Gastroenterology - Stanford University



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

Hepatocellular 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:

– AST: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 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

– If SPEP shows low alpha globulin levels, send for serum AT levels (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 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( 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

– History 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)

Background (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.

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.

– Renal 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 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)

• High 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 1.1, 97% accurate for portal HTN

• Sodium restriction is paramount ( other gram negative rods. Anaerobes are rare ( 1g/dL, glucose 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 HR6 | |INR |2.3 | |4. Albumin |>3.5 |2.8-3.4 |3.4

All other causes

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

Any three of the following

• Age 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

Deanna Nguyen, M.D.

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 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 ................
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