Federico Tanno, Hugo Tanno

Jaundice is called the yellow pigmentation that takes the skin, conjunctivae and mucous membranes as a consequence of the elevation in the concentration of bilirubin in plasma. Bilirubin is produced mainly by the breakdown of senescent red blood cells upon exhausting their half-life of 120 days. Mild hyperbilirubinemia can be clinically undetectable, becoming evident when the plasma concentration reaches 3 - 4 mg / dl, its recognition depends on the coloration of the individual's skin and the quality of light with which it is examined.

Pathophysiology

Bilirubin is the end product of heme metabolism, which is found as part of hemoglobin, myoglobin, and other hemoproteins. Bilirubin production occurs through a cascade of enzymatic processes. In the first, the porphyrin ring of the heme opens producing the release of iron, giving rise to the formation of biliverdin (a water-soluble tetrapyrrolic pigment). Through an enzyme, biliverdin reductase, biliverdin is converted to bilirubin. Its major production site is the spleen, followed by other organs in which the reticulum endothelial system is distributed. It has recently been shown that certain enzymes involved in the synthesis of bilirubin are also powerful antioxidant agents and important vasoactive regulators located throughout the body. In normal individuals, its production reaches 4 mg per kg of weight per day. 80-85% comes from the hemoglobin of mature erythrocytes that are destroyed by the spleen.

Like other insoluble molecules, the bilirubin formed circulates in the plasma strongly bound to albumin; Being a potentially toxic product, as it is fat soluble and nonpolar, the liver is in charge of hydrosolubilizing it and then eliminating it through the digestive tract. This process is carried out in four interrelated steps: uptake by the hepatocyte, binding to specific intracellular proteins, conjugation with glucuronic acid, and canalicular excretion.

Uptake: the fenestrated epithelium of the hepatic sinusoids provides the bilirubin-albumin complex with rapid access to the space of Disse (extrasinusoidal). In this space they are in contact with the microvilli on the sinusoidal surface of the cell. Here bilirubin dissociates from albumin and is transported within the hepatocyte. This transport is saturable and inhibited by competition with other organic anions, being a process mediated by proteins not yet identified (transporter proteins), giving rise to a transport mechanism called facilitated diffusion.

Intracellular binding: within the hepatocyte, bilirubin binds to different proteins of which the best known are part of the glutathione-S-transferase superfamily, formerly called ligandins. They are believed to have an important role in presentation to microsomes for further conjugation.

Glucuronidation (conjugation) - The water insolubility of bilirubin reflects the rigid structure of the molecule. The subsequent glucuronidation with glucuronide acid changes its physical-chemical condition making it highly soluble in aqueous solutions (hydrosolubilization of bilirubin). The enzyme responsible for this process is called: uridine-5`-diphosphate glucuronosyltransferase (UGT1A1). The total or partial absence of it is the cause of unconjugated hyperbilirubinemic states known as Crigler-Najjar Syndrome type I and II respectively.

Canalicular bilirubin excretion: Conjugated bilirubin is transported through the apical plasma membrane to the canaliculus by an ATP-dependent process carried out by a plasma protein called MRP2.

The bilirubin thus excreted becomes part of the bile, giving it an intense yellow color, to later be concentrated in the gallbladder, where, by reabsorption of water, it reaches its highest concentration. By contraction of the gallbladder, before cholecystokinetic stimuli, it is excreted into the duodenum, reaching the colon almost intact. There it is deconjugated by the action of bacteria and degraded into urobilinogen and other products. Urobilinogen is partially reabsorbed in the enterohepatic circuit, most of it being re-excreted by the liver and its excess is eliminated by the kidney. Unconjugated bilirubin rarely appears in urine since, by having a strong union with albumin, it prevents it from passing through the renal glomerulus.

Hyperbilirubinemia and jaundice

When bilirubin is conjugated with glucuronide acid, it directly gives the Van der Berg reaction, which is the most used technique for its study in the clinical laboratory, being classified as unconjugated or indirect and conjugated or direct. In practice, pure conjugated hyperbilirubinemia is rare since in most cases the two fractions rise resulting in a mixed increase in bilirubin. The normality of liver function tests distinguishes familial hyperbilirubinemias from the majority of acquired ones. However, in some diseases, such as hemolytic anemias or inactive cirrhosis, elevations of bilirubin can be recorded without other abnormalities in the laboratory.

A. Pathophysiological classification of jaundice

Jaundice is a clinical sign caused by an alteration in the process of formation, uptake, conjugation or excretion of bilirubin, which makes it necessary to differentiate those jaundices with a predominance of unconjugated bilirubin (prehepatic) from those in which hyperbilirubinemia is predominantly conjugated type (post-hepatic jaundice). In turn, those in which both fractions are elevated are called hepatic jaundices, in these cases the cause is related to hepatocellular damage.

1. Jaundice predominantly unconjugated or indirect bilirubin.

In these cases the cause that originates jaundice can recognize different origins:

1.1 Increased production of bilirubin . This condition is observed mainly in hemolysis of any origin, as well as in ineffective erythropoiesis. Jaundice due to fetal erythroblastosis acquires special significance, since in these cases massive hemolysis, hypoalbuminemia of the newborn (deficit in transport) and the inability of the liver to conjugate bilirubin add up so that unconjugated bilirubin rises to levels very high, being able to pass the blood-brain barrier and cause brain damage (kernicterus).

The symptoms are related to the magnitude of the anemia, as well as the cause that produces it. In hemolytic jaundices, the palpatory semiology of the liver is normal, except that due to excessive hemolysis there is hepatic hemosiderosis. In these cases the liver is palpable enlarged and of greater consistency. The laboratory shows normal liver function.

1.2 Transportation deficit . It is most often seen in the newborn, where it is most noticeable due to low serum albumin production. Some medications (rifampicin, novobiocin, and contrast agents) can interfere with bilirubin transport by competing for albumin. In these cases the abdominal semiology, as well as the liver laboratory, are within normality.

1.3 Alterations in bilirubin uptake . There are cases of spontaneous portosystemic shunts in which the blood does not pass through the hepatocytes, being diverted towards the portal veins or through the capillary sinusoids, as frequently occurs in liver cirrhosis.

The delay in the expression of UGT1A1 in neonates is responsible for the physiological jaundice of the newborn. Familial disorders of bilirubin conjugation (Crigler Najjar Syndrome (CN) and Gilbert Syndrome) are caused by the mutation of the gene encoding UGT1A1. Gilbert's Syndrome is a hyperbilirubinemia frequently of familial origin, its natural history being absolutely benign. It is predominant in males and can be seen in 5% of the general population. Differential diagnosis between Gilbert Syndrome and Crigler Najjar Syndrome type II is difficult, since the liver function laboratory is normal in both. Given the benignity of both entities, their differentiation has no clinical implications.

2. Jaundice with elevation of both bilirubins.

In this type of jaundice there is usually hepatocellular involvement, making it difficult to list the different pathologies that produce it. For educational purposes, they should be divided into acute liver disease and chronic liver disease.

2.1 Jaundice due to acute liver disease.

The most frequent etiology is viral and currently the agents capable of producing the picture are: hepatitis viruses (A, B, C, D and E), cytomegalovirus, Epstein Barr, yellow fever, herpes type I virus and coxsackievirus.

The second etiology in order of frequency is that caused by toxic agents. This mechanism of injury corresponds to an idiosyncratic mechanism or to an immunoallergic injury. Alcoholic hepatitis is a very particular type of liver injury of toxic cause, and is, in turn, one of the most common forms of both acute and chronic liver disease.

A third type of acute injury is that of immune origin (self-harm diseases). This type of damage may not express symptoms in the acute period and become evident when it is perpetuated chronically.

Finally, a fourth type of damage is that caused by ischemia.

We will review some of the multiple circumstances in which this phenomenon can be evidenced in the clinic.

2.1.1 Acute injury of viral origin

At least five essentially hepatotropic viral agents (HAV-HBV-HCV-HDV and HEV) are recognized. None of them produce direct damage to the cell in immunocompetent patients, being the response of the immune system to destroy the infected cell that causes liver injury.

The immune system responds to viral insult with two types of response: innate immunity and acquired immunity.

The innate response is nonspecific and immediate and is the one produced by the cell when detecting viral proteins. The formation of interferon alpha and gamma, as well as the function of NK (natural Killer) cells, play an important role in it. An effective innate response delays virus replication and allows time for the activation of acquired immunity. It is essential for this to take place, the good function of the dendrites that activate the CD4 and CD8 cells. The efficient response of these cells allows, through cell lysis and the formation of blocking antibodies, to eliminate the virus and cure the disease (acquired immunity).

Given that HAV and HEV do not give chronic forms, a slightly symptomatic immune response is preferable, since without manifesting disease the patient is cured. The very severe forms, on the other hand, can evolve into fulminant forms.

In HBV or HCV infection, the symptomatic forms are the expression of a good immune system that is the determining factor of cure. The asymptomatic forms that are the majority in HCV infection and that of the immunosuppressed in HBV frequently progress to chronicity. In these patients there is a deficit of acquired immunity with less response on CD4 and CD8. This poor response, added to the great mutant capacity of the virus, favors the passage to chronicity of the infected patient.

Incorporating this knowledge leads to a better understanding of viral liver infections. None of the known viruses aims to destroy the cell it has chosen to multiply.

Those with more rudimentary strategies such as HAV and HEV are quickly recognized by the defense system, their response conditioning the magnitude of the clinical manifestation. The HBV, HCV and HDV viruses have managed to develop tactics to evade the immune system, especially HCV, which achieves its objective in 80% of infected patients. In addition, this virus, by having mutant capacity, manages to evade the formation of antibodies that prevent it from entering other cells until then not infected.

The perpetuation of viral replication and the unsuccessful attempt to eliminate the virus by the immune system favors hepatocellular damage and the production of fibrosis that marks the evolution to chronic hepatitis and then to cirrhosis.

2.2 Drug-induced liver damage

Drugs can cause liver damage by three mechanisms:

a) Direct toxicity is a dose-dependent damage and is currently rare unless the drug is used by mistake or premeditated. The most typical example is the action of paracetamol ingested for suicidal purposes. In these cases the dose is much higher (20 times) than that used for therapeutic purposes.

b) Idiosyncrasy: In these cases the patient has different drug metabolization mechanisms from the common population. In some of the steps it accumulates an intermediate metabolite in high doses that causes cellular injury. A typical example is isoniazid injury, in which the rapid acetylation exhibited by the cellular metabolism of some individuals conditions the accumulation of an intermediate product that causes cellular damage. This phenomenon can be favored when a drug is administered that interacts with another or that has an enzyme-inducing action. This is the case of rifampicin, which enhances isoniazid damage by inducing its acetylation.

c) Immunity: The immune mechanism occurs when the administered drug binds to a structural protein. This union constitutes a hapten (neo antigen) that is not recognized by the immune system that attacks it as if it were a foreign protein.

2.3 Immune-caused liver injury

This type of injury is caused by an alteration of the immune system that stops recognizing its own proteins, producing an injury mediated by the same cells of the defense system.

It is admitted that in an individual with a genetic predisposition, a noxa triggers the injury, the immune system, by not recognizing its own proteins, causes damage to the target organ. It has been seen that in these patients there is a deficiency of the suppressor T lymphocyte (TS). This is the one that limits the injury once the noxa that triggered it is eliminated. This process of perpetrating itself over time leads to an autoimmune disease. When the target cell is the hepatocyte, the disease that occurs is Autoimmune Hepatitis. When it is the cell of the biliary epithelium, another disease called Primary Biliary Cirrhosis occurs.

The detail of this mechanism and its pathologies can be covered in depth in internal medicine books.

2.4 Ischemia

Taking into account that the liver is an organ that receives double inflow (hepatic artery and portal vein), ischemia is not frequent since it supposes a significant deficit of the same. Usually the liver cell supports acute hypoxia very well, which is why other organs of the economy are much more sensitive to ischemia (brain, kidney, lung). However, when an antegrade failure (flow deficit) is added to a retrograde failure (venous stasis), ischemia becomes manifest. This is the case of a congestive liver (heart failure) to which is added a hypoflux (digestive bleeding).

These pictures are reversible if the hemodynamic condition is quickly corrected, otherwise the clinical symptoms become evident.

Ischemic hepatitis usually occurs in an icteric form, its symptoms being related to the cause that motivated the hemodynamic imbalance. The very symptomatic forms accompany the severe and poor prognosis pictures.

The laboratory shows a rise in ASAT that exceeds ALAT levels, with a marked increase in LDH. The reversal of ischemia translates into a decrease in ALAT / ASAT, predominantly in this case ALAT (inversion of the relationship), accompanied by a decrease in LDH.

Elevated bilirubin is seen in the most severe forms. The alteration of the prothrombin rate is an excellent marker of injury, its normalization is an index of good prognosis.

Hepatic regeneration prevails in most cases and restores its cellular capital to the liver while preserving its architecture. Severe forms (massive necrosis) can lead to the death of the patient.

3. Jaundice from chronic liver disease.

The most common are chronic hepatitis B due to HBV and HCV. As mentioned before, alcohol is an important cause of chronic liver disease, as well as nonalcoholic fatty liver, which occurs more frequently in hypertensive, obese, and diabetic patients. Cirrhosis of the liver, of any etiology, can decompensate and produce jaundice, generally with a reserved prognosis. In chronic liver disease, jaundice is often the final expression of organ claudication. These issues are covered in detail later.

4. Jaundice with elevation of conjugated or direct bilirubin.

In jaundice of this type the usual cause is obstructive. Mechanical obstruction to the flow of bile gives rise to a jaundice with certain clinical, laboratory and histological characteristics, called cholestasis. Due to its location, cholestasis is divided into intrahepatic and extrahepatic. The differentiation between the two is important due to the therapeutic implication, the first being medical treatment and the second essentially surgical. The cholestasis enzymes used for diagnosis are alkaline phosphatase, gamma glutamyl, and 5 'nucleotidase. However, they do not make the differential diagnosis of intra- or extra-hepatic cholestasis. The clinical differences between the two are sometimes not clear, and the use of complementary methods is necessary for the differential diagnosis. Ultrasound is the most frequently used resource. Magnetic resonance imaging with cholangiography can complement the biliary tree in more detail. Endoscopic retrograde cholangiography is a diagnostic and therapeutic method.

B. Clinical classification of jaundice.

Once this type of introduction is made, the type of jaundice must be classified in practice, in order to later know what is the cause that produces it.

1 prehepatic jaundice.

The cause that produces them is not in the liver, since their origin is prior to the entry of bilirubin into the hepatocyte. They usually have a healthy liver. The symptoms are given by the existence of anemia, with the clinical manifestations of this entity (asthenia, paleness, dizziness, etc.). The urine is clear and the catharsis is normal with hyper-colored stools. The diagnosis is complemented with a hematological study that certifies the type of anemia. The liver laboratory is normal.

2. Jaundice of hepatocellular cause.

a) Acute liver disease.

The icteric forms of viral etiology are generally more symptomatic than the antichteric. The patient presents asthenia, anorexia, fever, nausea, and abdominal discomfort. The liver is larger and may be mildly tender. The surface is smooth and slightly increased in consistency. Urine is coluric and hypocolic or acholic stools. Sensory compromise, drowsiness, clouding, and behavioral changes are elements that accompany the patient with severe liver failure. In these cases, there is liver breath and neurological alterations that reveal involvement of the extrapyramidal pathway (tremor, asterixis, cogwheel sign, etc.). This set of manifestations is known as portosystemic encephalopathy. In these cases,

The laboratory in acute liver disease shows elevation of both types of bilirubin. Sometimes the increase in the conjugate fraction causes it to simulate an obstructive condition. Transaminases elevated more than 10 to 20 times above the normal value is the main element of diagnostic value. Erythrocytosis is normal and the blood count shows slight lymphocytosis. In mild or moderate forms, liver function is preserved, while in severe forms there is a decrease in the prothrombin rate, a drop in serum cholinesterase and coagulation factor V. Albumin only decreases if liver failure is prolonged.

The determination of IgM antibodies for hepatitis A and the surface antigen for the B virus (HBsAg) allow rapid diagnosis of these diseases. Through the Elisa technique, the detection of IgG for the C virus makes the diagnosis of acute hepatitis C, although on occasions this can be negative at the beginning of the disease (window period)

b) Chronic liver disease.

Jaundice in patients with chronic liver disease is usually an index of decompensation, since it becomes manifest sporadically during the course of the disease. The magnitude of it is closely related to the severity of the process. Symptoms frequently overlap with that of acute liver disease (asthenia, anorexia, nausea, weight loss). Semiologically, the presence of cutaneous stigmata of chronic liver disease (hepatic palm, stellar nevi, etc.) can be detected. The liver is enlarged, and it is frankly palpable due to its greater consistency. The surface irregularity is found in patients with cirrhotic evolution. However, in advanced stages the liver reduces in volume and is difficult to palpate. In these atrophic forms, only the left lobe is palpated, the border of which is located in the epigastrium. Splenomegaly is often present. The existence of collateral circulation is more frequent in those patients with portal hypertension.

In the laboratory, hyperbilirubinemia is found with variable levels of both bilirubins. Transaminases are elevated, but to a lesser degree than in acute hepatitis. Dysproteinemia (hypoalbuminemia and hypergammaglobulinemia) is often found as a hallmark of chronic liver disease. Often, jaundiced patients with typical chronic liver disease are found without a clear history or negative diagnostic tests to assign a defined etiology. The use of liver biopsy is a diagnostic option to implement in them.

3. Jaundice of obstructive cause.

As already mentioned above, it can correspond to an intra- or extrahepatic cause. The set of symptoms that characterizes extrahepatic biliary obstruction is known as choledocian syndrome. This can be complete or incomplete depending on the total or partial passage respectively, from the bile to the duodenum. The most frequent etiologies are lithiasic and neoplastic.

Jaundice of lithiasic origin usually presents with intense pain of epigastric location that may be accompanied by nausea and vomiting. The onset is sudden, hours after a copious intake, and often at night, in such a way that the patient wakes up due to its intensity, which usually lasts between 15 minutes and 2 hours; it radiates to the right upper quadrant or to the back in case of pancreatic involvement. Coluria, after the episode of pain, is the first manifestation of the obstructive picture. Stools are putty-colored (acholia), depending on the degree of obstruction. Jaundice depends on the extent of the obstruction and the concomitant infection (cholangitis). Pruritus follows jaundice as clinical evidence of cholestasis.

In the semiology of the abdomen there is pain on palpation of the liver. The existence of a palpable and painful gallbladder with abdominal defense is characteristic of acute cholecystitis. It is accompanied, in 25% of cases, by jaundice that resolves in subsequent days.

The laboratory shows an elevation of white blood cells with elevated erythrocyte sedimentation that is related to the infectious component. The early increase in transaminases, followed by a sharp decrease, is sometimes the earliest finding to acquire a defined profile when accompanied by an increase in alkaline phosphatase and gamma-glutamyl.

The diagnosis is confirmed by performing an abdominal ultrasound, which can show intra- and / or extrahepatic bile duct dilation, as well as the presence of hyperechoic images compatible with gallstones. In doubtful cases, the performance of an MRI-cholangiogram or endoscopic retrograde cholangiopancreatography allows visualizing the biliary tree, being useful for diagnostic precision.

Obstructive jaundice of neoplastic origin has a less symptomatic clinical course and an often “cold” presentation, without pain, in which only coluria, hypocholia, and jaundice with itching are the initial manifestations of the disease. When the choledochal obstruction is below the cystic, a large, painless gallbladder can be palpated, constituting the Courvoisier-Terrier sign. A history of weight loss, anorexia, and general deterioration may be present as part of the neoplastic syndrome. The presence of diabetes, or the existence of signs of malabsorption, may be clinical elements that suggest a pancreatic neoplasm with extension to the body and tail.

The laboratory does not define the diagnosis, except for the existence of tumor markers such as Ca 19-9. Retrograde cholangiography is the method of choice for the diagnosis of papilla neoplasia (ampulla of Vater).