Mario Tanno and Hugo Tanno

Cirrhosis is the common final stage of various toxins that attack the liver.

The list of most common diseases includes viral hepatitis that can chronically infect the liver, liver damage from alcohol, certain autoimmune diseases, and genetic or metabolic disorders, which are summarized in Table 1:

Table 1: Causes of cirrhosis

  • Viral infections
    • Chronic hepatitis B (with or without Delta virus coinfection)
    • Chronic hepatitis C
  • Toxic
    • Alcohol
    • Drugs (eg metrotexate)
    • Environmental toxics (ex: arsenic)
  • Autoimmune disorders
    • Autoimmune hepatitis
    • Primary biliary cirrhosis
    • Primary Sclerosing Cholangitis
  • Non Alcoholic Steato-hepatitis (NASH)
  • Hereditary
    • Hemocromatosis
    • Wilson disease
    • Alpha-1 antitrypsin deficiency
    • Hepatic porphyrias
    • Byler's disease
    • Galactosemia
    • Tyrosinemia
    • Glycogenosis
  • Chronic obstruction to extrahepatic bile flow
    • Secondary biliary cirrhosis
  • Hemodynamic Disorders
    • Heart failure
    • Pericarditis Constrictiva
    • Veno-occlusive disease
    • Budd-Chiari syndrome
  • Parasites
    • Schistosomiasis
  • Unknown origin
    • Cryptogenic cirrhosis

Liver cirrhosis is the generic name, which is used to refer to a chronic, diffuse and morphologically irreversible process characterized by the presence of fibrosis and regenerative nodules, the consequence of which is the loss of the vascular architecture of the organ.

Signs and symptoms

From a clinical point of view, it can be classified as compensated and decompensated cirrhosis. The former, like chronic liver disease in the non-cirrhotic stage, is asymptomatic and is only detected incidentally through a routine physical examination (hepatomegaly and / or splenomegaly) or through laboratory or imaging tests (ultrasound). . In this period, the diagnosis of cirrhosis is only possible through the histopathological study carried out through a liver biopsy. Decompensated cirrhosis is detected when the disease begins to manifest itself by alterations that translate into the failure of one or more liver functions or by the presence of portal hypertension evidenced through any of its complications.

The history can collect data suggesting the etiology of liver disease. A correct interrogation must include the antecedent of all past clinical and surgical pathologies, recording in detail pharmacological treatments with start date, dose and form of consumption. The consumption of alcohol should always be included in the dietary habits. The threshold for chronic liver damage is approximately 80 g / day in men (equivalent to 750 ml of wine) and 40 g / day in women (equivalent to 1 L of beer) for a prolonged period of time of at least less 5 years. The history of blood transfusions and their derivatives, can in turn induce the suspicion of a chronic viral infection, as well as sexual promiscuity or the abuse of intravenous drugs. Personal and family history of diabetes, dyslipidaemia, overweight and high blood pressure suggest the presence of non-alcoholic steatohepatitis. A family history of liver disease may point to the hereditary origin of liver disease. Certain pathologies of autoimmune origin are more frequent in the female gender. The age of presentation is another factor to consider, since the development of cirrhosis at an early age leads us to think about metabolic or genetic diseases (Byler's disease, or -1 antitrypsin deficiency, to name a few examples).

On physical examination, some skin signs of chronic liver disease may be seen. Stellar nevi consist of a central arteriolar dilation from which small capillaries emerge in a radiated form, their center is pulsatile and usually disappears at digital pressure. They are found in the territory of the superior vena cava, mainly on the face, torso and arms. Telangiectasias are other finer cutaneous vascular dilations, without central dilatation in the same territory. Both lesions are not specific for cirrhosis.

Palmar erythema is redness of the thenar and hypothenar eminence. There are signs in the nails consisting of nail fragility, “watch glass” nails, stretch marks and whitish opacity. Drumstick fingers are another common but nonspecific finding. The lips and tongue may turn purple (liver tongue). In the mouth, teeth are often missing in cases of prolonged cholestasis, or due to local infections and deficiency and / or nutritional disorders. These lesions are also not specific for cirrhosis of the liver, but may be present in cirrhotic patients.

The skin is usually dry and rough, often with hyperpigmented pellagroid-like macules. In hemochromatosis there is a characteristic diffuse hyperpigmentation. Parotid hypertrophy and palmar retraction of Dupuytren are very common in cirrhotic patients with alcoholic etiology.

Jaundice is not found in the patient with compensated cirrhosis. This appears when some noxa decompensates it (infection); or in the terminal phase of the disease. In this case, its presence is an expression of liver failure and is an index of poor prognosis. In decompensated cirrhosis, it is common to see hemorrhagic lesions such as petechiae, ecchymoses, hematomas, gingivorrhagia, and epistaxis. Also in advanced phases, weight loss, decreased muscle mass and malnutrition are observed.

Fetor hepaticus (liver breath) is a sui genneris odor that is perceived in patients with advanced cirrhosis.

Hepatosplenomegaly is found in most cirrhotic patients. The liver can be palpated enlarged at the beginning of the cirrhotic stage, painless, with an irregular surface, with a smooth and sharp edge. Many times it is palpated only in the epigastrium and it is not possible to do so in the right upper quadrant. This is due to hypertrophy of the left lobe and atrophy of the right. The spleen may also be enlarged, being an indirect sign of portal hypertension.

The finding of endocrine alterations is common. In men, testicular atrophy, sexual impotence, decreased libido, gynecomastia (unilateral or bilateral), and feminoid distribution of pubic hair are common. These disorders are due to an alteration in the metabolism of sex hormones. Gynecomastia is common in patients taking spironolactone, a diuretic used for the treatment of ascites-edematous syndrome due to portal hypertension. In women there are alterations in the menstrual cycle, being irregular at the onset of the disease, and then developing amenorrhea. In advanced stages, abortions are frequent, sterility being a consequence of insufficient estrogen metabolism.

Collateral circulation can be found in the trunk, being an indirect sign of portal hypertension.

Study methodology

There are complementary methods that allow the diagnosis, guidance on possible etiologies and assess the prognosis of each patient in particular.

Laboratory exams

Bilirubin can be elevated in its two fractions. Its rise in cirrhotic patients is due to the presence of cholestasis or liver failure, in the latter case being an index of poor prognosis.

Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) are markers of damage (alteration of the membrane without lysis), or hepatocellular death. In compensated cirrhosis, they may be normal or slightly elevated. Their increase indicates the presence of necroinflammatory activity, but they are not an index of liver function.

Alkaline phosphatase (ALP) is usually normal. Its elevation suggests the existence of cholestasis or the presence of neoplastic transformation. Gamma glutamyltranspeptidase (GGT) is usually elevated in the presence of cholestasis or in alcoholic patients with active intake. It is also elevated in the squatting mass syndrome, being in these cases accompanied by ALF.

The decrease in serum of the rate of prothrombin, cholesterol and albumin translate the deficit in the synthesis functions of the liver cell, constituting an index of poor prognosis. In the hemogram, the presence of anemia can be caused by different causes. Among them is bleeding due to portal hypertension, hemolysis due to hypersplenism or deficiency anemia due to deficiency of vitamin B12 and folic acid. Plateletpenia is related to hypersplenism, and is an indirect sign of portal hypertension. -feto-protein is a marker of neoplastic transformation (hepatocarcinoma), but it may be slightly elevated as an index of cell regeneration.

Viral (HBV and HCV), immunological (anti-nucleus factor, anti-smooth muscle antibodies, anti-mitochondrial antibodies) or metabolic (cerulopasmin, ferritin) markers are used for the etiological diagnosis.

Image methods

Ultrasound is helpful in establishing the size of the liver and spleen, as well as their anatomical irregularities. It evaluates the presence of ascites, as well as the existence of collaterals, being the diameter of the portal and splenic veins, indexes of portal hypertension. It is an excellent method for the early detection of neoplastic transformation (HCC)

Color Doppler ultrasound allows to evaluate the patency of the portal vein, as well as the suprahepatic veins. The portal flow velocity is decreased in the presence of portal hypertension and shows the type of hepatic circulation, differentiating it into hepatopetal (flow to the liver) or hepatophobic (flow from the liver). These methods are useful for assessing the extent of portal hypertension.

The Computed Axial Tomography with intravenous contrast and the Nuclear Magnetic Resonance with gadolinium serve to improve the diagnostic precision of cirrhosis and its complications. MRI is useful to establish the diagnosis of hepatocarcinoma, being the method of choice for angiographic study of the liver.

In all patients with a diagnosis of cirrhosis, the presence and size of esophageal varices should be evaluated, being high video endoscopy the method of choice.

Laparoscopy and percutaneous or transjugular liver biopsy are the most reliable techniques to establish the diagnosis of cirrhosis with certainty.

Portal hypertension

Cirrhosis is the most common cause of portal hypertension in the Western world. Complications related to portal hypertension usually mark the passage from compensated cirrhosis to decompensation of the same.

Portal pressure is evaluated by establishing the difference between the pressure of the inferior vena cava and the portal vein. The normal range of portal pressure is 1-5 mmHg; Values ​​above it define portal hypertension. However, this does not become clinically evident until it exceeds 12 mmHg. Complications such as digestive hemorrhage due to ruptured esophageal-gastric varices, edematous ascitic syndrome and porto-systemic encephalopathy usually appear above this value.


According to Ohm's law, the pressure gradient (ΔP) - in mmHg - between two points of a hemodynamic circuit is directly proportional to the product of the flow (Q) that circulates through it in the unit of time (ml / min .) and the resistance (R) that opposes this flow.

ΔP = Q x R

These concepts are applicable to all hemodynamic circuits and, consequently, to the portal circulation. In the equation P represents the pressure gradient between the portal vein and the suprahepatic veins, Q is the blood flow of the portal vein and R means the vascular resistance that is constituted by the portal vein, intrahepatic portal venules, the sinusoids, the terminal hepatic venules and suprahepatic veins. Therefore, an increase in portal flow, and / or vascular resistance throughout this system, will result in an increase in portal pressure.

Although cirrhosis is the most common cause of portal hypertension, it is not the only one. Other pathologies characterized by increased vascular resistance also cause portal hypertension. Its classification is based on the anatomical site where said resistance is increased, in relation to the hepatic sinusoid:
a) pre-sinusoidal portal hypertension (eg thrombosis of the portal vein)
b) sinusoidal portal hypertension (eg cirrhosis)
c ) post-sinusoidal portal hypertension (eg Budd Chiari syndrome).

In cirrhosis, portal hypertension is the result of increased resistance to portal flow and increased volume of portal venous flow. The initial mechanism is an increase in intrahepatic (sinusoidal) vascular resistance due to sinusoidal fibrosis and compression of the regeneration nodules (structural component) and vasoconstriction of the hepatic sinusoids (functional component). In cirrhosis, the activated stellate cell acquires myofibroblastic properties including collagen synthesis and the ability to contract. Paradoxically, while nitric oxide (NO) decreases within the liver, there is an overproduction of extrahepatic NO that causes splanchnic vasodilation and consequently increases portal blood flow.

In this period, and progressively, the portal circulation will try to escape the growth of intrahepatic resistance with the formation of collaterals (shunts). Those that are most important are esophageal-gastric varices. When portal pressure exceeds 12 mmHg, upper gastrointestinal bleeding can be triggered by ruptured varicose veins of large size.

Splanchnic vasodilation develops due to a drop in resistance and an increase in portal blood flow; however, in the rest of the circulatory system vascular resistance remains normal, and in advanced stages of liver disease it even increases. Cardiac output and heart rate are also increased to maintain homeostasis and ensure blood flow out of the splanchnic bed (brain, kidneys, skin, muscle, etc.). However, when the disease progresses, these compensatory mechanisms are insufficient to maintain blood pressure. The consequences of this phenomenon are summarized in:

Activation of the renin-angiotensin-aldosterone axis.

Increased sympathetic activity of the autonomic nervous system.

Increased circulating levels of antidiuretic hormone (ADH) also known as vasopressin.

These three mechanisms act on the kidney causing the retention of water and sodium, thus trying to maintain systemic arterial pressure and renal plasma flow, resulting in an increase in circulating plasma volume. Unfortunately, the retention of water and sodium will be targeted, for the most part, to the splanchnic bed, due to its vasodilation (see above), with the consequent greater increase in portal blood flow and, therefore, a progressive increase in blood flow. portal pressure causing the leakage of fluids into the peritoneal cavity, causing the formation of ascites and later peripheral edema.

As the disease progresses, kidney function begins to deteriorate, limiting its ability to excrete sodium and mainly free water in urine.

When compensatory hemodynamic mechanisms are insufficient to maintain hemodynamic homeostasis, systemic resistance increases (renal vasoconstriction) and cardiac output decreases, resulting insufficient to maintain renal perfusion. This scenario of deterioration of renal function secondary to portal hypertension is called hepatorenal syndrome. Fortunately, this complication, with a poor prognosis, is not very frequent and usually appears in the later stages of cirrhosis.


Portal hypertension is expressed clinically through indirect signs and their complications. Among the complementary methods, Doppler ultrasound has already been mentioned. The most reliable method to establish portal pressure is portal manometry obtained by suprahepatic catheterization.

Complications of portal hypertension

Variceal digestive hemorrhage

Portal hypertension promotes the opening of vessels (collaterals), which communicate the portal system with the superior and inferior vena cavae. Among the collaterals that develop are esophageal-gastric varices. Upper gastrointestinal bleeding due to ruptured varices represents the most serious complication and is one of the most frequent causes of death in cirrhotic patients.

Hematemesis and / or melena are the most common forms of presentation. When the bleeding is very intense, patients may have enterorrhagia. If bleeding cannot be verified at the time of evaluation, digital rectal examination and placement of a nasogastric tube are of practical use. The evaluation of vital signs, (heart rate, blood pressure and respiratory rate), should be carried out without delay, by providing valuable information on the patient's hemodynamic status. In the emergency laboratory, special attention should be paid to the patient's hematocrit and hemoglobin, evaluating renal function through serum urea and creatinine. Prothrombin time, KPTT, and platelet count are often altered in cirrhotic patients.

The diagnosis of certainty will be made through a high video endoscopy. This procedure not only has diagnostic implications, but also therapeutic implications by allowing sclerosis or ligation of bleeding varices.

Edematous ascites syndrome

The accumulation of fluid within the peritoneal cavity is called ascites. It is the most common complication of cirrhosis and is associated with a distant poor prognosis.

The appearance of ascites is clinically manifested by abdominal distention. If the amount of liquid is small, less than 2-3 l, its presence may go unnoticed. When the volume of ascites is significant, abdominal percussion highlights it, finding dullness on both flanks and in the hypogastrium, which shifts when the patient is lateralized in different decubitus positions (“displaceable dullness”). When ascites is significant and the abdominal wall is tight, palpation of the liver or spleen is very difficult. In these circumstances it is useful to look for the iceberg sign, which consists of abruptly depressing the wall of both hypochondria or epigastrium and perceiving the return shock of the liver or spleen. When fluid is scarce (<2-3 l), ultrasound is the most useful method to diagnose it.

Dyspnea is common due to elevation of the diaphragms or the presence of pleural effusion. Increased abdominal pressure is responsible for the appearance of wall hernias, especially the umbilical hernia. A high percentage of patients with ascites present lower limb edema. In most, the edema is soft and with a positive godet sign. A classification has been proposed to assess the intensity of widespread ascites in clinical practice:
Grade 1: Mild ascites , only detectable by ultrasound.
Grade 2: Moderate ascites, clinically evident by symmetrical distention of the abdomen.
Grade 3: Severe ascites, tense ascites with gross abdominal distention.

Paracentesis is a necessary diagnostic procedure in every patient with ascites. Cirrhotic ascites is a sallow-colored fluid with a protein concentration generally less than 20 g / l, ranging from 20 to 100 cells / mm3. Another useful procedure is to calculate the serum albumin / ascites gradient (GASA). When it is greater than 1.1 g / dl, the diagnosis of portal hypertension is very likely.

Spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis (SBP) is a common and characteristic complication of cirrhotic patients with ascites. The term spontaneous is used to emphasize that there is no primary focus of infection. In half of the cases it manifests itself only by fever and chills. Notably, spontaneous abdominal pain or palpation is usually absent. The diagnosis of certainty is made with the positivity of the cultures of the ascitic fluid. Ascitic fluid culture is usually negative in almost half of the cases, which is why SBP treatment is indicated with the sole presence of a polymorphonuclear count greater than 250 / mm3 in the ascitic fluid examination. In most positive cultures, the most common bacteria are Gram Negative rods.

Hepatorenal syndrome

Hepatorenal syndrome (SHR) is a clinical condition that develops in patients with decompensated cirrhosis, advanced liver failure, and portal hypertension characterized by impaired renal function and the presence of severe abnormalities in intrarenal circulation. In the kidney, the fall in glomerular filtration is secondary to systemic vasoconstriction that also involves other organs. Two forms of clinical presentation are recognized: a) HRS type 1 is characterized by the severe and rapidly progressive installation of renal failure, which has been defined as a more than double increase in blood creatinine and this figure exceeding 2.5 mg / dl in a period no longer than 2 weeks. The main clinical manifestations are oligoanuria and arterial hypotension. This type of presentation has a high mortality despite current treatment. b) HRS type 2 is characterized, on the other hand, by the moderate and slowly progressive onset of renal failure with serum creatinine less than 2.5 mg / dl. The most important clinical manifestation is refractory ascites (lack of response to treatment with diuretics). Table 2 summarizes the diagnostic criteria for HRS.

Table 2 .

  1. Cirrhotic patients with ascites;
  2. Serum creatinine> 133 mmol / L (1.5 mg / dl);
  3. Lack of response evidenced in serum creatinine (decrease to 133 mmmol / L or less) after at least 48 hours of suspension of diuretics and expansion with albumin. The recommended dose of albumin is 1 g / Kg body weight / day up to a maximum of 100 g / day
  4. No shock
  5. No recent or concomitant administration of nephrotoxic drugs
  6. Absence of organic kidney disease {evidenced by proteinuria> 500 mg / day, microhematuria (> 50 erythrocytes per high-resolution field), and / or abnormal renal ultrasonography}

Hepatopulmonary syndrome

Hepatopulmonary syndrome is defined by the increase (corrected for age) in the alveolar / arterial oxygen gradient with or without hypoxemia that occurs as a result of intrapulmonary vasodilation in the presence of liver disease and portal hypertension. In clinical practice, this entity is underdiagnosed and is usually found in the context of one of the evaluation for liver transplantation. Most patients are asymptomatic, symptomatic patients complain of insidious onset dyspnea. Platypnea (dyspnea that occurs in a standing position) is a typical symptom of hepatopulmonary syndrome. Patients frequently present with drumstick fingers and telangiectasias. In extreme cases, patients present cyanosis. The chest x-ray is usually normal.

Porto-systemic encephalopathy

Porto-systemic encephalopathy (EPS) or hepatic encephalopathy, represents the reversible neurological dysfunction caused by acute or chronic liver disease. In the setting of cirrhosis, the onset is often insidious, characterized by subtle and sometimes intermittent changes in memory, personality, concentration, and reaction times. The changes that occur during the early stage are subclinical, but latent encephalopathy can be important (decreased ability to drive). With the progression of EPS, neurological abnormalities become more evident and are usually graded on a numerical scale widely used in clinical practice that reflects increasing degrees of neurological dysfunction (Table 3).

Table 3: Clinical stages of hepatic encephalopathy

Clinical stage Intellectual function Neuromuscular function
Subclinical  Normal examination, but work or driving may be disturbed Subtle changes in psychometric tests or in number connection
Grade 1 Altered attention, irritability, depression, or personality change Trembling or apraxia by incoordination
Grade 2 Drowsiness, behavior changes, poor memory and difficulty with calculations, difficulty sleeping Asterixis (o flapping) bradilalia, ataxia
3rd grade  Confusion stupor, drowsiness, amnesia Hypoactive reflexes, nystagmus, clonus, muscle stiffness
Grade 4 Stupor and coma

Dilated pupils and decerebrate posture; oculocephalic reflex; lack of response to stimuli

Neurological abnormalities in grade 1 reflect the compromise of higher cortical functions with shortened attention span, personality changes, irritability, etc. The alteration of the circadian cycle with drowsiness during the day and insomnia at night is notable in this period. Grade 2 encephalopathy is characterized by a marked intensification of these cortical manifestations, with more drowsiness and lethargy, and by the appearance of movement disorders that reflect a compromise of the descending reticular system or other neurological structures. This includes tremors, incoordination, and asterixis (flapping). Progression to grade 3 encephalopathy is defined by the presence of increasing clouding in a still excitable patient. In grade 4, the patient is in a coma with severe bilateral cortical dysfunction. Although encephalopathy is reversible, it is an indication of advanced liver disease, being a sign of poor long-term prognosis.

Precipitating factors can be identified in acute-onset florid encephalopathy and always need to be investigated. The most common are impaired kidney function, gastrointestinal bleeding, the use of sedatives (benzodiazepines), hypokalemic alkalosis, excess of certain proteins in the diet, infections and constipation.

Despite the frequency and characteristic clinical aspects of EPS, the pathophysiological mechanisms have not been fully elucidated. In the context of a porto-systemic shunt in which blood is diverted away from the liver to the inferior vena cava, a clear lack of hepatic clearance of nitrogenous elements has been observed that can reach the central nervous system (CNS) and trigger EPS. Ammonia is one of the toxins that produces EPS as it is not purified, however, the mechanisms by which it produces neurological alterations are not fully defined.