Case Conference
January 5th, 2015
53 year old man
CC: Turning yellow
PMH
Type 2 DM
Hyperlipidemia Chronic Back Pain
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Meds (Stopped 6 months ago) Glipizide Metformin Simvastatin Gabapentin Aspirin Lisinopril Furosemide Social History Single On disability
36 oz/wk of ETOH for years Drinks mostly vodka
40 pack year smoking history
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Family History Father: CAD
Mother: Colon cancer Sister: Healthy
HPI
One week history of:
Feeling tired
Poor appetite but very
thirsty
Increased urinary frequency
Has appt scheduled with PCP in
1 month (couldn’t get in sooner)
Mother & sister visited 3 days
PTA and noticed that he
“looked yellow”
They convinced him to seek care
sooner, so now coming to ED
Additional ROS:
Early satiety for 1 month
Unintentional weight loss of 40-60 pounds over the past 2 years
Dark urine for the past 2 wks Intermittent subjective fevers No SOB
No CP or edema No N/V/D
No abdominal pain
No constipation or stool color changes
Exam
BP 98/64 | P 95 | T 98.5 F | RR 24 | Ht 6’2” | Wt 332 lb | SaO2 100%
General: NAD
Eyes:
Scleral icterus
HEENT: Poor dentition
Resp: Clear
CV: Distant heart sounds, RRR, no M/R/G, no JVD or edema
Abd: Obese,
distended
, non-tender, dull to percussion, could not
palpate liver
Lymph: No LAD
Skin:
Diffuse jaundice; spider nevi on face
T-I-N-C-H-E-M-P-V-I
Albumin
2.8
Total Protein
6.3
Total Bilirubin
38.2
Direct Bilirubin
16.2
Indirect Bilirubin
22
Alk Phos
332
130
!
94
!!
7
!
3.0
26 0.8
158
12
!
15
!!
229
ALT
40
AST
141
INR
1.4
Lipase
33
Amylase
12
What would you guys like next?
Ultrasound
Considerable hepatomegaly with
increased echogenicity most
commonly associated with fatty
infiltration
No gross biliary obstruction
Splenomegaly - 15.3 cm
CT abdomen/pelvis
Hepatomegaly & liver fatty
infiltration
No extrahepatic biliary dilatation
Contracted gallbladder, not
overtly inflamed
GI Consult
Bilirubin too high to be obstruction
Findings are consistent with severe alcoholic hepatitis
+ Factors: preserved renal function, near normal INR
- Factors: high bilirubin, low sodium
Does have risk factors for fatty liver
Hospital Days 2-4
Started on lactulose due to
asterixis
GI recommended deferring
prednisolone
Serologies negative
HAV, HBV, HCV
HIV negative
Bilirubin stable in mid 30s
Liver biopsy
Cholestatic steatohepatitis
Marked steatosis
Moderate inflammatory activity
(grade 2 of 3)
Moderate pericentral &
periportal fibrosis (stage 2 of 4)
No superimposed liver disease
Hospital Days 5-17
Hospital Day 5
Cr 0.9 -> 1.5 -> 2.6 over 3 days Na 129 -> 125
Renal consulted: felt patient was likely dry
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Hospital Day 6 Cr 2.6 > 3.1
UOP Decreased
Renal: now consistent with Type 1 hepatorenal syndrome
MELD score 40 (83% 90 day mortality)
Midodrine, prednisolone & octreotide
Hospital Days 7-11
Cr 6.9
Bilirubin peaked at 46.8
Patient intermittenty encephalopathic
Care Conf: proceed with HD
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Hospital Day 17
INR 2.6
Final Course
Tolerated dialysis
LFTs & lytes stabilized
Discharged to home with plans
for HD T-Th-Sat
Readmitted 2 months later with
line sepsis (enterococcus)
HD discontinued
Renal function normalized (Cr 1.3)
Bilirubin normal
Alcohol Related
Liver Disease
(ALD)
Plus some stuff on
cirrhosis & all the
Board Question
50 yro man is evaluated during a routine visit for alcoholic cirrhosis. He has a 3 month h/o hepatic encephalopathy, characterized by forgetfulness & personality changes, that is well controlled with lactulose. He has not consumed alcohol in the last 2 years. One year ago he developed ascites that required diuretics. At that time a screening upper endoscopy revealed no varices. His current
medications are lactulose, spironolactone, and furosemide.
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On exam, he is alert and in NAD. He is oriented but has a mild psychomotor slowing. Vitals are normal. Scleral icterus, temporal wasting, and spider angiomata are noted. Neuro exam reveals mild asterixis.
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Labs: Hct 33%, Platelets 75,000, INR 1.4, Albumin 2.9, ALT 32, AST 45, Bili 4, Cr 1.3, Lytes normal.
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Which of the following is the most appropriate management? 1. Add nadolol
2. Begin a low protein diet
3. Continue medical treatment without changes 4. Refer for liver transplantation
He has manifestations of decompensated liver disease. These individuals have higher mortality rates and all should be evaluated for
How does alcohol damage the liver?
Our understanding of the pathogenesis is incomplete
Alcohol is a direct hepatotoxin
It initiates a variety of metabolic responses that influence the final hepatotoxic response Thought to begin with the production of toxic
protein aldehyde products (which promote lipogenesis, inhibit fatty acid oxidation) Results in a host of cytokine release causing
liver injury
TNF whoops in to help facilitate hepatocyte apoptosis & necrosis
More cells get activated to make collagen —> causes fibrosis
Fibrosis affects the liver architecture & progression leads to cirrhosis
Alcohol Related Liver Diseases
“ALD”
Steatosis
Alcoholic
Hepatitis
Cirrhosis
Alcohol Related Liver Disease
Fatty liver (steatosis) Occurs w/in 2 weeks of regular alcohol use (common) Resolves in 4-6 wks with abstinence If persistent use: ~1/3 will develop steatohepatitis 30% risk of progressing to cirrhosis
Histo: same as NAFLD
Abuse can lead to:
Alcoholic Hepatitis Acute form of liver injury
Usually heavy use (>100g/d) for 20+ yrs Range of severity (asypmtomatic transaminitis to fulminant liver failure)
Poor short term prognosis Cirrhosis Risk for decompensation (ascites, variceal bleeding , encephalopathy) Once decompensated, 5 yr transplant free survival is 60% if alcohol free vs. 30% if drinking HCC 80% of HCC cases occur in patients with cirrhosis Need to screen with US q6mo
Risk Factors
Ethanol Ingestion (30 + g/d)
Coexisting Hep B or C
Females
Obesity
Iron Overload states
Hispanic/American Indian
Not everyone gets ALD
But once it develops, continued use typically leads to persistent & often
progressive liver disease
Both binge & chronic drinkers are at risk Development is directly related to
Alcohol Related Liver Disease
Fatty liver (steatosis) Asymptomatic
Exam is generally normal, but may also have hepatomegaly
Clinical Manifestations
Alcoholic Hepatitis Can be jaundiced or have mild fever and RUQ pain Anorexia, proximal muscle wasting Hepatomegaly (+/- tender) Again, manifestations are variable (asymptomatic to fulminant liver failure)
Cirrhosis Peripheral stigmata of liver disease Signs of hepatic decompensation (ascites, edema, encephalopathy ) HCC
Alcohol Related Liver Disease
Fatty liver (steatosis) ALT and AST may be normal or moderately elevated
Elevated alk phos & GGT
Lab Tests
Alcoholic Hepatitis
Elevated AST & ALT (can last months)
Elevated alk phos & GGT
Elevated bilirubin Leukocytosis
Cirrhosis
ALT and AST may be normal or moderately elevated
Elevated alk phos, GGT Elevated bilirubin (decompensated) Low albumin Elevated INR Elevated Cr (HRS) Hyponatremia
Other tests that can be seen in all
forms of ALD Low platelets Anemia Elevated MCV Low Lymphos High ESR High INR
Classic finding is AST > ALT (ratio > 1 & classically >2)
AST is usually < 8x ULN (<500) and ALT is usually < 5x ULN (<200)
Degree of elevation does not correlate with severity of disease
Alk phos generally not >2/3 ULN (if higher, consider cholestatic liver disease such as PSC or PBC )
The History
How much alcohol is too much
Average consumption of >210g of alcohol
per week in men
Average consumption of >140g of alcohol
per week in women
Over a 2 year period
FYI: an average drink is 14 grams of alcohol
12oz of beer, 5 oz of wine, 1.5 oz of 80
proof spirits
Translates to >15 drinks/week for men & >10
drinks/week for women
Those drinking >30g / day - increased risk for
cirrhosis
The Questions
ETOH use (including patterns, type, amount)
Medications (herbals & OTC) Parental exposures to viruses (transfusions, IVD, tattoos, sex) Occupational exposures to
hepatotoxins
Family hx of liver disease Metabolic syndrome, Celiac
disease, Autoimmune Disorders
Definition c/w 2012 joint guideline from Am. Gastroenterological ASsoc, Am. Assoc for the study of liver disease, &
Diagnosis
Suspected in patient with a compatible hx who has elevated transaminases &
suggestion of fatty liver on imaging
2010 guideline from American Association for the Study of Liver Diseases
and American College of Gastroenterology & 2012 guideline from European
Association for the Study of Liver
Obtain detailed hx (ETOH use, evaluate for other causes)
Physical exam to ID stigmata of chronic liver disease
Lab tests to look hepatic inflammation & to assess synthetic function
Transaminases, bili, Alk Phos, GGT, CBC, Albumin, Coags (INR)
Lab tests to ID other causes of chronic hepatic injury
Hep B surface Ag, anti-hep B core IgG, Abs to HCV
Serum ferritin
Total IgG or gamma-globulin level, ANA, Anti-smooth muscle Ab,
anti-liver/kidney microsomal-1 (anti-LKM-1)
Diagnosis Continued
Just a few words on extra stuff
Liver imaging
May provide evidence of hepatic steatosis or cirrhosis
But can’t differentiate alcoholic liver disease from other causes
US is ALWAYS indicated to evaluate the liver & to exclude other causes
of abnormal liver tests (is biliary obstruction or hepatic masses)
US detects steatosis, but misses those with <30% steatosis (fat
appears hyperechoic, fibrosis reveals coarse echo texture, and
cirrhosis may shows nodules causing irregular liver outline)
Biopsy
May be required if diagnosis remains uncertain
It can also establish the severity of disease
Differential Diagnosis
Nonalcoholic steatohepatitis
Acute viral hepatitis
Drug induced liver injury
Alpha-1 antitrypsin deficiency
Wilson’s disease
Hemochromatosis
Ascending cholangitis
Autoimmune hepatitis
Assessing Severity of Alcoholic Hepatitis
Maddrey Discriminate Function = 4.6 (Patients PT - Control PT) + T bili
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MELD score = [0.957 (serum Cr) + 0.378(serum bili) + 1.20(INR)] * 10
If on hemodialysis (automatically set Cr to 4.0)
Several models have been proposed to assess severity of alcoholic hepatitis But the MDF & MELD are most commonly used
Also helpful to predict prognosis / mortality & are used to determine who needs treatment
MDF >= 32 has HIGH short term mortality (as high as 50%) & should be treated with steroids MELD (???): MKSAP says a score of 18+ has similar prognostic implications as the MDF
Mortality
Factors associated with increased mortality: Older age
AKI
Elevated bilirubin level Elevated INR
Leukocytosis
Alcohol consumption >120 g/day
Presence of infection (sepsis, SBP, PNA, UTI, aspergillosis) Hepatic encephalopathy
UGIB
A bilirubin to gamma glutamyl transferase ratio >1 High hepatic histology
Which patient should be started on
corticosteroid therapy?
1. All patients with alcoholic hepatitis
2. Mild to moderate alcoholic hepatitis only
3. Severe alcoholic hepatitis only
4. Steroids have not been proven to improve outcomes in patients with
alcoholic hepatitis
Treatment for ALD
Abstinence
Essential to prevent progression & improve survival Steatosis will resolve
Portal pressures & Ascities will also improve or normalize
More likely among those who receive treatment for alcohol abuse or dependence
Nutrition
Almost all patients have some degree of malnutrition (protein - calorie malnutrition) Degree of malnutrition correlates with mortality (increased risk for infection,
ascites, & encephalopathy)
All should have a nutritional assessment
Nutritional therapy is indicated for alcoholic fatty liver + malnourished &/or vitamin/mineral deficiencies
If not malnourished & no vitamin/mineral deficiencies: encourage healthy, balanced diet
Additional Treatments
for Alcoholic Hepatitis
General Principles for all cases Treat withdrawal
Hemodynamic
Caution with over-hydration
May worsen ascites, cause variceal hemorrhage
Nutritional support
Thiamine, folate, pyridoxine Phosphate & magnesium
Tube feedings if unable to meet caloric needs
Infection surveillance
If febrile, obtain cultures
If Fever + HE, hold on LP unless no improvement with lactulose
Prophylaxis aginst GI bleeding (PPI)
For severe hepatitis ONLY(MDF >= 32) Corticosteroids
Pentoxyfylline Liver Transplant
Corticosteroids
Prednisolone
40mg/day x 28 d
Finish with 16 d taper
Contraindications:
Active bacterial/
fungal infection
Chronic Hep B/C
Pancreatitis, Renal
Failure, or GIB
(hasn’t been studied)
Pentoxyfylline
Phosphodiesterase
inhibitor that also
inhibits TNF synthesis
Alternative to steroids
Use for cases when
steroids are
contraindicated
400mg TID x 28 d
(does need to be
adjusted for CKD)
Liver TransplantThose with active alcoholic hepatitis are typically not candidates
High risk for morbidity & mortality & also higher risk for relapse
Most centers require 6+ months of sobriety +
enrollment in alcohol rehab program
Refer patients with manifestations of
decompensated liver failure (ascites, HE, varices) should be referred to transplant center (estimated 50% mortality rate at 2 yrs)
Additional Treatments
Note:
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Prednisolone is favored over prednisone
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Prednisone has to be converted to active
prednisolone by the liver.
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Cirrhosis
A late stage of progressive hepatic fibrosis
Characterized by distortion of hepatic architecture & formation of
regenerative nodules
Generally irreversible in its advanced stages
Develops due to chronic hepatic inflammation or cholestasis
MCC in developed countries include chronic viral hepatitis (B/C), Alcohol, Hemochromatosis, and Non-alcoholic fatty liver disease
Less common causes: Autoimmune
Primary & secondary biliary cirrhosis Primary sclerosing cholangitis
Meds (MTX, INH) Wilson disease
Alpha 1 Antitrypsin deficiency Celiac disease
Granulomatous liver disease Idiopathic portal fiborsis Polycystic liver disease
Infection (brucellosis, syphillis, echinococcosis, schistosomiasis) Right sided HF
Herediatry hemorrhagic telangiectasia Veno-occlusive disease
Clinical Manifestations of Cirrhosis
Jaundice / Conjunctival Icterus
Ascites (30%) / Abdominal distension
Anorexia / Weight loss
Proximal muscle loss
Encephalopathy (if severe) / Asterixis
Fetor Hepaticus
Hepatomegaly / Splenomegaly
Gynecomastia / Hypogonadism
Spider angiomata (telangiectasias)
Palmar erythema
Nail changes
Anovulation / Hypogonadism
Muerke Nails
Diagnosing Cirrhosis
There are no standard lab tests
But certain lab tests do help show poor liver function (INR, albumin)
Imaging is typically obtained if cirrhosis is suspected
Though still not sensitive or specific to make the diagnosis (so use in
context of exam & labs to help support the diagnosis)
Start with abdominal US (tells about the appearance of the liver & blood
flow w/in portal circulation, less expensive, no contrast or radiation)
Liver may appear: small, nodular, increased echogenicity
May give clues to portal HTN (dilated portal vein)
CT & MRI generally not performed (dye, radiation, cost)
Other Complications of Liver
Disease
Portal Hypertension
Gastroesophageal Varices
Variceal Hemorrhage
Ascites
SBP
Hepatic Encephalopathy
Hepatorenal Syndrome
Hepatopulmonary Syndrome
Portopulmonary HTN
HCC
Portal Vein Thrombosis
Cirrhotic Cardiomyopathy
Indicate Decompensated Cirrhosis Risks: Bleeding Infection ETOH Meds Dehydration Constipation Obesity
Portal Hypertension & GE Varices
Portal Hypertension
Leads to alterations in portal venous blood flow
MC manifestations are GE varicies, ascities, & HE
Portal pressure >12 is generally enough to start causing
problems (ascites, varices) If pressure can be reduced to < 12, then ascites will resolve The increased pressure leads to progressive splanchnic
vasodilation, which causes a whole host of down stream effects (decreased BP, poor renal perfusion, varices)
Portal Hypertension & GE Varices
Gastroesophageal VaricesPresent in 30-60% of patients with cirrhosis at the time of diagnosis
Enlarge over time and may spontaneously rupture
Tx hemorrhage with Octreotide
(vasoconstriction), Antibiotics (Ceftriaxone or Norfloxacin for 5-7 d or until DC), &
Endoscopic therapies (band ligation or sclerotherapy)
Initiate secondary prophylaxis: nonselective BBs
If re-bleeding occurs - consider TIPS
Mortality has been reduced to 15-20% with treatments
Those with cirrhosis should be screened for varices
Positive Screen (lg varices) Primary prophylactic treatment: Non-selectivve BBs (propranolol, nadolol)
Reduce HR by 25% or 55-60bpm No further surveillance needed Endoscopic variceal band ligation (if can’t take BBs)
Requires ongoing surveillance Both reduce hemorrhage by 40%
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Negative screens (not lg varices) Screen q2-3 yr if no varicies
Screen annually if small to medium varicies
Ascites & SBP
Ascites
The most frequent complication of cirrhosis Its secondary to portal hypertension
~50% of patients with compensated cirrhosis get it w/in 10 years
All new ascites requires diagnostic paracentesis (cell count, diff, albumin, total protein, & culture) Calculate SAAG
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Treatment (for CLINICALLY apparent cases): < 2g NaCl/day + diuretics (spironolactone + furosemide, ratio of 100:40 mg/day)
+/- large volume paracentesis (+ albumin 8g/ L fluid)
Refractory cases: serial paras, TIPs, & liver transplant
Salbumin - Aalbumin
SAAG > 1.1 AND Ascites protein < 2.5 = portal HTN
SBP
+ fluid culture + Abs PMN >= 250 cells/microL Treatment: 3rd generation cephalosporin (5 d)
Albumin (shown to decrease mortality) Stop BB (increases HRS & LOS)
MC pathogens: E.Coli, Klebsiella pneumoniae, and pneumococcus
Secondary Prophylaxis: Norfloxacin (Bactrim if allergic)
Primary Prophylaxis: if low protein ascitic fluid (<1g/dL) and severe liver dysfunction (esp if hospitalized)
Mortality has dropped from 50% to 15%
Clinically apparent ascites: Abd distension, edema
Exceptions: huge salt intake, fluid resuscitated, or Hep B (sincee these have other potential remedies)
Hepatic Encephalopathy
Disturbance in CNS dysfunction
Due to hepatic insufficiency and portosystemic shunting
Many hypotheses (low O2, toxin release from injury liver cells, impaired gluconeogenesis) But Ammonia is certainly the big factor at play
It is produced by colonic bacteria in the gut during catabolism of nitrogenous sources (proteins, secreted urea) & is reabsorbed from gut and enters circulation via the portal vein
Normally a HEALTHY liver clears almost all of it before it enters systemic circulation Increased frequency and severity predict an increased risk of death
Need to rule out other causes: metabolic disturbances, infections, meds, intracranial lesions or events Other risks: recent TIPS or large portosystemic shunts (seen on CT imaging)
Serum ammonia levels do NOT correlate with stage of encephalopathy (but helpful to evaluate for unexplained confusion)
Treatment: focus on reducing excess nitrogen in the gut
Lactulose: nonabsorbable disaccharide the decreases absorption of ammonia (goal of 3-4 BMs daily)
Oral antibiotics (neomycin and rifaximin): reduce effects of colonic bacteria on ammonia production & are added for refractory cases
Hepatorenal Syndrome
Portal HTN —> arterial vasodilation in splanchnic circulation (due to increased vasodilator production / release) —> Systemic vascular Resistance falls —> Reduced BP —> Activates RAS —> Renal Vasoconstriction &
reduced renal perfusion —> severe reduction in GFR (minimal histo changes)
Type I: rapidly progressive (Cr doubles to > 2.5 or Cr clearance drops by 50% to < 20 mL/min/1.73 m2 in < 2 weeks Type II: Is not rapidly progressive & commonly associated with refractory ascites
Major Criteria (diagnosis of exclusion): Serum Cr > 1.5
No improvement after 2 days of diuretic withdrawal & volume expansion with albumin(to < 1.5) Absence of septic shock or hypotension
No current or recent treatment with nephrotoxins
Absence of identifiable parenchymal kidney disease (no significant proteinuria of <500 mg/d, hematuria, ATN, obstruction)
Treatment:
RCTs have shown improved creatinine with albumin volume expansion
Raise BP: norepinephrine (if in the unit) or midodrine (alpha 1 agonist, vasoconstricts) & octreotide (inhibits endogenous vasodilator release to help maintain splanchnic vasoconstriction)
Perhaps TIPS (this is a newer indication — not our call)
Hepatopulmonary Syndrome &
Portopulmonary Hypertension
HPS:
Defect in arterial oxygenation due to pulmonary vascular dilation in the setting of cirrhosis and portal hypertension
Dyspnea on exertion or at rest is the hallmark symptom
Suspect in patients with cirrhosis who develop hypoxemia (pO2 < 70) in absence of other causes Microbubble visualization w/in LA after 3-6 cardiac cycles on a contrast enhanced TTE is diagnostic No effective medical therapies
Those with arterial PO2 < 60 become high priority candidates for liver transplant
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PPH:
Coexisting primary portal HTN + pulmonary HTN Confirmed by RHC
Poor prognosis
For those with PAPs > 35 to 50, transplant is no longer an option due to increased risk of preoperative death
Board Question
A 45yro man is admitted for new onset RUQ pain, ascites, fever, and anorexia. History is notable for HTN & alcoholism. Hi only med is HCTZ.
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On exam, Temp is 100.6F, BP 110/50, HR 92, RR 16. BMI is 24. Spider angiomata are noted on chest and neck. Liver is palpable and tender. + Abd tenderness with flank dullness to percussion.
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Labs: Alk phos 210, ALT 60, AST 125, Bili 6.5, Cr 1.8
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The Maddrey discriminant function score is 36. US discloses coarsened hepatic echo texture, splenomegaly, and moderate to large amount of ascites. Diagnostic para reveals SBP and IV ceftriaxone is started. EGD is notable for small esophageal varices w/o red wale signs and no evidence of recent bleeding.
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In addition to continuing ceftriaxone and starting albumin, which of the following is the most appropriate treatment?
1. Etanercept 2. Infliximab 3. Pentoxifylline 4. Prednisolone
MDF of 32 or greater = severe alcoholic hepatitis . ALL severe cases should get treated. Prednisolone is the preferred treatment unless there are contraindications such as INFECTION, renal failure, or GIB. This guy has SBP. In this case,
