Pocket Medicine: The Massachusetts General Hospital Handbook of Internal Medicine (47 page)

• Transmission: fecal–oral; travelers to central & SE Asia, Africa and Mexico, exp. to swine • Natural hx: acute hepatitis w/ ↑ mort. (10–20%) if pregnant; rare chronic in transplant Pts • Dx: IgM anti-HEV (through CDC)

• Extrahepatic sx: arthritis, pancreatitis, neuro (GBS, inflam polyradic., meningoenceph.)
Other viruses
(HGV, CMV, EBV, HSV, VZV)

AUTOIMMUNE HEPATITIS (AIH)

Classification
(
J Hep
2011;55:171;
Hep
2010;51:1)
• Type 1: antismooth muscle Ab (ASMA), ANA; antisoluble liver antigen (anti-SLA), a/w more severe disease and relapsing disease • Type 2: anti–liver/kidney microsome 1 (anti-LKM1) or liver/cytosol (LC1); kids (2–14 y) • Overlap syndrome: AIH + PBC or PSC; Rx-induced: minocycline, nitrofurantoin, infliximab
Diagnosis and treatment

• 70% female; 40% present acutely (occ. fulminant); 34% asx; ALT can be >1000

• Extrahepatic syndromes: thyroiditis, arthritis, UC, Sjögren’s, Coombs’
hemolytic anemia • Dx: scoring system combining serologies, ↑ IgG,  viral hepatitis, & characteristic liver bx (lymphoplasmacytic infiltrate & interface hepatitis) has high Sp & mod Se (
Hep
2008;48:169) • Rx: if LFTs 10× ULN, or if 5× ULN w/ IgG 2× ULN, or bridging/multiacinar necrosis on bx •
Prednisone
+ azathioprine → 65% remission w/in 3 y; 50% relapse on withdrawal of meds at 6 mo; up to 90% by 3 y; ∴ most will require long-term Rx; consider substituting budesonide for pred in noncirrhrotics w/ Rx-naive AIH (
Gastro
2010;139:1198) • Liver transplant for ESLD; recurs in ~30% of Pts, but generally easily treated

OTHER CAUSES OF HEPATITIS OR HEPATOTOXICITY

Alcoholic hepatitis
(
NEJM
2009;360:2758;
Clin Liv Dis
2012;16:371)
• Sxs: can range from asx hepatomegaly to decompensation w/ ascites, encephalopathy and death. AST & ALT usually <300–500 w/ AST:ALT > 2:1, in part b/c concomitant B
₆
defic (ALT can be normal); ↓ plt, ↑ iron sat, ↑’d Tbili & INR indicate severe hepatitis.

• Rx: if discriminant fxn (= 4.6 × [PT-control] + Tb in mg/dL) >32 or encephalopathy

methylprednisolone 32 mg/d × 4 wk → 4–6 wk taper; ↓ death (
NEJM
1992
;
326:507) contraindications: GIB, chronic HBV, severe infections such as sepsis

pentoxifylline 400 mg tid ↓ mortality due to reduction in HRS (
Coch
2009;4:CD007339)

NAC + steroids ↓ 30-d but not 6-mo mortality (
NEJM
2011;365:1781)

• Lille model predicts nonresponse to corticosteroids & mortality, powered by Δ Tb from day 1 → 7; nonresponders have 6-mo survival of 25% (
www.lillemodel.com
;
Hep
2007;45:1348)
Acetaminophen hepatotoxicity
(
NEJM
2008;359:285;
BMJ
2011;342:d2218)
• Normal metabolism via glucuronidation and sulfation → nontoxic metabolites • Overdose (usually >10 g): CYP2E1 hydroxylation → reactive electrophilic species (NAPQI) that are scavenged by glutathione until reserves exhausted → hepatotoxicity • CYP2E1
induced
by fasting and alcohol allowing for “therapeutic misadventure” in malnourished alcoholics taking even low doses (2–6 g) of acetaminophen • Liver dysfunction may not be apparent for 2–6 d • 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 if chronic ingestion >4 g/d

Rumack-Matthew nomogram (
www.tylenolprofessional.com/assets/Nomogram.pdf
) predicts risk of hepatotoxicity from serum level of acetaminophen when time of ingestion is known

Low threshold to start NAC even w/ low or undetectable serum acetaminophen levels

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

IV NAC: 150 mg/kg over 1 h → 50 mg/kg over 4 h → 100 mg/kg over 16 h; risk of anaphylaxis; use if unable to tolerate POs, GIB, preg, fulminant hepatic failure

Ischemic hepatitis

• “Shock liver” w/ AST & ALT >1000 + ↑↑ LDH; delayed ↑↑ Tbili • Seen in HoTN & CHF; often requires ↑ venous + ↓ portal/arterial pressure + hypoxia
Nonalcoholic fatty liver disease
(NAFLD, a spectrum of disease;
Hep
2012;55:2005)
• Definition: fatty infiltration of liver
and
absence of EtOH or other cause of steatosis (TPN, rapid wt loss or Rxs such as HAART, tamoxifen, amiodarone, MTX)

NAFL
= steatosis,  inflammation;
NASH
= steatosis + inflammation ± fibrosis on liver bx

• NAFLD: 10–30% 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 • Pathophys: hepatic lipotoxicity w/ oxidant stress & inflammatory response;
PNPLA3
high-risk SNP confers ↑ risk of hepatic fat content, NASH, & fibrosis (
Hep
2011;53:1883) • Clinical: 80% asx, ↑ ALT > AST, but nl ALT/AST does not exclude poss. of NASH on bx • Dx: based on clinical variables & imaging. Liver bx remains gold standard. NAFLD fibrosis score (
www.nafldscore.com
) = clinical variables to predict NASH w/ advanced fibrosis.

• Rx: wt loss, exercise, DM/lipid control (statins;
Lancet
2010;376:1916); pioglitazone + vit E ↓ steatosis & inflam, not fibrosis (
NEJM
2010;362:1675). Pentoxifylline under study (
Hep
2011;54:1610).

ACUTE LIVER FAILURE

Definition

• Acute hepatic disease + coagulopathy + encephalopathy; w/o known pre-existing liver dis.

• Fulminant = develops w/in 8 wk; subfulminant = develops between 8 wk and 6 mo
Etiology
(
Lancet
2010;376:190)
•
Viral
(12% of cases)

HAV, HBV, HCV (rare), HDV + HBV, HEV (esp. if pregnant)

HSV (immunosupp Pt), EBV, CMV, adenovirus, paramyxovirus, parvovirus B19

•
Drugs
/toxins (nearly 80% of cases;
Hep
2010;52:2065)

Drugs: acetaminophen (most common cause; >40% of all cases), phenytoin, INH, rifampin, sulfonamides, tetracycline, telithromycin, amiodarone, PTU, valproate

Toxins: fluorinated hydrocarbons, CCl
₄
,
Amanita phalloides

•
Vascular
: ischemic hepatitis, Budd-Chiari syndrome, hepatic SOS, malignant infiltration •
Autoimmune hepatitis
(initial presentation) •
Misc
.: Wilson’s, acute fatty liver of pregnancy (HELLP, Reye’s), idiopathic (up to 20%)
Clinical manifestations

• Initial presentation usually nonspecific, w/ nausea, vomiting, malaise, followed by jaundice • Neurologic

encephalopathy
: stage I = DMS; stage II = lethargy, confusion; stage III = stupor; stage IV = coma

asterixis
in stage I/II/III encephalopathy; hyperreflexia, clonus, rigidity in stage III/IV

cerebral edema
→ ↑ ICP, ↓ CPP → cerebral hypoxia, uncal herniation, Cushing’s reflex (hypertension + bradycardia), pupillary dilatation, decerebrate posturing, apnea

•
Cardiovascular: hypotension
with low SVR

•
Pulmonary: respiratory alkalosis
, impaired peripheral O
₂
uptake, pulm edema, ARDS

• Gastrointestinal: GIB (↓ clotting factors, ↓ plt, DIC), pancreatitis (? due to ischemia) •
Renal: ATN, hepatorenal syndrome
, hyponatremia, hypokalemia, hypophosphatemia •
Hematology: coagulopathy
(due to ↓ synthesis of clotting factors ± DIC) •
Infection
(~90% of Pts): esp. with
Staph
,
Strep
, GNRs and fungi (↓ immune fxn, invasive procedures); SBP in 32% of Pts;
fever and
↑
WBC may be absent
•
Endocrine: hypoglycemia
(↓ glc synthesis), metabolic acidosis (↑ lactate), adrenal insuf.

Workup
(
Hep
2012;55:965)
• Viral serologies (see “Acute Hepatitis Workup”) • AIH serologies, ceruloplasmin & serum/urine copper, pregnancy test, arterial NH3

• Toxicology screen (acetaminophen levels q1–2h until peak determined) • Imaging studies (RUQ U/S or abd CT, Doppler studies of portal and hepatic veins) • Liver biopsy (unless precluded by coagulopathy → in which case consider transjugular)
Treatment
(
Hep
2012;55:965)
•
ICU care at liver transplant ctr
for hemodynamic & ventilatory support; CVVH for ARF

•
IV
N
-acetylcysteine
(same dose as for acetaminophen): all Pts w/ hepatic failure and grade 1–2 enceph: ↑ cerebral blood flow and ↑ transplant-free survival (
Gastro
2009;137:856) • Cerebral edema: rare w/ NH
₃
<75 mM/L, invariable if >200 mM/L; consider ICP monitoring if stage III/IV enceph; if ↑ ICP → mannitol 0.5–1.0 mg/kg; prophylactic 3% saline for goal Na 145–155 mEq/L if NH
₃
>150 mM/L, grade 3/4 enceph, ARF or on vasopressors; barbiturates & hypothermia if ↑ ICP refractory to osmotic agents • Encephalopathy: intubate for grade III or IV; lactulose (avoid diarrhea & overdistension) • Coagulopathy: vit K; FFP/plts/cryo if active bleeding; ? recomb. factor VIIa; PPI prophylaxis • Infection: low threshold for abx (broad spectrum, eg, vancomycin & 3rd-gen ceph.), albeit no proven mortality benefit to empiric abx • Treatment of specific causes: nucleo(s/t)ides for HBV; steroids for AIH; consider plasma exchange for Wilson’s; IV acyclovir for HSV; gastric lavage & PCN-G for
Amanita phalloides;
delivery of child for pregnancy related; TIPS and anticoag for Budd-Chiari • Liver transplantation if poor prognosis w/ grade II or III encephalopathy (see below)
Prognosis

• Non-acetaminophen ALF mortality
80%, acetaminophen-induced ALF mortality
30%

• Predictors of poor outcome

Acetaminophen-induced: pH <7.3 after fluids
or
INR >6.5, Cr >3.4, or grade III/IV enceph.

Non-acetamin.-induced: INR >6.5
or
3 of the following: non-A/B viral hep; other drug toxicity; time from jaundice to enceph. >7 d; age <10 or >40 y; INR >3.5; Tbili >17.4

• ALFED model: NH
₃
, Tbili, INR, & ≥2 enceph (
Gut
2012;61:1068) & ALFSG index: coma grade, INR, Tbili, PO
₄
, & serum CK18 (
Gastro
2012;143:1237) are new indices for predicting need for liver Tx and mortality • ~25–30% of Pts w/ ALF undergo liver transplantation w/ 5-y survival rate of 70%

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