonary Syndrome (HPS)
| Patient with pulmonary problems: 54-yr-old Hispanic man with new onset ascites; diagnosed 6 yr ago with cirrhosis
and hepatitis C; former alcohol and intravenous (IV) drug user but clean for past 20 yr; treated with interferon
and ribavirin for 3 to 4 mo; variceal bleeding treated with endoscopic vein ligation; dyspneic; biopsy showed
interstitial lung disease; on home O2 and inhalers; temporal wasting and jugular venous distention; expiratory
wheezes; edema; mild basal, pleural and parenchymal changes on chest x-ray; pulmonary function tests (PFTs)—
forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1 ), FEV1 /FVC ratio, and total lung capacity
(TLC) good, but diffusing capacity of lung for carbon monoxide (DL co ) 50% of normal; no pulmonary hypertension
on echocardiography; pulmonary note describes patient as “OK on room air”; cirrhotic patient with dyspnea—
differential most commonly ascites or hydrothorax; pulmonary fibrosis (had interferon in past); most patients with
portopulmonary hypertension do not have dyspnea; echocardiography suggests no portopulmonary hypertension;
hepatopulmonary syndrome (HPS) likely diagnosis
|
| Pulmonary diseases associated with hepatic dysfunction: HPS—vascular dilatation, capillary and precapillary
dilatation, arteriovenous communications (anatomic shunting); portopulmonary hypertension (POPH)—
vascular obstruction; proliferation of endothelium causes vasoconstriction, leading to thrombosis and hypertension
|
| Further evaluation of patient: pH 7.47; PO 2 49.5 mm Hg (50% of expected); ventilation-perfusion scan (V/Q)
normal. but increased uptake noted in thyroid, brain, and kidney, indicating blood shunting through lungs; saline-
contrast echocardiography showed delayed contrast in left atrium consistent with right-to-left intrapulmonary
shunt; diagnostic of HPS—low O2 and intrapulmonary shunting
|
| Hepatopulmonary syndrome: based on portal hypertension, not pulmonary disease; increased alveolar-arterial
(Aa) O2 gradient on room air; intrapulmonary vascular dilatations (IPVDs) are anatomic shunts; clinical features—
no relation to severity of liver disease, just shunting around liver; platypnea-orthodeoxia syndrome (dyspnea standing);
spider angiomata; higher Aa gradient and shunt fraction, hyperdynamic circulation, low systemic vascular resistance
(SVR) and pulmonary vascular resistance (PVR); patient—O2 increased to 15 L/min to maintain saturation
at 90%; however, with V/Q mismatch and intrapulmonary shunting, O2 diffusion, limited, even at 100% O2 ; sent
home on 4 L/min of O2 and saturation of 91%
|
| Diagnosis of HPS: screen all patients; indication for transplantation; criteria—pulse oximetry <96%, confirm with
ABG in sitting position; echocardiography with contrast; other tests not helpful but may exclude other processes
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| Study data: Schenk et al (2003)—111 patients, 24% with HPS; median survival in HPS 10.6 mo, 2.9 mo in patients
with Child’s C cirrhosis; cause of death liver disease, not HPS; PAO 2 <60 mm Hg predicts high mortality (accelerates
liver disease); Krowka study—extra Model for End-stage Liver Disease (MELD) points for transplantation if
patient has HPS; all patients deteriorate; screen every 6 to 12 mo; increased mortality when PO 2 50 to 60 mm Hg;
list for transplantation; HPS cured by transplantation
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| Summary HPS: severity of HPS does not correlate with severity of liver disease; screen all dyspneic patients with
cirrhosis and all transplant patients; ABGs and contrast echocardiography to diagnose; patients deteriorate over
time; hypoxia accelerates liver disease; MELD underestimates mortality risk, so extra points needed; severe hypoxemia
(O2 <50 mm Hg) and large shunt (>20%) associated with 30% transplant mortality
|
Portopulmonary Hypertension (POPH)
| Case: 43-yr-old woman; 2 wk of progressive jaundice, and severe right upper quadrant pain; fever, vomiting, diarrhea;
risk factors—blood transfusion (1984), interferon-cured hepatitis C, drinks 2 to 3 whiskies daily (women underestimate
drinking by 5-fold); diagnosis—alcoholic hepatitis; started on steroids and pentoxifylline; not
transplant candidate until 6 mo off alcohol; patient stopped drinking; evaluated and listed for transplantation; on
day of surgery, had MELD of 28 and mean pulmonary artery pressure (PAP) of 37 mm Hg (associated with high
mortality); procedure cancelled; treatment—epoprostenol (Flolan [formerly prostacyclin], potent vasodilator given
with pump by catheter into right atrium); within 2 mo, PAP decreased; patient received transplant and doing well
|
| Portopulmonary hypertension: contraindication to transplantation; diagnostic criteria—cirrhosis; right heart
catheterization shows mean PAP (mPAP) >25 mm Hg, pulmonary vascular resistance (PVR) >240 dyne x sec/cm5 ,
pulmonary artery occlusion pressure normal (<15 mm Hg); characterized by thickening of muscular arteries
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| Severity of POPH: moderate to severe—MAP >35 mm Hg, PVR >400 dyne x sec/cm5 , PA opening pressure <15
mm Hg; these patients have high cardiac output; at right heart catheterization, must determine cardiac output,
whether resistance in vessels high or transpulmonary pressure high and whether left ventricular failure present to
explain findings; pathophysiology—precipitating factor portal hypertension, not cirrhosis; not related to degree of
portal hypertension; may be related to blood bypassing liver; contraindication to transjugular intrahepatic portosystemic
shunt (TIPS); must perform echocardiography when evaluating patient for possible TIPS
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| Epidemiology of POPH: frequency 4% to 16.5%; ≤10% of patients have noncirrhotic portal hypertension; ≤30%
of patients have surgical portocaval shunt; no association with any particular liver disease or degree of portal hypertension;
study data—series of patients with POPH who underwent transplantation; mortality rate high (50% if
mPAP >35 mm Hg; 100% if mPAP >50 mm Hg); debate whether PAP more important than PVR or if both needed;
PAP gives information on left heart
|
| Vasodilators: epoprostenol (most potent, given IV; remodulin (Treprostinil), given IV or subcutaneously; iloprost
(Ventavis), inhaled; bosentan (Tracleer), oral, associated with liver failure (black box warning against use in cirrhosis);
sildenafil (Revatio), high dose, given orally; relation to transplantation—can control POPH; extra MELD
points if patient on IV vasodilator; dangerous point for patient when epoprostenol starts to work, because systemic
BP drops, renal failure worsens, and fluid accumulates in every body compartment; at same time, PAP remains
high due to massive cardiac output, causing concern about transplantation
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| POPH conclusions: lethal complication of cirrhosis; MELD does not predict mortality; epoprostenol rapidly reduces
mPAP; transplantation safe when mPAP <35 mm Hg; transplantation may remove need for vasodilators
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Suggested Reading
Belfort R et al: A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J
Med 355:2297, 2006; Castro M et al: Frequency and clinical implications of increased pulmonary artery pressure
on liver transplant patients. Mayo Clin Proc 71:543, 1996; Hickman IS et al: Modest weight loss and physical activity
in overweight patients with chronic liver disease results in sustained improvement in alanine aminotransferase,
fasting insulin, and quality of life. Gut 53:413, 2004; Klein S et al: Gastric bypass surgery improves metabolic and
hepatic abnormalities associated with nonalcoholic liver disease. Gastroenterology 130:1564, 2006; Krowka MJ et
al: Portopulmonary hypertension: Results from a 10-yr screening algorithm. Hepatology 44:1502, 2006; Krowka
MJ et al: POPH syndrome and PPH: a report of the multi-center liver transplant database. Liver Transpl 10:174,
2004; Krowka MJ et al: Pulmonary hemodynamics and perioperative cardiopulmonary related mortality in patients
with POPH undergoing liver transplantation. Liver Transpl 6:451, 2000; Schenk P et al: Prognostic significance
of the hepatopulmonary syndrome in patients with cirrhosis. Gastroenterology 125:1042, 2003; Swanson KL
et al: Natural history of hepatopulmonary syndrome: Impact of liver transplantation. Hepatology 41:1122, 2005.
Educational Objectives
| The goal of this activity is to improve the management of fatty liver disease, hepatopulmonary syndrome, and portopulmonary
hypertension. After hearing and assimilating this program, the clinician will be better able to:
|
 | 1. Describe the physiology and characteristics of nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty
liver disease (NAFLD).
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| 2. Discuss metabolic syndrome and its relationship to NASH.
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| 3. Advise patients on lifestyle modifications for prevention and management of metabolic syndrome.
|
| 4. Relate pulmonary processes to hepatic diseases, eg, hepatopulmonary syndrome (HPS) and portopulmonary
hypertension (POPH).
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| 5. List some criteria for risks of liver transplantation in patients with HPS and POPH.
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Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following
has been disclosed: Dr. Lucey reports Grant support from BMS, Roche Pharmaceuticals, Salix, and Schering Plough.
Dr. Sussman is a consultant for Cotherix.
Acknowledgements
Dr. Lucey spoke in Madison, WI, at the 5th Annual Update in Gastroenterology and Liver Disease, presented April 21,
2007, by the University of Wisconsin School of Medicine and Public Health, and Office of Continuing Professional
Development in Medicine and Public Health. Dr. Sussman spoke in San Diego, CA, at New Treatments in Chronic
Liver Disease, presented March 31-April 1, 2007, by the Scripps Clinic. The Audio-Digest Foundation thanks the
speakers and the sponsors for their cooperation in the production of this program.
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