Hugo Tanno

Jaundice can be considered a syndrome that is classically defined as that set of symptoms and signs that accompany yellow pigmentation of the skin and mucosa, and in which a serum increase in bilirubin is found. However, the best knowledge of pathophysiology has led to broadening this concept, since those reasons that lead to the production of jaundice can occur without the presence of this coloration in skin and mucosa. In other words, jaundice is the clinical expression of a biological phenomenon produced by different causes, which can be present without the patient necessarily being jaundiced.

Pathophysiology

If it is taken into account that jaundice is the result of the increase in the bile pigments in the blood, which then spread to the organic tissues, it is important to review the normal metabolism of bilirubin in its different steps: production, humoral transport, liver uptake, conjugation and transport and excretion to the bile pole.

The main origin of bilirubin is the breakdown of red blood cells, which after 120 days (half-life) destroy and release hemoglobin. This is divided into globin and heme, which, when its molecule opens and iron is released, is transformed into protoporphyrin that after successive steps will become bilirubin.

Bilirubin is carried in the blood by albumin, since in its unconjugated form it is, at physiological pH, practically insoluble in plasma. Thus carried, bilirubin is offered to the different parenchyma. Entry into the liver cell is by passive transport of facilitated diffusion. Its diffusion within the hepatocyte is carried out with the intervention of two protein acceptors, Y (ligandin) and Z. Subsequently, bilirubin is conjugated with two glucuronic acid molecules in the presence of the enzyme glucuronyltransferase. Thus transformed into a more soluble pigment, bilirubin is excreted through the reticuloendoplasmic system into the canalicular membrane. Importance has recently been attributed to the role of pericanalicular microfilamenia in biliary excretion. This excretion process is carried out by an active transport mechanism against the gradient, partly independent and partly linked to bile salts. The bilirubin thus excreted becomes a component of the bile, giving canalicular bile a lemon yellow color; later it is concentrated in the gallbladder, site where, by reabsorption of water, it reaches its highest concentration. By contraction of the gallbladder (cholecystokinetic stimuli) it is excreted in the duodenum. In the intestinal lumen it is reduced by the action of intestinal bacteria and then partially reabsorbed by the enterohepatic circuit (urobilin), by which it is offered again to the liver for its metabolization; the rest is eliminated with fecal matter (stercobilin). partly independent and partly attached to bile salts. The bilirubin thus excreted becomes a component of the bile, giving canalicular bile a lemon yellow color; later it is concentrated in the gallbladder, site where, by reabsorption of water, it reaches its highest concentration. By contraction of the gallbladder (cholecystokinetic stimuli) it is excreted in the duodenum. In the intestinal lumen it is reduced by the action of intestinal bacteria and then partially reabsorbed by the enterohepatic circuit (urobilin), by which it is offered again to the liver for its metabolization; the rest is eliminated with fecal matter (stercobilin). partly independent and partly attached to bile salts. The bilirubin thus excreted becomes a component of the bile, giving canalicular bile a lemon yellow color; later it is concentrated in the gallbladder, site where, by reabsorption of water, it reaches its highest concentration. By contraction of the gallbladder (cholecystokinetic stimuli) it is excreted in the duodenum. In the intestinal lumen it is reduced by the action of intestinal bacteria and then partially reabsorbed by the enterohepatic circuit (urobilin), by which it is offered again to the liver for its metabolization; the rest is eliminated with fecal matter (stercobilin). later it is concentrated in the gallbladder, site where, by reabsorption of water, it reaches its highest concentration. By contraction of the gallbladder (cholecystokinetic stimuli) it is excreted in the duodenum. In the intestinal lumen it is reduced by the action of intestinal bacteria and then partially reabsorbed by the enterohepatic circuit (urobilin), by which it is offered again to the liver for its metabolization; the rest is eliminated with fecal matter (stercobilin). later it is concentrated in the gallbladder, site where, by reabsorption of water, it reaches its highest concentration. By contraction of the gallbladder (cholecystokinetic stimuli) it is excreted in the duodenum. In the intestinal lumen it is reduced by the action of intestinal bacteria and then partially reabsorbed by the enterohepatic circuit (urobilin), by which it is offered again to the liver for its metabolization; the rest is eliminated with fecal matter (stercobilin). by which it is offered again to the liver for its metabolization; the rest is eliminated with fecal matter (stercobilin). by which it is offered again to the liver for its metabolization; the rest is eliminated with fecal matter (stercobilin).

Pathophysiological classification of jaundice

It is evident, then, that jaundice is a clinical sign caused by some alteration in the normal process of formation, uptake, conjugation or excretion of bilirubin, which forces us to differentiate those jaundices with a predominance of unconjugated bilirubin (prehepatic jaundice) from those in which hyperbilirubinemia is predominantly of the conjugated type (posthepatic jaundice). In turn, hepatic jaundice are those in which both bilirubins are elevated. In these cases, the cause is usually related to hepatocellular damage.

1. Jaundice with a predominance of unconjugated or indirect bilirubin. In these pictures the cause of the jaundice can recognize different origins:

1. 1. Increased bilirubin production. It is the typical jaundice of hemolysis in any of its etiologies. Jaundice due to fetal erythroblastosis acquires special significance, since in these cases massive hemolysis, hypoalbuminemia of the newborn (transport deficit) and the inability of the liver to conjugate bilirubin (glucuronyltransferase deficiency) cause the unconjugated bilirubin to rise at very high numbers (> 20 mg%), which can cause brain injury (kemicterus). The symptoms are those that correspond to the type of hemolytic anemia that produces it.
      
      In hemolytic jaundice, the palpatory semiology of the liver is normal, except that there is hepatic hemosiderosis due to excessive hemolysis. In these cases, the liver is palpated, increased in size and consistency. In general, the spleen is enlarged and is a semiological constant of this type of anemia. Laboratory studies show that liver function is normal.
      
      
   2. Transportation deficit. This circumstance is seen more frequently in the newborn, where the transport deficit is made more noticeable by the low serum albumin at this stage of life. Certain antibiotics (novobiocin, sulfa drugs) can interfere with the transport of bilirubin by albumin. In these cases the abdominal semiology, as well as the liver laboratory, are within the limits of normality.
      
      
   3. Alterations in bilirubin uptake by the hepatocyte. Although this entity was known years ago as Gilbert syndrome, today it is known that in this syndrome there can be both an uptake and a conjugation deficit, often finding a deficiency of glucuronyltransferase. Gilbert's syndrome is more frequent in men than in women (4: 1 ratio) and begins to show itself at puberty.
      
      She is pressured with conjunctival jaundice that usually increases with fasting. The urine is clear and the stool is normal in color. The laboratory shows unconjugated hyperbilirubinemia, without anemia or abnormal liver function tests. It is common for the family study to detect other cases of unconjugated hyperbilirubinemia of different hierarchy. The prognosis is good and the picture does not require any therapy.
      
      
   4. Alteration in the conjugation of bilirubin (Crigler-Najjar syndrome). In these cases, there is a total deficiency of glucuronyltransferase (type I) or partial (type II). In type I the prognosis is poor and the patient usually dies in the first years of life. Type II has a good prognosis and, except for the icteric coloration of the conjunctivae, the patient is absolutely normal.
      
      Differential diagnosis between Gilbert syndrome and Crigler-Najjar type II syndrome is difficult, since the conventional laboratory of liver function is normal in both.

1. Jaundice with elevation of both bilirubins. In this type of jaundice, there is usually hepatocellular involvement. It is difficult to list the different pathologies that can produce them. With didactics, however, it is possible to divide them into jaundice due to acute liver disease and jaundice due to chronic liver disease.
   
   
   1. Jaundice due to acute liver disease. This topic will be covered briefly. The most frequent etiology is viral, and in the activity a series of viral agents capable of producing the condition are recognized: hepatitis viruses (A, B, non-A-no B virus), cytomegalovirus, Epstein Barr virus, congenital rubella, yellow fever, herpes simplex type I and coxsackie virus, to name the best known. However, the three types of hepatitis viruses are among the most important for their frequency and for their ability to generate jaundice.
      
      The second etiology in terms of frequency of acute jaundice is that caused by toxic agents. Toxic substances can damage the liver either directly (predictable action) or indirectly (non-predictable action). In the first group, the damage is related to the amount of the toxic received, while in the second there is no dose-effect relationship. Alcoholic hepatitis is a very particular type of toxic liver damage, and it is, in turn, one of the most common forms of liver disease. It can present with or without jaundice, the icteric forms corresponding to those of higher clinical hierarchy.
      
      
   2. Jaundice due to chronic liver disease. Among the most frequent chronic liver diseases that cause jaundice are chronic hepatitis, and among them the active call (active chronic hepatitis), liver cirrhosis, in any of its etiologies, can decompose and cause jaundice. Jaundice in these patients is generally linked to an active form with a reserved prognosis.
      
      In chronic liver disease, jaundice is the final expression of parenchymal claudication. Hence, the appearance of jaundice may be the common denominator of a number of factors that lead to decompensation in chronic liver disease.
      
      Jaundice with elevation of conjugated or direct bilirubin. In jaundices of this type the cause is usually obstructive. Mechanical obstruction to the flow of bile gives rise to a jaundiced condition with certain clinical, laboratory and histological characteristics, called cholestasis.

Due to the location of the obstructive process, cholestasis is divided into intrahepatic and extrahepatic. The differentiation between these two forms makes therapeutic behavior, since intrahepatic cholestasis is for medical treatment, while extrahepatic cholestasis is for surgical resolution. Perhaps this chapter is the most complex in the required diagnostic methodology, since the clinical differences between the two are not always clear, with overlapping clinical and laboratory manifestations in both types of cholestasis. Later we will refer to the methodology to follow in the differential diagnosis of jaundice.

Clinical classification of jaundice

Once this type of introduction has been made, the type of jaundice must be classified in practice, in order to later find out what causes it.

Prehepatic jaundice. They usually have a healthy liver. The symptomatology is given by the existence of an anemia, with the clinical manifestations that accompany it (asthenia, weakness, dizziness, etc.). The urine is clear and the stools are normal or hyper-colored. This presumptive diagnosis is corroborated by a hematological study that certifies the type of anemia. Unconjugated type hyperbilirubinemia occurs with normal transaminases.

Jaundice of hepatoceluiar cause. a) Acute liver disease. Icteric forms of viral etiology are generally more symptomatic than nonicteric forms. The patient presents asthenia, anorexia, low-grade fever, nausea and abdominal discomfort. The degree of jaundice is revealed by observing the skin and mucosa in daylight. The liver is enlarged and the patient feels pain when "hooked" in palpatory maneuvers. The surface is smooth and its consistency discreetly increased. The spleen is enlarged in 30% of cases, being sensitive to palpation and with somewhat increased consistency. The urine is coluric.

Sensory involvement, drowsiness, clouding and changes in behavior are elements that accompany the icteric patient with severe liver failure. In these cases there is the so-called hepatic breath and neurological disorders that reveal involvement of the extrapyramidal pathway (tremor, asterixis, sign of the cogwheel, etc.). This set of manifestations characterizes what is known as portosystemic encephalopathy. The liver is palpable with difficulty and is often not palpable due to its reduced size, which is considered a sign of an evident poor prognosis.

Laboratory in acute liver diseases in these cases with elevation of both types of bilirubin. Sometimes the frank predominance of the conjugated form makes it simulate an obstructive picture (cholestatic hepatitis).

Transaminases raised more than 10 to 20 times above normal values ​​constitute the main element of diagnostic value. Erythrocyte sedimentation is normal and the blood count is slightly lymphocytic. Urine analysis detects the presence of conjugated (or direct) bilirubin.

In common forms the hepatic reserve is conserved, whereas in severe forms, on the contrary, there is a decrease in the prothrombin rate and drop in serum cholinesterase. The albumin rate only decreases if liver failure continues.

Protein electrophoresis shows no significant change; dysproteinemias in acute hepatitis are related to a change in the quality and not in the quantity of the proteins. This led to the flocculation tests (Hanger, thymol, Kunkel) being used decades ago as elements of diagnostic value in acute hepatitis. Their non-specificity and the replacement by enzymatic studies to assess necrosis caused them to be discontinued. Alkaline phosphatase, like cholesterol, is elevated in cholestatic forms.

The determination of IgM antibodies for acute hepatitis A and of the surface antigen for virus B (HBsAg) nowadays makes possible the diagnosis of hepatitis A and B, and by exclusion, of type non-A-no B. Taking into account the good prognosis of the first and the most uncertain evolution in the other two (B and not A-not B), it is necessary to complement the etiological diagnosis in order to better determine the future of the patient with hepatitis.

Chronic liver disease.

The different types of chronic hepatitis with or without cirrhosis are included globally here, since in another chapter they will be developed in depth.

Jaundice in the patient with a chronic form of liver disease is usually an index of decompensation, since jaundice manifests itself sporadically in the course of chronic liver disease. The magnitude of it is closely related to the severity of the process.

The symptoms frequently overlap with that of acute hepatitis (asthenia, anorexia, nausea, weight loss). Semiologically, the presence of cutaneous stigmas of chronic liver disease (liver palm, stellar nevi, etc.) is detected in this type of patients. The liver is enlarged, and is frankly palpable for its greater consistency. The irregularity on the surface marks the evolution towards cirrhosis. Splenomegaly is often present. The existence of collateral circulation and ascites accompanies cases with portal hypertension.

In the laboratory, hyperbilirubinemia is verified with variable figures for both bilirubins. Transaminases are elevated, but to a lesser degree than in acute hepatitis. The decrease in parenchymal reserve (bromosulftalein test) demonstrates the compromise of the chronic form. Dysproteinemia (hypoalbuminemia and hypergammaglobulinemia) stands out as a patent for chronic liver disease.

The anamnesis reveals the alcoholic or viral etiology of the disease. However, jaundiced patients with typical chronic liver disease are frequently found without a clear history to assign a definite cause.

The resource of laparoscopy with liver biopsy is a good complement to study these patients,

Jaundice of obstructive cause. As previously mentioned, this may correspond to an extrahepatic cause (surgical jaundice) or to an intrahepatic obstruction (medical jaundice).

The set of symptoms that characterize extrahepatic biliary obstruction is known as Coledocian syndrome. This can be complete or incomplete depending on the total or partial absence, respectively, of passage of bile to the intestine. The most frequent etiologies respond to a lithiasic or neoplastic cause, while parasitic ones are less common.

Jaundice of lithiasic origin usually presents with pain, which is intense and epigastric. The onset is sudden, hours after eating excesses, and often during the night, so that the patient wakes up from the intense pain, which usually lasts between 15 minutes and 2 hours. The pain radiates to the right hypochondrium or to the back (pancreatic involvement). It can be accompanied by nausea and vomiting. Coluria, after the episode of pain, is the first manifestation of the obstructive picture. The stool is putty colored (acolia), depending on the degree of obstruction. Jaundice depends on the degree of obstruction and concomitant infection (cholangitis). Itching follows jaundice as clinical evidence of cholestasis.

The semiology of the abdomen shows pain on liver palpation. The existence of a palpable and painful vesicle with abdominal defense is the expression of acute cholecystitis. The latter is accompanied, in 25% of cases, by jaundice that resolves in the course of the following days. The coloration of the stool and the evolution of coluria are good clinical parameters for follow-up.

The laboratory demonstrates an increase in white blood cells that is related to the infectious component. Erythrocyte sedimentation rises in the following days. The early increase in transaminases, followed by a sharp decrease, is sometimes the earliest laboratory exponent, which acquires a truly defined profile when accompanied by an increase in alkaline phosphatase, 5-nucleotidase, and gamma-glutamyltranspetidase. This last enzyme is the one that rises most dramatically.

The presumptive diagnosis can be confirmed by performing an abdominal ultrasound, which shows the dilatation of the bile duct (intra and / or extrahepatic) as well as the presence of ecorefrigerating images compatible with biliary lithiasis. Visualization of the biliary tree is achieved by endoscopic retrograde cholangiopancreatography or by a fine needle trasparietohepatic cholangiography (Chiba type),

Neoplastic obstructive jaundice has a less symptomatic clinical course and an often “cold” presentation, in which only coluria, hypocolia, and jaundice with itching are the initial manifestations of the disease. When the choledochian obstruction is below the cyst, palpation reveals a large, painless gallbladder, constituting the Courvoisier-Terrier sign.

A history of weight loss, anorexia and deterioration of the general state may be present as an expression of a neoplastic syndrome. Diabetes, or the existence of symptoms of malabsorption, may be clinical elements that suggest a neoplasm of the pancreas.

The laboratory does not define the diagnosis; Most useful is an abdominal ultrasound or eventually a computed axial tomography. Retrograde cholangiography is useful in studying the bile duct to determine the site of obstruction, and is the method of choice for detecting papilla neoplasia. Transparietohepatic cholangiography is another method that is routinely used in many centers, and its main application is in the study of high obstructions in order to know the level of obstruction.

Differential diagnosis (intrahepatic vs. extrahepatic) in cholestatic jaundice is a challenge for the clinician's exercise of common sense, since it requires the measured use of complementary examinations and the reconsideration of the benefits of a good semiological examination. sometimes forgotten.

The good use of the clinic and the use of a conventional laboratory make it possible to establish the diagnosis in 80% of jaundices. The remaining 20% ​​require other complementary exams whose study algorithm is proposed in fig. 15-1.