Gastroenterology



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General considerations


  • See American Gastroenterology Association technical review on liver function tests in Gastroenterology 2002;123:1367.

  • If asymptomatic, repeat to confirm; if still abnormal, decide which pattern LFT abnormalities fit into:

  • Hepatocellular, elevated transaminases with normal-mildly elevated alk phos and normal to elevated bilirubin

  • Cholestatic, elevated alk phos and bilirubin with normal to mild elevations in aminotransferases

  • Mixed picture and infiltrative

H
Causes of chronically elevated transaminases

Hepatic causes


Alcohol abuse

Medication

Chronic hepatitis B and C

Steatosis and nonalcoholic steatohepatitis

Autoimmune hepatitis

Wilson’s disease (in patients <40)

Alpha1-antitrypsin deficiency

Non hepatic causes


Celiac sprue

Inherited disorders of muscle metabolism

Acquired muscle diseases

Strenuous exercise

From N Engl J Med 2000;342:1266
epatocellular pattern, etiologies


  • AST (SGOT) can be found in, in decreasing order: liver, cardiac muscle, skeletal muscle, kidney, brain, pancreas, lungs, leukocytes, and erythrocytes

  • ALT (SGPT) much more specific to liver

  • Causes of acute transaminitis

  • Acute viral hepatitis (A, B, C, D, E)

  • Toxin or drug (e.g. acetaminophen)

  • Ischemic (e.g. shock liver)

  • In critical illness, transaminitis usually multifactorial from intrahepatic cholestasis secondary to sepsis, hepatic congestion from CHF, and/or medications

  • Degree of aminotransferase elevation does not correlate with hepatocyte necrosis

  • Alcoholic liver disease:

  • A
    Drugs associated with liver injury

    Hepatitis-like injury

    Acetaminophen

    Alpha-methyldopa

    Diclofenac and other NSAIDs

    Glyburide

    Isoniazid

    Methorexate

    Niacin


    Nitrofurantoin

    Statin drugs


    Cholestasis


    Amoxicillin/clavulanate

    Androgens

    Captopril

    Chlorpromazine

    Erythromycin

    Estrogens (oral contraceptives)

    Parenteral nutrition

    Tolazamide

    Tolbutamide

    Trimethoprim-sulfamethoxazole


    ST:ALT > 2 because of relative deficiency of ALT given alcohol-related deficiency of pyridoxal-6-phosphate, required for ALT activity

  • AST can be elevated up to 8x normal

  • ALT could be normal to 5x normal

  • Hepatic steatosis and NASH

  • Associated with increased body mass index, diabetes, and hypercholesterolemia

  • Can progress to cirrhosis

  • AST and ALT < 4x normal and AST:ALT < 1; alk phos normal or up to 2x normal; usually asymptomatic; can be evaluated by RUQ ultrasound and then liver biopsy

  • Hereditary hemochromatosis

  • Initial test Fe and TIBC

  • Ff Fe/TIBC > 45%, check ferritin

  • Ferritin > 400 ng/ml in men and > 300 ng/ml in women suggestive; then send for HFE genotype

  • Hepatic iron index (ratio of liver concentration of iron to age of patient) > 2.0 is diagnostic

  • Autoimmune hepatitis

  • Screen with SPEP; 80% patients will have hypergammaglobulinemia (2x upper limit of normal is specific)

  • Check ANA (>1:160, especially in homogeneous pattern) and anti-smooth muscle antibody

  • Liver biopsy for definitive diagnosis

  • Wilson’s disease

  • Most patients <40

  • Screening test is serum ceruloplasmin; suggestive if low (<200mg/L) or presence of Kayser-Fleischer rings or 24-hr urine copper >100 mcg/d

  • Definitive diagnosis by liver biopsy showing >250 mcg Cu/g liver

  • Celiac sprue

  • Suspect if weight loss, malabsorptive diarrhea, arthritis, vague abdominal pain

  • Screen with antiendomysial IgA (most sensitive and specific) and/or antigliadin IgA and IgG

  • Alpha1-AT deficiency

  • I
    ALT and AST >15X upper limit of normal

    • Acute viral hepatitis (A-E, herpes)

    • Medications/toxins

    • Ischemic hepatitis

    • Autoimmune hepatitis

    • Wilson’s disease

    • Acute bile duct obstruction

    • Acute Budd-Chiari syndrome

    • Hepatic artery ligation
    f SPEP shows low alpha globulin levels, send for serum AT levels (<80 mg/dL suggestive) and PiZZ phenotyping

  • Ischemic hepatitis

  • Rapid rise in AST and ALT in 24 hrs but rapid resolution in 2-6 days

  • Mild bilirubin elevation (<4x normal); alk phos < 2x normal

Transaminitis, evaluation


  • Degree of AST and ALT elevation and AST:ALT ratio

  • AST:ALT > 2 and AST < 300 IU/L suggest alcoholic hepatitis

  • AST:ALT ratio 1 in fatty liver disease or acute or chronic viral hepatitis

  • AST:ALT >1 can be seen in cirrhosis from any cause

  • AST:ALT >4 is highly suggestive of fulminant Wilson’s hepatitis

  • AST and ALT levels of >15X upper limit normal, see table

  • If not clearly medication- or alcohol-induced liver disease, initial tests include hep B sAg, hep B sAb, hep B cAb, hep C Ab, hep A IgM and IgG (if clinically indicated), Fe/TIBC, ceruloplasmin (if age < 40), SPEP (assess for autoimmune hepatitis and alpha1-antitrypsin deficiency), TSH

  • If hypergammaglobulinemia on SPEP, check ANA and anti-smooth muscle Ab to assess for autoimmune hepatitis; will need liver biopsy for definitive diagnosis

  • If alpha-globulin band low on SPEP, check alpha1-antitrypsin level

  • If Fe/TIBC > 45%, high suspicion of hemochromatosis, send for ferritin.

  • If ferritin high, check genotype of HFE and liver biopsy; hepatic iron index of >1.9 on liver biopsy c/w homozygous HFE

  • If suspicion of Wilson’s high (e.g. neurologic symptoms, age <40), and ceruloplasmin level not decreased, check for Kayser-Fleischer rings; if still negative, check 24-hr urine for copper excretion (>100 mcg/d is suggestive)

  • If all the above negative, check abdominal ultrasound to assess for fatty infiltration into the liver to suggest hepatic steatosis or NASH; definitive diagnosis requires liver biopsy

  • Additional tests if initial ones are negative to evaluate for nonhepatic source of transaminases

  • Antiendomysial and antigliadin Abs to look for celiac sprue, CK to look for muscle disease

  • Consider liver biopsy if no clear diagnosis

Cholestatic pattern


  • Causes include biliary obstruction (stones, cancer, stricture), PBC, PSC, intrahepatic cholestasis of sepsis, medications, infiltrative disease

  • Alkaline phosphatase present in liver, bone, intestine, kidney, placenta, leukocytes, small intestine, and neoplasms

  • Rise of alk phos up to 3x normal nonspecific; striking elevation seen in infiltrative processes (primary or metastatic tumor) or biliary obstruction (intra- or extrahepatic)

  • 5
    Infiltrating diseases of the liver that can cause elevated serum alk phos

    • Sarcoidosis

    • Tuberculosis

    • Fungal infection (e.g. coccidiodomycosis, histoplasmosis)

    • Other granulomatous diseases

    • Amyloidosis

    • Lymphoma

    • Metastatic malignancy

    • Hepatocellular carcinoma
     nucleotidase found in liver, cardiac muscle, brain, blood vessels, and pancreas but significant elevation of serum levels almost exclusively seen in liver disease; may take several days for elevated levels to be detected; sensitivity comparable to that of AP in detecting biliary obstruction, hepatic infiltration, and cholestasis

  • Primary biliary cirrhosis

  • Seen in women in their 50-60s, especially those with hypercholesterolemia

  • Bilirubin normal initially

  • AMA IgM highly suggestive of PBC

  • Definitive diagnosis by liver biopsy

  • Primary sclerosing cholangitis

  • Affects men in their 30-40s

  • H

    Isolated hyperbilirubinemia


    • Indirect hyperbilirubinemia, >85% of total bilirubin is unconjugated

    • Total bilirubin usually never >6 mg/dL in hemolysis

    • Check reticulocyte count and hemolysis labs

    • Direct hyperbilibinemia, >50% of total bilirubin is conjugated
    Causes of indirect hyperbilirubinemia

    Hemolysis

    Ineffective erythropoiesis

    Resorption of large hematoma

    Crigler-Najjar syndrome

    Gilbert’s syndrome (bilirubin usually <3)

    Shunt hyperbilirubinemia


    Hepatic causes of direct hyperbilirubinemia

    Bile duct obstruction

    Hepatitis

    Cirrhosis

    Medications/toxins

    Primary biliary cirrhosis

    Primary sclerosing cholangitis

    Sepsis

    Total parenteral nutrition



    Vanishing bile duct syndromes

    Dubin-Johnson Syndrome



    Rotor’s Syndrome

    istory of inflammatory bowel disease (especially UC) suggestive

  • Diagnosis by ERCP and/or liver biopsy

  • Infiltrative diseases (see box)

Cholestatic pattern, evaluation


  • Confirm hepatic origin of elevated alkaline phosphatase with 5 nucleotidase (more commonly performed at MGH than GGT)

  • Right upper quadrant ultrasound to assess for cholestasis or infiltrative disease

  • If U/S negative, check anti-mitochondrial Ab (good sensitivity and specificity) to evaluate for primary biliary cirrhosis

  • If positive, consider liver biopsy

  • If both RUQ U/S and anti-mitochondrial Ab negative

  • Consider liver biopsy and/or ERCP if alk phos > 50% above normal (ERCP can assess for PSC; liver biopsy may miss it)



Deanna Nguyen, M.D.


B

Etiologies


  1. Alcohol and gallstones are the most common two causes comprising 75% of cases

  2. Ampullary obstruction (diverticula, tumor, worms, foreign body)

  3. Hypertryglyceridemia (>1000 mg/dL and accounts for <4% of cases)

  4. Hypercalcemia (<2% pts with hyperparathyroidism)

  5. Drugs (ddI, tetracyclines, sulfa agents, furosemide, valproic acid, tamoxifen, pentamidine, azathioprine, metronidazole, mercaptopurine)

  6. Infections (mumps, EBV, HIV, CMV, HSV, ascariasis, coxsackie, viral hepatitis)

  7. Vascular causes (vasculitis, ischemia, atherosclerotic emboli)

  8. Trauma (blunt)

  9. Iatrogenic (post-ERCP, post-abdominal surgery)

  10. Toxins (scorpion venom, organophosphorous insectisides, methyl alcohol)

  11. Pregnancy (multifactorial)

  12. Idiopathic (10%)
ackground (Do Not Edit This Line This is Hidden Text)


  • Pancreatitis is a common reason for admission for management of pain and emesis/dehydration and for management of complications.

  • Complications include (see below):

  • Pseudocyst formation

  • Pancreatic necrosis

  • Abscess formation

  • Chronic pancreatitis (and possible pancreatic cancer) with chronic pain and exocrine insufficiency.

Points to consider in the history


  • Time frame of symptoms (nausea and vomiting, abdominal pain radiating to back, pain may be relieved while sitting up/forward and may worsen with food)

  • Travel history

  • History of and risk factors for dyslipidemia (DM, hypothyroidism) or hypercalcemia (e.g., hyperparathyroidism)

  • Good medication and alcohol history

  • History of biliary colic or known risk factors of cholelithiasis

Helpful studies and laboratory information (Do Not Edit)


  • Serum amylase: increases 2-3 hrs after attack and stays high for 3-4 days

  • No correlation between peak level and severity

  • Non-pancreatic causes of elevation are renal failure, viscus perforation/infarct, ectopic pregnancy, cancer, macroamylassemia

  • Serum lipase: more sensitive and specific and remains elevated longer than amylase

  • Serum calcium, lipids, LDH, CBC, albumin, glucose, liver chemistries

  • RUQ ultrasound to evaluate biliary tree for obstruction/cholelithiasis

  • CXR may show pleural effusion or ARDS

  • CT scan with contrast to evaluate for necrosis or presence of pseudocyst or abscess (evaluate for necrosis after 1 week). Consider CT scan in patients who are deteriorating or who have severe pancreatitis, i.e. not all patients require CT scan.

  • Note that controversy exists whether or not ionic contrast may worsen pancreatitis.

  • ERCP ± sphincterotomy in setting of biliary obstruction

Complications


  • Pseudocyst. Non-epithelial lined cavity often presenting with persistent pain and hyperamylasemia. 50-80% resolve within 6 weeks

  • Pancreatic abscess. Develops within 2-4 weeks, often presenting with fever, pain, and persistent hyperamylasemia

  • 100% mortality if not drained; affects 30% pts with severe acute pancreatitis.

  • E. coli, Pseudomonas, Klebsiella, and Enterococcus spp are most common; 75% are monomicrobial

  • Systemic inflammatory response syndrome

  • Pancreatic ascites and pleural effusion (left>right)

  • Metastatic fat necrosis/panniculitis(Do Not Edit)

  • Chronic pancreatitis

Main goals and mainstays of treatment (Do Not Edit)


  • Reversal of precipitants

  • Early ERCP in patients with gallstone pancreatitis who have obstructive jaundice (bilirubin >5) or biliary sepsis

  • Treatment of hypercalcemia

  • Cessation of possible causative drugs

  • Mild pancreatitis is treated for several days with supportive care consisting of analgesia, IVF, and NPO.

  • Consider nasogastric tube for ileus or vomiting.

  • Role of antibiotic prophylaxis (in absence of necrosis) is controversial. Studies have shown decreased frequency of sepsis but no different in mortality rate with imipenem.

  • Surgery is indicated only when necrotizing pancreatitis is infected.

  • Acute necrotizing pancreatitis (involving more than 30% of pancreas) generally warrants broad spectrum antibiotics (e.g. imipenem or meropenem).

  • Enteral feeding via nasojejunostomy tube should be attempted with high protein/low fat preparations if pts are NPO for more than 7-10 days. Consider TPN in patients who do not tolerate enteral feeding.

  • Oral refeeding when abdominal pain and tenderness resolve and there is no complication. Begin with liquids.


Deanna Nguyen, M.D.


Background


  • Severe acute hepatitis = jaundice and coagulopathy without hepatic encephalopathy

  • Fulminant hepatic failure, as defined by Trey and Davidson initially = severe acute hepatitis + hepatic encephalopathy within 8 weeks of onset of jaundice without previous existing liver disease

  • More recently, ALF defined as fulminant hepatic failure if hepatic encephalopathy develops within 2 weeks after onset of jaundice and as subfulminant hepatitis if encephalopathy develops in 2-12 weeks.

Etiologies (Do Not Edit This Line)


  • Multiple etiologies have been demonstrated to cause acute liver failure.

  • Data from NIH ALF Study of 206 patients identified these as etiologies:

  • Acetaminophen 38%

  • Indeterminate 18%

  • Drug reaction (INH, rifampin, PTU, amiodarone) 14%

  • Viral hepatitis (0.2-0.4% of hep A, 1.0-1.2% of hep B) 12%

  • Other 19%

  • Autoimmune

  • Ischemic (Budd-Chiari, shock, veno-occlusive disease)

  • Wilson’s

  • Pregnancy (acute fatty liver of pregnancy, HELLP)

  • Malignancy (lymphoma most common)

  • Other etiologies have been described: carbon tetrachloride, Amanita phalloides mushrooms, NSAIDs, halothane, Ecstasy, HDV, HEV in pregnant women in their third trimesters, valproic acid, tetracycline, Reye’s syndrome

Complications


  • Main complications are:

  • Cerebral edema (develops in 80% of pts with grade 3-4 encephalopathy, due to increased permeability of BBB), most common cause of death.

  • R
    King’s College Criteria
    Acetaminophen

    • Arterial pH <7.3 (irrespective of grade of encephalopathy) OR

    • Grade III/IV encephalopathy AND PT >100 s AND creatinine >3.4
    All other causes

    • PT >100 s (irrespective of grade of encephalopathy) OR

    Any three of the following


    • Age <10 or >40

    • Etiology: non-A, non-B hepatitis, halothane hepatitis, idiosyncratic

    • Duration of jaundice before onset of encephalopathy >7 days

    • PT >50 s

    • Bilirubin >18 mg/dL
    enal failure

  • Bacterial infection

  • Additional complications include:

  • Hemodynamic instability (high cardiac output but low peripheral resistance), hemorrhage, hypoglycemia, pulmonary edema, respiratory alkalosis, hyponatremia, hypophosphatemia, pancreatitis

Prognostic tools


  • King’s College Criteria for need for liver transplantation (most often used); see box

  • APACHE II score (worse if >15 in acetaminophen group, >13 in non-acetaminophen)

  • Serum AFP (increase in AFP from day 1 to day 3 had a 83% sensitivity and 68% specificity for predicting outcome)

  • Clichy criteria

  • Hepatic encephalopathy (grade III-IV) and factor V level <20% in pts <30 y.o. or <30% in pts >30 y.o. are associated with low likelihood of spontaneous recovery

  • Admission encephalopathy grade and bilirubin level have been noted to be independent predictors of spontaneous survival.

  • Specifically, a mean total bilirubin of 6 among survivors and 17 among non-survivors. Also 65-70% survival in patients with grade I-II encephalopathy compared to <20% survival in patients with grade IV encephalopathy.

  • Liver pathology: >70% necrosis associated with 90% mortality rate without transplantation

  • MELD scale. Model End Stage Liver Disease. New model for scoring severity (calculator also available on Palm software MedCalc).

  • Score = 9.57  ln (creatinine) + 3.78  ln (total bilirubin) + 11.2  ln (INR) + 6.43
    where creatinine, bilirubin, and INR > 1, creatinine <4, maximum MELD score is 40

  • In acute liver failure from acetaminophen toxicity, arterial lactate >3.5 mmol/L had good predictive value

  • Early after admission (median 4 h), 67% sens, 95% specific for death; after fluid resuscitation (median 12 h), arterial lactate >3.5 mmol/L 76% sens, 97% spec (Lancet 2002;359:558).

Main goals and mainstays of treatment (Do Not Edit)


  • Airway and hemodynamic stabilization of patient

  • Refer (to GI liver fellow) for possible transplantation evaluation

  • Look for potentially reversible cause.

  • Acetaminophen (N-acetylcysteine), Amanita poisoning (consider high dose penicillin and parenteral silibinin), Budd-Chiari (surgery), acute fatty liver of pregnancy (delivery), autoimmune (steroids +/- cytotoxic agents).

  • N-acetylcysteine most helpful when given within 12 hours of acetaminophen ingestion but should be given to all patients with acetaminophen toxicity; consider it even for non-acetaminophen ALF since there is some evidence to suggest efficacy

  • For hepatic encephalopathy, consider lactulose; avoid benzodiazepenes due to upregulation of GABA receptors

  • Supportive therapy for cerebral edema (often the mode of death):

  • ICP monitoring to maintain cerebral perfusion pressure >50 mm Hg, mannitol for elevated ICP in pts without renal failure (elevation of head of bed, hyperventilation, steroids probably not useful)

  • Frequent monitoring of glucose given possible impaired hepatic gluconeogenesis and glycogenolysis, dextrose drips for hypoglycemia

  • FFP, platelets only if evidence of bleeding

  • Vasopressors to support organ perfusion

  • Serial blood cultures q48 hrs and low threshold for broad spectrum antibiotics since ALF pts may not mount elevated WBC or fever due to impaired immune system

  • If dialysis necessary, CVVH better than HD to avoid rapid fluid shifts

  • Transplantation remains best therapy with survival of about 50-90% but organ supply and high acute mortality from sepsis and cerebral herniation remain as obstacles. Most recent data show that only 29% are transplanted.

  • On the horizon:

  • Molecular Adsorbent Recycling System (MARS), hemodiafiltration against albumin able to remove low molecular weight toxins

  • Extracorporeal liver assist devices as a bridge to transplantation and to possibly, spontaneous recovery (uses pig or human hepatocytes)

Survival data


  • Overall survival = 60%; outcomes are best for acetaminophen (65% overall survival) and worst if idiosyncratic drug reaction or indeterminate cause (14% and 11% survival, respectively)

  • H
    Deanna Nguyen, M.D.
    igh mortality rate from cerebral edema, renal failure, sepsis, multisystem organ failure

Toxic dose


  • Minimal toxic single dose, 7.5 to 10 g for an adult.

  • Toxicity likely to occur with single ingestions greater than 250 mg/kg or those greater than 12 g over a 24-hour period.

  • Virtually all patients who ingest doses in excess of 350 mg/kg develop severe liver toxicity.

Pathophysiology (Do Not Edit This Line)


  • Route. Oral ingestion, peak serum levels can occur within 30-60 minutes but can take up to 4 hours depending on the rate of gastric emptying. The serum half-life is 2-3 hours and is not affected by renal clearance.

  • Mechanism. Acetaminophen is primarily cleared by the liver metabolism. The majority (95%) of acetaminophen is converted to glucuronidated or sulfonated metabolites that are inactive and non-toxic.

  • 5% of acetaminophen is converted by hepatic P450 enzymes to N-acetyl-p-benzoquinoneimine (NAPQI), a highly reactive species. NAPQI is further conjugated to glutathione to produce an inactive metabolite.

  • In overdose, the sulfonation and glucuronidation pathways are saturated and more drug is shunted to P450 pathways to produce NAPQI. Increased levels of NAPQI rapidly deplete glutathione stores.

  • Once glutathione stores are exhausted, NAPQI reacts with cellular components resulting in hepatocyte necrosis.

  • Modifying factors. Alcoholism, pre-existing liver disease, and medications that induce microsomal P450 enzymes may all augment hepatotoxicity in acetaminophen use.

Clinical manifestations





Stage I. Initial 24 hours post ingestion

Anorexia, nausea, vomiting, diaphoresis, and malaise

Stage II. 24-48 hours post ingestion

Improved symptoms,  right upper quadrant pain, elevation of liver enzymes (transaminases), LDH, bilirubins and increased PT.

Stage III. 72-96 hours post ingestion

Hepatic enzymes peak. Develop sequelae of hepatic failure including jaundice, coagulopathy, and encephalopathy.
Renal failure and myocarditis may occur. Death can result

Stage IV. >4-14 days

Complete resolution and recovery

Emerg Med Clin North Am 1984; 2:103-119

Diagnosis


  • History of ingestion, stage I symptoms (see above), evidence of unexplained hepatic failure

  • Key information includes amount of drug ingested and time elapsed from ingestion

  • Serum acetaminophen levels—draw at  4 hours post ingestion (level of drug peaks at 4 hours), refer to nomogram—use serum level and time elapsed since ingestion to determine toxicity risk

Management


  • Gastric decontamination. Gastric lavage if ingestion <4 hours to presentation

  • Activated charcoal. 50-100 g, adsorbs drug, most effective if given <4 hrs, but may help >4hrs

  • N-acetylcysteine. Replenishes glutathione stores. Can be given with charcoal without loss of efficacy.

  • Initial dose of N-acetylcysteine. 140 mg/kg po or nasogastric tube, draw serum acetaminophen level at 4 hrs post ingestion

  • Subsequent therapy. If the serum level is toxic per nomogram, then admit patient and administer 17 doses of 70 mg/kg N-acetylcysteine po or nasogastric tube q4h over the next 72 hours.

  • Draw LFTs (AST, ALT, bilirubin), LDH, and PT for a baseline, follow daily for 72 hours. Also consider checking lactic acid (see acute liver failure section).

  • See acute liver failure section for prognostic indicators.







Hours after acetaminophen ingestion

nomogram adapted from Harrison’s Principles in Internal Medicine


Ravi Joshi, M.D.




G
Modified Child-Turcotte-Pugh score

Parameter

1 point

2 points

3 points

1. Ascites

none

slight

moderate or worse

2. Total bilirubin

<2

2-3

>3

3. Prothrombin time










Sec over control

1-3

4-6

>6

INR

<1.7

1.8-2.3

>2.3

4. Albumin

>3.5

2.8-3.4

<2.7

5. Encephalopathy

none

1-2

3-4




CTP score

CTP class

1 yr survival

2 yr survival

5-6

A

100%

85%

7-9

B

80%

60%

10-15

C

45%

35%



eneral considerations


  • Liver biopsy is gold standard for diagnosis of cirrhosis

  • RUQ ultrasound to look for ascites, vascular patency, echogenicity/morphology of liver, biliary tree, hepatocellular carcinoma

  • Serum AFP (for HCC)

  • Hyponatremia (volume overloaded), anemia (multifactorial), thrombocytopenia (hypersplenism and thrombopoieten deficiency)

Ascites


  • Most common complication of cirrhosis

  • 50% develop ascites within 10 years

  • Multifactorial etiologies leading to avid Na retention by the kidney and transudation across the peritoneum, as well as hypoalbuminemia, and increased hepatic lymph production

  • Differential diagnosis includes portal hypertension (cirrhosis, cardiac, hepatic vein obstruction, portal vein/splenic vein obstruction, schistosomiasis) vs. non-portal hypertension (malignancy, pancreatitis, nephrogenic, infectious (TB), chylous, biliary

  • Diagnostic tap: cell count with differential, albumin, total protein, amylase, triglycerides, gram stain, culture (in blood culture bottles at bedside), cytology

  • SAAG = serum albumin  ascites albumin gradient.

  • SAAG >1.1, 97% accurate for portal HTN

  • Sodium restriction is paramount (<90 mEq/day)

  • Fluid restriction to <1500 mL/day (<1000 mL/day if serum Na <120 mEq/L)

  • Diuretics

  • UNa>30 mEq/L: spironolactone 100 mg po qd alone

  • UNa 10-30 mEq/L: furosemide 40 mg po qd and spironolactone 100 mg po qd

  • UNa < 10 mEq/L: furosemide and spironolactone (40:100 ratio), sodium/fluid restriction, and large volume paracentesis

  • Paracentesis, indicated in tense ascites and/or refractory ascites with low UNa

  • TIPS as a bridge to transplantation if ascites refractory

Spontaneous bacterial peritonitis (SBP)


  • Risk factors: low ascites total protein (<1.0)

  • Must be ruled out in all cirrhotics who are admitted since its presentation ranges from asymptomatic state to sepsis; 10-30% hospitalized cirrhotics have SBP

  • Diagnose with paracentesis; three categories:

  • Culture positive/neutrocytic (>250 PMN/cc), most common

  • Culture negative/neutrocytic >250 PMN/cc,

  • Culture positive/non-neutrocytic (<250 PMN/cc)

  • Bacteriology: E. coli > Klebsiella > Strep pneumoniae > other gram negative rods. Anaerobes are rare (<5%)

  • Treat with cefotaxime (or equivalent) 2 gm IV q8h x 5 days

  • Some repeat paracentesis at day 3 to show cell count decline

  • Albumin infusions (1.5 gm/kg on day 1 and 1.0 gm/kg on day 3) have been shown to improve mortality when given with antibiotics potentially by preserving renal function through volume expansion (N Engl J Med 1999;341:403)

  • Consider prophylaxis with quinolone since 60% will recur within 1 yr

Secondary peritonitis


  • If ascitic fluid is neutrocytic, and has 2 out of 3 of following: total protein > 1g/dL, glucose <50 mg/dL, LDH >nl for serum.

  • Must exclude bowel perforation or intra abdominal abscess.

  • Treat with metronidazole and cefotaxime; consider emergency surgery.

Esophageal variceal bleeding


  • Requires hepatic venous-wedge gradient of >12 mm Hg to occur.

  • Average lifetime risk is 30% in cirrhotics without previous variceal bleed.

  • Predictors: Child class C, large varices, red wale markings, alcohol.

  • Volume resuscitate, pRBCs, and FFP transfusion.

  • Octreotide drip 50 mcg IV bolus then 50 mcg/hr.

  • Endoscopic band ligation slightly more effective than injection sclerotherapy

  • Rarely, urgent TIPS.

  • Prophylaxis with surveillance banding, non-selective beta blockers (nadolol or propranolol).

  • Goal HR<25% of baseline ± nitrates

Non-variceal upper GI bleeding


  • Gastric varices accounts for 10% of all UGI bleeding in cirrhotics.

  • Portal hypertensive gastropathy accounts for up to 40% of all UGI bleeding in cirrhotics.

  • Average lifetime risk is 30% in cirrhotics without previous variceal bleed.

  • Treatment same as for esophageal variceal bleeding, although tend to be more difficult to treat.

  • Propranolol is treatment of choice for portal hypertensive gastropathy.

Hepatic encephalopathy


  • Manifestation of porto-systemic shunting with ammonia, and benzodiazepene-like false neurotransmitters accounting for encephalopathy

  • Often precipitated by infection (SBP), azotemia, GI bleeding, dietary indiscretion, sedatives, hypoxia, hypotension, development of HCC

  • L
    Grading hepatic encephalopathy

    • Grade 1, restless, inverted sleep pattern, mild confusion, irritable with tremor and apraxia

    • Grade 2, lethargy, slow responses, inappropriate behaviors, disoriented to time, asterixis, hypoactive DTRs

    • Grade 3, omnolence but rousability, disoriented to place and time, + asterixis, hyperactive DTRs

    • Grade 4, coma.
    actulose titrated to 2-4 bowel movements/day (usually requires 30-60 g/day)

  • Neomycin (4-6 g/day) but caution because of potential nephrototoxicity

  • Metronidazole (800 mg/day) x 1 week as effective as neomycin

Hepatorenal syndrome


  • Probability of occurrence 18% at 1 yr, 39% at 5 yr

  • Poor prognostic event marked by azotemia and oliguria refractory to volume challenges.

  • Urine sediment is bland and low urine sodium

  • Rule out other causes (hypovolemia, ATN, obstruction, drug effects, abdominal compartment syndrome (check “bladder” pressure, abdominal compartment syndrome not likely <10 mm Hg and usually present when >25 mm Hg)

  • Precipitants: infection, over-diuresis, large volume paracentesis, aminoglycosides, NSAIDs

  • Fluid challenges, remove all diuretics, nephrotoxins, and precipitants, consider large volume paracentesis

  • Midodrine (7.5-12.5 mg po tid) and octreotide (100-200 mcg sc tid) (Hepatology 1999;29:1690)

  • Norepinephrine and albumin (Hepatology 2002;36:374).

  • Transjugular intrahepatic portosystemic shunt (TIPS)

  • Transplant evaluation

Hepatopulmonary syndrome


  • Rare complication of unknown etiology characterized by dyspnea, pulmonary vascular dilatation, and hypoxemia (PaO2 <70 mm Hg); associated with orthodeoxia (upright hypoxia)

  • Pathologically marked by diffuse (type I) large (type II) arterio-venous shunts in the pulmonary circulation (possibly related to increased circulating NO)

  • Diagnose by trans thoracic echo with bubble and macroaggregated radioactive albumin lung scan

  • Improves with transplantation

  • IR-guided embolization of AV communications if PaO2 <150 mm Hg on 100% O2

  • Methylene blue (Ann Intern Med 2000;133:701)

Portopulmonary hypertension


  • Rare cause of secondary pulmonary hypertension (all pts have signs of portal HTN)

  • Present with DOE, syncope.

  • Diagnosis of pulmonary hypertension by TTE and/or cath and demonstration of reversal of flow in portal vein on Doppler ultrasound

  • High mortality with liver transplant if mean PA pressures >35 mm Hg

  • Responds to IV prostacyclin in some patients

Hepatic hydrothorax


  • Right (66%) > bilateral (17%) = left (17%) pleural effusion which is transudative and often in association with large ascites; caused by migration of fluid across diaphragm

Endocrinopathies


  • Hypogonadism

  • Thyroid dysfunction: high TSH, low T4, low T3, high rT3 akin to euthyroid sick syndrome

Vasculitis (hepatitis B, hepatitis C)


  • Polyarteritis nodosa with hepatitis B

  • Essential mixed cryoglobulinemia (type II cryoglobulinemia) and type III cryoglobulinemia with hepatitis C

Hepatocellular carcinoma


  • Associated with cirrhosis (from any cause)

  • A
    Deanna Nguyen, M.D.
    ssociated with hepatitis B carrier state


Deanna Nguyen, M.D.




B

Some literature regarding bowel regimens


  • Psyllium superior to docusate sodium in patients with chronic constipation in randomized double blind study (Aliment Pharmacol Ther 1998;12:491-7)

  • Comparison of Miralax with lactulose in chronic constipation showed higher stool frequency with Miralax (Gut 1999;44:226)

  • Although these [docusates, e.g. Colace] remain very popular agents, clinical studies suggest that docusates are of little use in the prophylaxis of constipation in elderly bed-ridden patients” (Aliment Pharmacol Ther 2001;15:749)

ulking


  • Psyllium (Metamucil)

Osmotic agents


  • Poorly absorbed salts

  • Milk of magnesia

  • Poorly absorbed disaccharides

  • Lactulose. Metabolized in colon by bacteria to short chain fatty acids.

  • Sorbitol

  • Polyethylene glycol

  • GoLYTELY (polyethylene glycol 3350, sodium sulfate)

  • NuLYTELY (polyethylene glycol 3350, NaHCO3, KCl)

  • Miralax (polyethylene glycol 3350)

Stimulant laxatives


  • Docusates (Colace)

  • Ionic detergents leading to stool softening; perfusion studies suggest that docusates inhibit fluid absorption or stimulate secretion in jejunum.

  • Diphenylmethane derivatives

  • Phenolphthalein (withdrawn from U.S. market because of rodent data suggesting carcinogenesis).

  • Bisacodyl (Dulcolax)

  • Alters net fluid and electrolyte transport, direct effects on colonic motility (e.g. as suppository).

  • Anthraquinones

  • Senna (Senokot)

  • Stimulates intestinal formation of prostaglandins, serotonin, and histamine to increase colonic secretions.

Other agents


  • Enemas, disimpaction in selected circumstances (may need to individualize treatment)

  • Neostigmine

  • Acetylcholinesterase inhibitor, given 2 mg iv, useful for colonic decompression in Ogilvie’s syndrome (N Engl J Med 1999;341:137).

  • Side effects include symptomatic bradycardia requiring atropine, crampy abdominal pain, excessive salivation and vomiting.

  • Metoclopramide (Reglan)

  • Dopamine antagonist, useful in diabetic gastroparesis; has rarely been associated with tardive dyskinesia and extrapyramidal side effects.

  • Erythromycin

  • Given 200 mg iv q8h (not po); acts on motilin receptors.

  • Improves gastric emptying in critically ill patients, delayed gastric emptying in diabetic gastropathy (Crit Care Med 2000;28:2657); effects comparable to metoclopramide.

  • Naloxone (Narcan) enterally

  • In critically ill patients on fentanyl sedation, naloxone 8 mg po q6h decreased gastric tube reflux and frequency of pneumonia, no effect on inducing bowel movements (Crit Care Med 2003;31:776).

  • V
    Evan Dellon, M.D.

    Andrew Yee, M.D.
    arious studies suggest reversal of opioid-associated constipation.

MGH Medical Housestaff Manual

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