As the largest internal organ and gland, the liver weighs about 3–4 lbs. It is composed of four unequal lobes. The right (largest) and left lobes are separated by the falciform ligament. The much smaller caudate and quadrate lobes are located on the visceral side of the organ, between the other two lobes.

The liver is further divided into a total of eight segments, all of which is covered by a thin layer of connective tissue known as Glisson’s capsule.

This refers to the central hilum where the common bile duct, portal vein, and hepatic artery enter the liver.

The liver has a dual blood supply and receives approximately 25% of cardiac output. The common hepatic artery arises from the celiac trunk (off the aorta) and sends off the cystic artery before entering the liver. Although it only provides a quarter of the total blood flow, it provides half of the hepatic oxygen supply. The portal vein is formed from the confluence of the splenic and superior mesenteric veins and receives blood from the digestive tract, spleen, pancreas, and gall bladder. It supplies the majority of hepatic blood flow (75%), although less oxygen than its arterial counter part. There is a reciprocal flow relationship between the two systems, known as the hepatic arterial buffer response (HABR), which is mediated by adenosine and functions to maintain the adequacy of perfusion [1].

Hepatic sinusoids refer to a type of open pore vessel or discontinuous capillary. This type of discontinuous endothelium allows for the passage of proteins, as large as albumin to pass freely. The sinusoids are separated from the hepatocytes by the space of Disse.

Sinusoids receive oxygen-rich blood from the hepatic artery and the nutrient-rich blood from the portal vein. They are also the home of Kuppfer cells, which filter and process microbes, toxins, and antigens.

From the sinusoids, blood flow empties into the central vein of each lobule, which is the basic structural unit of the liver. The central veins coalesce into hepatic veins, which leave the liver and drain blood to the IVC.

This refers to the basic functional unit of the liver. It is formed around a portal canal, which is comprised of an arteriole and bile ductile, as well as nerves and lymph tissue. Blood from the portal canal is directed toward a central venule via sinusoids. This flow is divided into three circulatory zones, based on proximity to the canal. Zone 1 receives the highest flow, whereas Zone 2 and Zone 3 receive successively less in terms of both oxygen and nutrients, making hepatocytes in the latter zones more vulnerable to ischemia from circulatory disruption.

The hepatic portal venous system channels drainage from the gastrointestinal tract into the liver. Blood drained from the distal esophagus to the proximal anal canal joins venous return from the spleen and pancreas to empty into the venous system destined for the liver. This allows many of the substances absorbed by the GI tract to undergo the first pass effect, allowing selective metabolism and detoxification, before reaching the general circulation.

The various functions of the liver are carried out by hepatocytes. The liver is responsible for hundreds of separate functions, usually in combination with other systems and organs. Some of the main functions are listed below, arranged by endocrine, anabolic, and catabolic features:

Cirrhosis is the end result of a variety of chronic liver diseases, all leading to irreversible scarring of the liver. The resultant fibrosis (scarring) is an impedance to flow and requires higher pressures for entering blood. Flow ultimately favors the lower resistance provided by portosystemic shunts and begins to bypass the liver (and hepatic functions) entirely.

Fortunately, the liver is an organ with a tremendous reserve. Normal function may be maintained when as little as 20% of the liver remains, which is why many of the insidious hepatic diseases can take years to manifest signs or symptoms. It also provides the key to successful living-donor transplantation.

Although it is the most common cause of cirrhosis in the US, alcoholism only develops in 10–20% of excessive drinkers [2]. The metabolism of EtOH, catalyzed by alcohol dehydrogenase, results in significant oxidative damage, which depletes antioxidants and induces liver injury.

In contrast, viral hepatitides (specifically types B and C) are the most common causes of cirrhosis worldwide.

The etiology of liver failure can be divided into noncholestatic and cholestatic causes of cirrhosis.

Causes of Noncholestatic cirrhosis include:

Causes of Cholestatic cirrhosis (intrahepatic or extrahepatic) include:

Acute liver failure (aka fulminant hepatic failure) refers to the new onset of encephalopathy and an elevated INR (≥1.5) in patients without previous liver disease, over a period of less than 26 weeks. More than half of the cases are attributed to drug-related toxicity (usually acetaminophen). Due to the rapid progression of the disease, signs of portal hypertension and cirrhosis are generally absent.

Only 40% of patients with acute liver failure will recover spontaneously [3].

In adults, the primary metabolic pathway for acetaminophen is glucuronidation.

The main metabolite is relatively nontoxic and is excreted into bile. A small amount of the drug is metabolized via the CYP-450 pathway into NAPQI, which is a strong, highly hepatotoxic, oxidizing agent. Following a supratherapeutic ingestion, the levels of NAPQI produced by the CYP system overwhelm the ability for conjugation/inactivation by the available glutathione stores. The toxic metabolites accumulate and begin to destroy liver cells.

Oral activated charcoal readily binds acetaminophen and can be of significant benefit if administered within 1 h following ingestion.

N-acetylcysteine (NAC) given within 8 h of overdose can dramatically decrease the risks of toxicity, as it is a precursor of glutathione and increases the concentration of the latter for conjugation of NAPQI.

Hep A—The most common viral hepatitis (50% of all cases) due to a high degree of contagiousness. Primary spread is due to fecal–oral transmission. Course is usually benign and self-limited. However, an estimated 100 patients die each year in the US from acute hepatic failure related to infection [4]. Inactivated HAV vaccine may provide protection for 10 years or longer.

Hep B—Five-percent of world’s population is chronically infected [5]. Ninety percent recover from the acute infection, however, 1–5% of adults will remain in carrier state. Eighty to ninety percent of infected children will become carriers. Primary spread is from contact with infected body fluids. According to the CDC, three doses of the HBV vaccine provide greater than 90% protection to infants, children, and adults who are immunized prior to exposure and boosters are no longer recommended for patients with normal immunity who have completed the series. In women who are seropositive for both HBsAg and HBeAg vertical transmission is approximately 90% [6].

Approximately 25% of those who become chronically infected during childhood and 15% of those who become chronically infected after childhood die prematurely from cirrhosis or liver cancer and the majority remain asymptomatic until the onset of cirrhosis or end-stage liver disease [7].

Hep C—An estimated 1.8% of US population carries HCV, representing the estimated 75% of acute infections, which have become chronic. It is generally transmitted through contact with infected blood. Progression from infection to cirrhosis or hepatocellular cancer may take decades, similar to HBV. Newly approved medications can cure infection upwards of 90% of individuals, depending on the subtype [8].

Hep D—HDV can propagate only in the presence of the hepatitis B virus (HBV), and is spread in a similar manner [9]. Transmission of HDV can occur either via simultaneous infection with HBV or be superimposed on a chronic infection. In combination with HBV, hepatitis D has the highest fatality rate of all the hepatitis infections, at 20%.

Hep E—HEV is similar to hepatitis A in both transmission and clinical course. However, during pregnancy the disease is much more severe and can result in acute hepatic failure. During the third trimester, the mortality rate from acute infection approaches 20% [10].

Acute hepatitis is considered a significant risk for elective surgery, predisposing patients to significant morbidity and mortality. Similarly, cirrhosis is a major risk factor for nonhepatic procedures. As such, elective procedures should be avoided in the decompensated state, as evidenced by increased INR, encephalopathy, or infection.

It is a rare condition caused by thrombosis of the major hepatic veins, which generally presents with abdominal pain, jaundice, ascites, and hepatomegaly. In about half of cases, patients are found to be hypercoagulable, relating to pregnancy, polycythemia vera, oral contraceptive agents, lupus anticoagulant, among other causes. The majority of patients do not respond/are not candidates for medical therapy and will require some type of invasive intervention, such as the surgical shunting of blood around the clot. Unfortunately, many will become transplant candidates secondary to progression to acute hepatic failure.

It is a microvesicular fatty infiltration of hepatocytes, possibly related to an inherited enzyme deficiency in the mitochondrial beta-oxidation of fatty acids [11]. The incidence is generally estimated at 1 in 7000 to 1 in 20,000 deliveries.

Symptoms usually present in the third trimester with nausea, vomiting, jaundice, abdominal pain, and encephalopathy. Laboratory evidence may reveal elevated LFTs and a prolonged PT. Liver biopsy is diagnostic and treatment involves the prompt delivery of the fetus, regardless of gestational age. Most patients recover; however in one population-based study in the UK of 57 patients, one woman required a liver transplant and a second case proved fatal [12].

It is an autosomal recessive disorder (0.5% homozygous in US [13]) associated with increased intestinal absorption of iron. Iron overload results in excessive and injurious deposition in tissues, especially the liver, heart, pancreas, and pituitary. Pathogenesis is usually less severe in women due to menstruation. Hemochromatosis may lead to diabetes, CHF, and increased pigmentation of skin (“bronze diabetes”). Labs reveal increased serum iron and ferritin, as well as increased transferrin saturation. Diagnosis is confirmed by liver biopsy. Treatment is scheduled phlebotomy. Excessive EtOH intake and coexisting viral hepatic infection worsen disease progression, and a late diagnosis may leave few options other than a transplant.

It is an autosomal recessive disorder associated with the accumulation of copper. It is universally fatal if untreated, and most will die of liver disease [14]. It results from the defective excretion of copper into bile. Symptoms include wide-ranging neurologic dysfunction and hepatic dysfunction, eventually leading to cirrhosis. Initial testing includes LFTs, CBC, and serum ceruloplasmin, as well as an ocular slit-lamp exam and a 24-hour urine test for copper excretion. A Kayser Fleischer ring, referring to a crescent of pigmentation at the periphery of the cornea, may be present on exam and is included in a scoring system for diagnosis. Treatment often involves copper chelation with penicillamine depending on the severity of disease. Liver transplant can be lifesaving for patients with Wilson disease presenting with acute hepatic failure or chronic liver disease unresponsive to treatment.

AAT is an inherited disorder that involves both the lungs and liver. In the US, individuals with severe deficiency are estimated to be between 80–100,000 [15]. AAT is a serine protease inhibitor of elastase, trypsin, chymotrypsin, and thrombin. In the lung, this deficiency predisposes to panacinar emphysema due to a loss of elasticity. Therapy frequently involves the transfusion of purified pooled human antiprotease.

Accumulation of abnormal alpha-1 AT in the liver causes liver disease and is associated with cirrhosis and/or the development of hepatocellular carcinoma. Transplantation is reserved for patients with end-stage liver failure. Fortunately, a normal phenotype donor liver will produce and secrete normal AAT following transplant and is curative.

A chemical, banned for consumer use in 1970, whose metabolism results in a highly toxic metabolite capable of causing centrilobular necrosis. It was previously used in cleaning solvents, refrigerants, and fire extinguishers. Use has declined significantly since it was realized that CCl₄ is one of the most dangerous hepatotoxins, capable of producing acute liver failure.

The clinical definition of portal hypertension is the elevation of hepatic venous pressure gradient to >5 mmHg. It occurs in the setting of portal venous congestion (resistance to flow) and leads to the development of low pressure collateral routes for venous blood leaving the stomach and small intestine to return to the central circulation. A gradient ≥10 mmHg (termed clinically significant portal hypertension) is predictive of the development of complications of cirrhosis, including death.

Portosystemic shunting, resulting from this pressure increase, allows toxins and waste to enter the central circulation without having to pass through hepatic filtration. The presence of these substances in the circulation contributes to the development of encephalopathy. It may also produce a conduit for bacteria absorbed from GI tract to bypass the Kuppfer cells in the sinusoids [16].

Because of the reciprocal relationship between hepatic arterial flow and that from the portal venous system, portal hypertension results in an increased dependence on hepatic arterial flow for perfusion.

A diagnosis of portal hypertension can be made in a patient with a known risk factor who has clinical manifestations consistent with the diagnosis. Although the direct portal pressure measurement is possible, the assessment more often focuses on the hepatic venous pressure gradient (HVPG), which quantifies the gradient attributed to sinusoidal resistance to blood flow.

The free hepatic venous pressure (FHVP) is obtained first by advancing a catheter from the RIJ down to the hepatic vein and measuring the venous pressure, which provides a correlate of intra-abdominal pressure (⇧ by ascites). Subsequent inflation/wedging of the balloon occludes the hepatic vein and provides a value reflective of portal venous pressure downstream, termed the wedged hepatic venous pressure (WHVP). This is conceptually similar to the wedge pressure measurement in the pulmonary artery, creating a distal column of static fluid reflective of the downstream pressure.

The HVPG is calculated by subtracting the FHVP from the WHVP and approximates the gradient between the portal vein and the IVC. Normal range is 3–5 mm Hg.

Varices refer to the dilated submucosal veins that form lower resistance passages from the portal venous system to the azygous and hemiazygous veins, effectively a pop-off valve for portal hypertension. A gradient above 12 mmHg is generally the threshold pressure for variceal rupture.

Gastric varices bleed less commonly than esophageal varices, though significant gastric bleeding can be more difficult to control.

Variceal bleeding is one of the hallmarks of decompensated cirrhosis and unfortunately causes about a third of the cirrhosis-related deaths. As such, patients will frequently require endoscopic surveillance and treatment, as 20–30% of patients will bleed within 2 years of diagnosis of elevated portal pressures. Of the patients who survive the initial event, 60% will rebleed within 1 year [17].

Bleeding can be managed with banding, endoscopic ligation or sclerotherapy. Acute bleeding should also be treated with volume resuscitation, correction of severe coagulopathies, and lowering of the portal pressure. Intubation is often indicated for airway protection. Medications to reduce portal pressure include vasopressin, somatostatin, and/or octreotide. Although β-blockers can reduce portal pressures, hypotension from volume loss may not allow for safe utilization.

Balloon tamponade can also be an effective option for emergent variceal bleeding, but is associated with significant complications, including esophageal rupture and aspiration. Historically, the Blakemore–Sengstaken tube was passed down into the esophagus and a gastric balloon was inflated in the stomach. Upward traction with a 1 kg weight was applied based on the theory that the balloon would compress the GE junction and reduce blood flow to the varices. Continued bleeding, despite the upward pressure, would necessitate the inflation of the esophageal balloon to directly tamponade the involved vessels.

It is described as a sweet, malodorous, and fecal smell of the breath. Portosystemic shunting allows thiols to pass directly to the lungs, where they can be exhaled and appreciated on exam.

The liver normally functions as a reservoir for blood in the splanchnic system. In healthy individuals, it is capable of redistributing up to one liter of blood into the systemic circulation when faced with sudden intravascular loss. In the setting of compromised hepatic function and altered blood flow, an individual’s ability to tolerate sudden massive hemorrhage would be diminished.

Thrombocytopenia is a well-known feature of cirrhosis and likely multifactorial in its etiology. Normally, the spleen pools approximately one-third of the circulating platelets, in part due to the prolonged transit time (10 min) to pass through splenic tissue. In the setting of portal hypertension, increased pressures are transmitted back through the splenic vein and eventually lead to splenic enlargement. A larger spleen slows down transit even further and prolonged exposure to splenic tissue translates to an increased chance of platelet destruction by phagocyctic cells [18]. Associated factors may include depression of bone marrow function from alcoholism, and decreased production of thrombopoetin, synthesized in the liver.

Endocrine

Neurologic

Pulmonary

Cardiovascular

Renal

Hematologic

Platypnea is the opposite of orthopnea. It refers to shortness of breath in the upright position. Orthodeoxia refers to low oxygen saturation also in the upright position. This constellation of symptoms is generally associated with hepatopulmonary syndrome and serves as evidence of right-to-left shunting.

In general, this clinical sign requires both an anatomic and functional component, and is exceedingly rare [21]. The former may refer to an ASD, PFO, or fenestrated ASD aneurysm. Less well understood, the functional component (in this case cirrhosis) results in a positional modification of abnormal shunting, causing redirection of IVC flow through the atrial communication. This effectively worsens the R to L shunt with the upright position [22].

In general, the liver maintains the pool of approximately 500 g of circulating albumin by allocating approximately 15% of daily protein production [23]. The half-life of albumin is about 20 days. Although the liver is responsible for the production of albumin, low levels may also be attributed to increased renal loss or increased breakdown.

As the main determinant of oncotic pressure (80% [24]), low albumin may influence the tendency of capillary beds to draw fluid into vessels, resulting in worsening edema and ascites. It is important to note that albumin also plays a crucial role in plasma protein binding, due to its strong negative charge. Some of the highly bound drugs include warfarin, furosemide, benzodiazepines, and NSAIDS. Low albumin levels may result in a higher free fraction (metabolically active) of such medications.

Ascites refers to the accumulation of fluid in the peritoneal cavity, which can lead to varying degrees of abdominal distention. It can be either transudative or exudative, depending on the etiology. It is often characterized as having a “shifting dullness” or “fluid wave” on exam. Diagnosis is generally confirmed using ultrasound.

Ascites is most commonly associated with portal HTN. Low albumin levels and a tendency to retain fluid, both common in cirrhotics, only worsen this tendency. It is usually treated with salt restriction, diuretics (aldosterone antagonists) or paracentesis. In refractory cases, it is possible to surgically shunt fluid from the peritoneum back into the venous circulation (Leveen shunt), however, refractory ascites is considered as an indication for liver transplantation.