The final cause of jaundice mentioned in Table 7-1 is obstructive jaundice. Obstructive jaundice results when conjugated bilirubin is unable to be excreted into the gut either due to impaired liver secretion of bile (see item 3) or impaired bile flow (see item 4). The most common cause of obstructive jaundice is bile duct obstruction (e.g., gallstones, pancreatic tumor). Although conjugated bilirubin is produced and secreted into bile, the bile is unable to be secreted into the gut lumen due to an obstruction in the bile duct system. Bile backs up into the liver, causing engorgement and rupture of intrahepatic ducts. This leads to spillage of conjugated bilirubin into sinusoidal blood and, ultimately, the systemic circulation. Thus, conjugated bilirubin levels become elevated while urobilinogen levels decrease due to inadequate concentrations of conjugated bilirubin in the gut lumen. Urine color remains normal (conjugated bilirubin in the systemic circulation is water soluble and can be excreted by the kidneys), but stool becomes clay-colored due to lack of urobilinogen excretion into feces.

Now that you have a better understanding of the causes of jaundice, revisit Table 7-1 and attempt to fill it in on your own.

5 Which veins feed into the portal vein?

Venous return from the foregut, midgut, and hindgut feeds into the portal vein from the gastric veins, splenic vein, and superior and inferior mesenteric veins. Consequently, portal hypertension can cause venous congestion in any and all of these vascular beds (e.g., congestive splenomegaly from splenic vein, esophageal varices from gastric veins).

6 What are the symptoms of portal hypertension?

Portal hypertension leads to increased resistance to flow in the systemic venous system. As a result, blood cannot pass freely from the portal system to the systemic system and backs up into the portacaval anastomoses, which causes them to become engorged, dilated, or varicose. The location of these anastomoses determines the specific symptoms that result from portal hypertension. These symptoms and signs are listed in Table 7-2. General symptoms of portal hypertension include ascites (secondary to increased hydrostatic pressure), spontaneous bacterial peritonitis (note that ascitic fluid is a wonderful culture medium for bacteria), hepatorenal syndrome, and splenomegaly due to decreased drainage of venous blood from the spleen. Splenomegaly can result in anemia, thrombocytopenia, or pancytopenia due to cellular sequestration within the engorged spleen.

Table 7-2 Portal Hypertension: Anastomoses and Related Signs

Portacaval Anastomosis	Clinical Sign
Left gastric vein with esophageal vein (branch of azygos vein)	Esophageal varices (leading to heavy bleeding/hematemesis)
Paraumbilical vein with epigastric vessels	Caput medusae
Superior rectal vein with middle and inferior rectal veins	Internal hemorrhoids (unlike external hemorrhoids, these are not painful because the visceral nerves that are above the dentate line sense pressure and not pain)

Note: Portal hypertension results from prehepatic, intrahepatic, and posthepatic causes. Cirrhosis is a common cause of intrahepatic portal hypertension, while portal vein thrombosis is a prehepatic cause. Right-sided heart failure and Budd-Chiari syndrome (see next question) are common precursors to posthepatic portal hypertension.

Step 1 Secret

You should memorize each portacaval anastomosis and the symptoms that result from portal hypertension.

7 How can Budd-Chiari syndrome arise and what can it lead to?

Budd-Chiari syndrome occurs when the hepatic venous outflow becomes obstructed, usually because of thrombosis. Polycythemia vera, pregnancy, and clotting disorders predispose to thrombus formation and can lead to hepatic venous outflow obstruction. The obstruction may result in portal hypertension with a classic presentation of abdominal pain, ascites, and hepatomegaly. Although this may be confused with right-sided heart failure, Budd-Chiari syndrome does not cause jugular venous distention because it affects only the inferior vena cava.

8 What are the common liver biochemical tests and what do they indicate?

The most common laboratory tests ordered are the aminotransferases (alanine transaminase [ALT], aspartate transaminase [AST]), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGTP), bilirubin, prothrombin time (PT), and albumin. Serum protein concentration and PT tests evaluate synthetic function of the liver because albumin (the predominant serum protein) and clotting factors are manufactured by hepatocytes. PT, in particular, is not generally elevated until severe liver disease has occurred. Serum bilirubin concentration is used to evaluate functional clearance by the liver. ALT, AST, ALP, and GGTP more accurately reflect liver injury. Serum elevations in ALT and AST result from leakage of these enzymes from damage to hepatocytes. ALT is generally elevated more than AST with viral infection, but AST is elevated more than ALT with alcohol abuse. Serum elevations in ALP and GGTP are seen when increased production of these enzymes are induced by bile duct damage. ALP is less specific for bile duct/liver damage than GGTP, as it is often elevated during bone remodeling. Both ALP and GGTP levels should be obtained if bile duct damage is suspected. GGTP levels are also elevated with alcohol abuse because it is a marker of mitochondrial damage. As a general rule of thumb, ALT and AST show greater elevation in hepatitis, and ALP and GGTP show greater elevation in cholestatic disease.

Step 1 Secret

It is expected that you know the significance of abnormal liver function test (LFT) results for boards and for your clinical years. A silly trick for remembering that alanine transaminase (ALT) is elevated with viral hepatitis is to picture the ALT key on the keyboard of a VIRALLY infected computer.

Case 7-1

You are working in the emergency department when a man presents at 5 AM vomiting blood (hematemesis). At first glance, you can see that his mental status is impaired, his skin is jaundiced, and he has scleral icterus. Because you recognize him as the man you frequently see drinking from a brown paper bag in the park, you think you know why he is here.

1 What is the most common cause of upper gastrointestinal bleeding?

The most common causes of upper gastrointestinal (GI) bleeding are ulcers or erosions. These can occur in the esophagus, stomach, or duodenum and develop when acid secretion overruns protective factors (mucus and bicarbonate secretion). Infection with Helicobacter pylori, nonsteroidal anti-inflammatory drug (NSAID) use, and cigarette smoking all disrupt the protective factors. In other cases, there is hypersecretion of gastric acid, such as seen in Zollinger-Ellison syndrome (gastrinoma). Other causes of upper GI bleeding include Mallory-Weiss tear and ruptured esophageal or gastric varices.

2 Why should a Mallory-Weiss tear be included in the differential diagnosis?

Mallory-Weiss tears are seen most commonly in alcoholics, and are due to excessive vomiting that causes mucosal lacerations that extend through the gastroesophageal junction. It is another common cause of hematemesis in alcoholics or people with conditions causing excessive vomiting (e.g., bulimia). However, Mallory-Weiss tears do not typically cause massive hematemesis like that seen with ruptured esophageal varices.

3 What is scleral icterus?

Scleral icterus is yellow discoloration (icterus) seen in the “whites of the eye” (sclerae). It is an indication of increased unconjugated bilirubin in the serum, and is often the first place you will see jaundice on physical examination. Jaundice usually indicates hepatic or cholestatic pathology but may indicate bleeding or hemolysis.

Note: Vitamin A toxicity can cause yellow discoloration of the skin, which is distinct from the scleral icterus observed with jaundice.

4 To confirm your suspicion about severe liver disease in this patient, what physical examination findings might you expect and why?

Gynecomastia and testicular atrophy can be present, resulting from impaired ability of the damaged liver to metabolize estrogen. Estrogen also weakens vascular walls, leading to spider angiomata with increased estrogen levels. Hemorrhoids may result from a portacaval anastomosis between the superior rectal vein and the inferior rectal vein, and a caput medusae (engorged veins radiating from the umbilicus) can result from blood being diverted from the portal vein into the periumbilical veins that run along the round ligament of the liver to the anterior abdominal wall (see Table 7-2). An enlarged liver may be palpated with alcoholic hepatitis, but once cirrhosis develops, the liver will become firm and shrunken. A spleen tip may be palpable, as congestive splenomegaly may occur with portal hypertension because the splenic vein drains into the portal vein.

Case 7-1 continued:

On examination you do indeed find spider angiomata on his face and thorax, gynecomastia, and a periumbilical caput medusae. His abdomen is distended, his spleen is enlarged, he has pedal and periorbital edema, and his breath has a sweet, ammoniacal odor (fetor hepaticus).

5 What is the pathophysiology of his ascites, pedal edema, and periorbital edema?

In severe liver disease there is inadequate production of serum albumin, the major determinant of plasma oncotic pressure. Consequently, fluid reabsorption from the interstitium back into the capillary beds is reduced. This explains his pedal and periorbital edema. In addition to the reduced capillary oncotic pressure, the increased venous pressure in the portal system from portal hypertension causes greater intracapillary hydrostatic pressure, which opposes movement of fluid from the interstitium into the capillaries and results in ascites.

6 What is the pathogenesis of the suspected cause of hematemesis in this patient?

He most likely has ruptured esophageal varices (see Table 7-2). This patient has portal hypertension secondary to alcohol-induced cirrhosis. This creates portacaval anastomoses, in which the pressure in the portal venous system diverts blood from the portal system into the systemic circulation at sites where there are anastomoses. In this patient’s case, blood from the gastric veins backed up into his esophageal tributaries, which became distended and eventually ruptured (Fig. 7-2).

Figure 7-2 Diagram of the portal circulation. The most important sites for the potential development of portosystemic collaterals are shown. A, Esophageal submucosal veins, which are supplied by the left gastric vein and drain into the superior vena cava via the azygous vein. B, Paraumbilical veins, which are supplied by the umbilical portion of the left portal vein and drain into abdominal wall veins near the umbilicus. These veins may form a caput medusae at the umbilicus. C, Rectal submucosal veins, which are supplied by the inferior mesenteric vein through the superior rectal vein and drain into the internal iliac veins through the middle (mid.) and inferior (inf.) rectal veins. D, Splenorenal shunts, which are created spontaneously or surgically. E, Short gastric veins, which are supplied by the esophageal submucosal veins and drain into the splenic vein.

(From Feldman M, Friedman LS, Brandt LJ: Sleisenger & Fordtran’s Gastrointestinal and Liver Disease, 8th ed. Philadelphia, WB Saunders, 2006.)

Note: The round ligament of the liver (ligamentum teres hepatica) is an embryologic remnant of the umbilical vein. The major morphologic characteristics of cirrhosis are extensive fibrosis with nodules of regenerating hepatocytes.

Case 7-1 continued:

When an intravenous (IV) line is started to administer fluids, a fairly large hematoma develops at the IV site. Laboratory tests reveal an elevated direct bilirubin, indirect bilirubin, and PT; low blood urea nitrogen (BUN); and a normal creatinine level. Serologic tests for hepatitis B and C, as well as antimitochondrial antibodies, are negative. Serum iron, transferrin, iron saturation (%), ferritin, and ceruloplasmin are all within normal limits.

7 What is the value of the following tests: hepatitis serology, serum iron, ceruloplasmin, and antimitochondrial antibodies?

These tests all identify different causes of liver cirrhosis. Hepatitis B and C both can cause liver cirrhosis, as can hemochromatosis (too much iron), Wilson’s disease (too much copper), and primary biliary cirrhosis (antimitochondrial antibodies).

Note: All of the above-listed causes of liver cirrhosis increase the risk for hepatocellular carcinoma (HCC), as do α₁-antitrypsin deficiency and aflatoxin exposure.

8 Assuming he is not taking any anticoagulants, what is the most likely reason this patient developed a large hematoma at the intravenous site?

The liver is where most of the clotting factors are produced, and some (factors I, II, VII, IX, X) are modified post-translationally. Severe liver disease impairs their production and processing, producing a coagulopathy. Notice that his PT was elevated because of this.

9 List all the laboratory findings you would expect in a patient with liver failure

See Table 7-3 for the laboratory findings in liver failure and their underlying mechanisms.

Table 7-3 Common Findings in Patients With Liver Failure

Laboratory Value	Mechanism
Elevated or normal LFT values	Liver enzymes may be elevated during initial damage, but if cirrhosis is present or the liver shrinks over time, liver enzyme levels may appear normal in the context of decreased hepatic tissue.
Elevated PT	The liver is the site of coagulation factor production. With severe liver damage, PT becomes elevated.
Elevated serum bilirubin concentration	The liver is responsible for bilirubin uptake. Liver failure causes a spike in serum bilirubin concentration due to decreased hepatic uptake.
Hypoalbuminemia	The liver is the predominant site of albumin production. Decreased serum protein concentration may clinically manifest as ascites.
Fasting hypoglycemia	Impaired gluconeogenesis and glycogenolysis during fasting.
Elevated estrogen levels	The liver is the site of estrogen breakdown. Liver damage elevates estrogen levels, which can lead to testicular atrophy and formation of spider angiomata.
Elevated ammonia levels with decreased BUN	The liver produces the enzymes involved in the urea cycle, which converts ammonia to urea. Elevated ammonia levels can result in hepatic encephalopathy, marked by confusion, loss of consciousness, asterixis, irritability, tremor, and coma. Increased ammonia also can result in fetor hepaticus (“breath of the dead”), which is characteristic of liver disease.